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Proposed student degree projects

The Unit accepts and supervises students performing their degree projects (examensarbeten) within the BSc(Pharm)/receptarie and MSc(Pharm)/apotekare programmes as well as both domestic and foreign (eg. Erasmus) students from other universities.

The duration of projects are 10 or 20 weeks (15 or 30 ECTS) within the BSc(Pharm) programme and or 20 weeks (30 ECTS) within the MSc(Pharm) programme. The shorter projects within the BSc(Pharm) programme may be in the form of a literature review.

Below is a list of possible topics for projects in PKPD and bioanalytical chemistry, respectively. The list is not comprehensive but can serve to illustrate the types of topics which can be addressed. Some topics may not be available at a given time. Additional topics can become available.

For current students at the University of Gothenburg, a slightly extended list of projects can be accessed at ”Kursportalen” or ”GUL”.

List of degree projects 2019

List of degree projects 2019

Examples of experimental projects

1. Is artemisinin a mechanism-based inhibitor of CYP2B6? (15/30 ECTS)
Background: The antimalarial drug artemisinin can inhibit CYP2B6 which also happens to be the most important enzyme for its elimination. The duration of this inhibition will depend on whether if it is competitive or mechanism-based, in which case the enzyme is inactivated by reactive artemisinin metabolites.
Methods: Automated fluorescence detector for 96-well plates, recombinant CYP2B6 microsomes.

2. Using pharmacodynamic data to determine the degree of drug plasma protein binding. (30 ECTS)
Background: A number of antimalarial drugs are hydrophobic making it difficult to determine their plasma protein binding by conventional methods.
Methods: P.falciparum cultured in vitro. Drug growth inhibition IC50 values determined under varying protein concentrations. Development and testing of theoretical method to extrapolate results to estimate clinical drug plasma protein binding. In vitro experiments to be performed at Karolinska Institute, Stockholm, remaining work at UGOT or KI.

3. Degradation of artemisinins by heme/haemoglobin (15/30 ECTS)
Background: Red blood cells contain haemoglobin. Since artemisinins have an endoperoxide bridge (-oxygen-oxygen-) they exhibit an affinity to heme groups. As a result of this interaction, artemisinins are degraded. Some of the degradation products are toxic to malaria parasites. The degradation may also result in a clearance of the drug in blood. Although this interaction is of fundamental importance for this class of drugs, more needs to be understood of its characteristics. In this project the degradation of artemisinin and drihydroartemisinin in blood cells and hemoglobin solution will be investigated.
Methods: In vitro incubations of heme-containing solutions with artemisinin endoperoxides under different atmospheric conditions (oxygen or no oxygen).
HPLC analysis and data analysis of degradation kinetics.

4. Is artemisinin metabolised by non-CYP pathways? (15/30 ECTS)
Background: In humans, artemisinin appears to be metabolised by CYPs 2B6, 2A6 and 3A4. However, artemisinin could also be degraded by non-CYP pathways. This has not been exhaustively tested.
Methods: Degradation of artemisinin in vitro (rat liver microsomes and/or liver homogenate) in the presence/absence of NADPH, CO (or CO2). Measurement of artemisinin by HPLC.

5. Quantifying the relationship between adherence to HIV/malaria therapy and clinical response based on pharmacokinetic/pharmacodynamic modelling and simulation (30 ECTS)
Background: Neglecting to take medication as prescribed is associated with variability in drug exposure and may lead to treatment failure. Mechanistic drug-disease models, describing the time course of pharmacological response in relation to drug exposure, may be used for in silico prediction of treatment outcome. Model simulation represents a powerful tool in the exploration of dosage strategies and can be applied to optimize pharmacotherapy as well as facilitating drug policy decision-making. This project aims to investigate the impact of adherence on anti-infective treatment.
Methods: Drug-disease models are developed to relate dose intake to effect measurements from clinical drug studies or routinely monitored patients. Models, supported with literature and in vitro data, will eventually be used for clinical trial simulation, using state-of-the-art software such as WinNonlin, NONMEM and S-Plus.

6. Simulation of eflornithine PK in plasma and CSF during a 10-day treatment regimen using a physiological based PK model. (30 ECTS)
Background: Eflornithine is a polar compound intended for oral treatment of late-stage human African trypanosomisasis (HAT or sleeping sickness). It is important that a therapeutic dose regimen results in eflornithine concentrations high enough for a period of time long enough to kill the parasites lodging in the central nervous system. There is a risk that the proposed treatment will be inefficient due to the low CNS exposure. Concentrations in CSF are only 10% compared with plasma levels, which may be due to high polarity or due to efflux transporters in the BBB or CSF flux. This project will aim to use a physiologically based pharmacokinetic (+ PD maybe) model to simulate eflornithine concentrations in plasma and CSF after varying dosage regimens. Model development will be based on PK data in patients (plasma and CSF).
Methods: Model building and simulation in appropriate PC software (eg ACSL Xstreme). Graphical interpretation of simulation results. Simulation of how different dosage regimens may influence drug CNS levels. If of interest, the modeling can be complemented with a study with IV infusion of eflornithine to the laboratory rat.

7. Are artemisinin endoperoxides inhibitors of uridine diphosphate glucuronosyltransferase (UGT)? (30 ECTS)
Background: A clinical study + some preliminary in vitro work suggests that artemisinin type endoperoxides may inhibit the activity of UGTs. Since many drugs, including some antiretrovirals, depend on glucuronidation for their elimination, such an interaction may cause untoward effects.
Methods: In vitro incubations with rat and human liver microsomes, to study the potential of endoperoxide drugs to impair glucuronidation activity. HPLC and data analysis.

8. Is glucuronidation induced by artemisinins? (30 ECTS)
Background: There is some evidence that artemisinin can increase the elimination of 7-OH-coumarin, the major human metabolite of coumarin. Since 7-OH-coumarin is eliminated almost exclusively by glucuronidation, this could indicate that artemisinin can induce uridine diphosphate glucuronosyltransferase (UGT).
Methods: Preparation of hepatocytes from control and artemisinin-treated rats. Incubation with known UGT substrates and their depletion kinetics measured.

9. Model building and simulation of PKPD in antimalarial treatment (30 ECTS)
Background: Many studies which would normally be performed during drug development are not carried out for drugs against malaria and tropical diseases. This is especially true when it comes to dose optimization of new combination treatments. PKPD modeling can assist in both understanding the characteristics of the underlying relationships but also be extended for use in simulations of eg. the influence of varying dosage regimens on efficacy. Further, such models can form the base for clinical trial simulation whereby study design and outcomes can be explored in silico and be used for design optimization.
Methods: Model building and simulation. ACSLxtreme software or similar.

10. In silico simulation of drug-drug interactions (DDI) (30 ECTS)
Background: DDIs are one important source of pharmacokinetic variability. DDIs may lead to inadequate treatment due to too low or too high drug concentrations in the body. How enzyme induction or inhibition can change the pharmacokinetics of drugs can be computer simulated. In the coming years there will be an increased number of individuals becoming simultaneously exposed to both antiretroviral and antimalarial drugs. In this project the risk for DDIs between drugs in the two will be investigated.
Methods: Modelling and simulation in SimCyp, a trial simulation software developed for investigation of DDIs. Post-simulation processing in Excel (graphics etc.).


11. Can artemisinin induce drug metabolism by direct activation? (30 ECTS)
Background: Induction of drug metabolism is usually due to increased transcription, which in turn is commonly due to xenobiotic activation of (nuclear) receptors. This leads to increased amounts of the enzyme. It is recently been shown that artemisinin is an activator of the PXR (and CAR) receptor However, due to the unique endoperoxide bridge which can interact with Cytochrome heme, it could also be possible that artemisinin has a direct effect on the enzyme itself which may led to inhibition or induction. This would constitute a novel and unique mechanism of enzyme induction.
Methods: Rat liver microsomes are preincubated with artemisinin or vehicle for different durations of time after which different probe compounds (for CYPs and UGTs) are added and their depletion kinetics followed by HPLC.

Literature review projects (15/30 ECTS)

May be written in either the Swedish or English language.

1. Comparison of in silico prediction models for the estimation of drug plasma protein binding
2. Development and maturation of drug metabolising enzymes in neonates
3. Breastfeeding during drug treatment
4. Pharmacokinetic changes in burn patients
5. Disease models in drug development
6. Kinetics of antimalarials during pregnancy
7. Large-molecule pharmacokinetics
8. Cytokine effects on drug metabolism
9. OTC paracetamol and liver toxicity

Experimental projects in bioanalytical chemistry (30 ECTS)

a) Development and validation of a method for the simultaneous determination of HIV and antitubercular drugs in blood plasma.
Dose recommendations of HIV drugs are based on clinical trials performed in the Northern hemisphere. Such dose recommendations may not be optimal when these drugs are used in Africa or Asia, due to ethnic differences in drug metabolising capacity and/or the presence of other infections such as malaria or tuberculosis. In developing countries especially, co-infection with HIV and TB is common. By pharmacokinetic and pharmacogenetic analysis and modelling we are seeking to characterise and evaluate current and alternative dose regimens. Analytes of interest are antiretrovirals efavirenz, nevirapine, stavudine, lamivudine, and zidovudine and antitubercular drugs ethambutol, rifampicin, isoniazid and pyrazinamide. In addition, co-determination of drug metabolites where relevant.

b) Development and validation of a method for the determination of the antimalarial piperaquine and its major metabolites in blood plasma.

Piperaquine is an antimalarial undergoing clinical development for treatment of uncomplicated malaria when combined with dihydroartemisinin. It has a long biological half-life in the human body of about one month. This could be an underestimation due to lack of sufficiently sensitive assays. We have previously reported some pharmacokinetic and metabolic investigations on this compound. We are now in need of a more sensitive method for piperaquine which can co-determine the principal metabolites simultaneously. Being highly lipophilic, these compounds present with potential problems with respect to glass/plastic/metal adsorption.

c) Development and validation of a method for the determination of the endoperoxide class of antimalarial drugs in biological matrices.

Artemisinin and its derivatives (artesunate, dihydroartemisinin, artemether) are the most important new class of antimalarials in half a century and are today recommended as first-line treatment of malaria when combined with another, longer-acting, antimalarial drug. Lacking a chromophore, earlier methods of detection have used either post-column on-line derivatisation or electrochemical detection in the reductive mode. Within a EU-project aiming to study the potential risks of using this class of compounds during pregnancy, we are seeking to develop a sensitive LC-MS assay for these compounds to be used for tissue distribution studies in the laboratory rat.

d) Quantification of the plasma protein binding degree of highly bound drugs by chromatographic methods, eg frontal analysis.
Many drugs used in tropical medicine have high (eg atovaquone) or unknown (eg piperaquine) degrees of reversible binding to plasma proteins. The degree of binding can differ between individuals depending on quantitative or qualitative pathophysiological changes in the binding protein or concomitant drug use. Such differences will result in pharmacokinetic variability in patient population studies. One way to explain and understand such variability is to determine the degree of plasma protein binding in patient studies. For highly bound drug the standard procedures (filtration or dialysis) are less suitable. This project will explore whether chromatographic methods, eg by frontal analysis, can be an alternative approach.

e) Development of a LC-MS assay for the simultaneous determination of probe drugs and their metabolites used for the in vitro characterisation of Cytochrome P450 activity.
(pending)

AVAILABLE INSTRUMENTATION

LC-MS
2 Sciex API-365 triple quadropole LC-MS/MS systems (with 4 Perkin-Elmer pumps and 3 autoinjectors, Analyst software)

Several RP systems including
8 Shimadzu LC10 pumps
3 Bischoff LC pumps
6 Shimadzu UV 10A detectors
1 Bischoff UV detectors
2 Jaco UV detectors
2 Jaco fluorescence detectors
1 Spark Endurance autoinjector
2 Spark Midas autoinjectors
1 Spark Prospect 2 SPE robot/injector
Clarity data acquisition

Contact Information

Michael Ashton

Box 431 , 405 30 Göteborg

Visiting Address:
Medicinaregatan 13A

Phone:
+46 (0)31 786 34 12

Fax:
+46 (0)31 786 32 84

Page Manager: Webbredaktör|Last update: 10/31/2018
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