Dissertation Fu Berlin Chemie Medication

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HaupttitelPharmacometric modelling of processes in the haematopoietic system and blood
TitelzusatzLeukocyte progenitor proliferation and maturation in vitro and in cancer patients and erythrocyte ageing in diabetic patients
TitelvariantePharmakometrische Modellierung von Prozessen des hämatopoietischen Systems und im Blut
Zusatz zur TitelvarianteProliferation und Reifung von Leukozytenvorläuferzellen in vitro und in Krebspatienten und Alterung von Erythrocyten in Diabetes Patienten
AutorNock, Valerie
Geburtsort: Biberach an der Riß
GutachterFrau Prof. Dr. Charlotte Kloft
weitere GutachterHerr. Prof. Dr. Christoph Ritter
Freie Schlagwörterpharmacometrics; high-dose chemotherapy; autologous stem cell rescue; diabetes mellitus type 2; myelotoxicity
DDC540 Chemie
ZusammenfassungThe objective of this thesis was to contribute to the understanding and characterisation of proliferation, maturation and ageing processes of haematopoietic progenitor and blood cells applying the population pharmacokinetic/pharmacodynamic (PK/PD) approach. Impairment and damage of proliferation and maturation of leukocyte progenitor cells in the bone marrow was investigated based on data from a clinical investigation in patients receiving a combination high-dose chemotherapy (HDCT) regimen comprising an autologuous stem cell rescue (ASCR).
In Project 1, population PK models for carboplatin, etoposide and thiotepa were developed and individual PK parameter estimates for each drug were utilised to serve as input into a previously published semi-mechanistic population PK/PD model for myelosuppression[138].
This model was adjusted and further extended to account for the special setting of
HDCT (Project 2). The implementation of the drugs’ effects and possible drug-drug interactions were explored and the ASCR was integrated into the model. Additionally, concomitant medication influencing the time course of leukopenia was taken into account to describe all observed phases, i.e. an initial increase in leukocyte concentrations most probably attributed to the administration of dexamethasone, followed by a steep decrease caused by the high doses of the cytotoxic drugs and a fast recovery with a pronounced rebound due to ASCR and additional administration of granulocyte colony-stimulating factor.
Based on the final PK/PD model, simulations were conducted (Project 3) to investigate the
optimal day for the performance of the ASCR with respect to nadir and time below (at least) grade 3 leukopenia, as both are associated with the development of serious infections. The simulations showed that not only the day on which the ASCR was performed but also the amount of retransfused CD34+ cells influenced both parameters. Recommendations for planning of the myelosupportive treatment were derived.
The drug effect was further explored in Project 4, in which different PD models for the description of data from an in vitro cytotoxicity assay were investigated. Furthermore, a model for myelosuppression which enabled the estimation of EC50 values from clinical data that were comparable to those obtained from in vitro assays was proposed. This model might prove useful when, in return, in vitro data is used to predict myelosuppression in patients.
In Project 5, an existing lifespan model186 for the description of glycated haemoglobin (HbA1c), a long-term biomarker in diabetes mellitus type 2 patients, which incorporates the ageing process of erythrocytes, was extended to describe the influence of a new drug on fasting and postprandial plasma glucose.
All developed semi-mechanistic models contributed to the deeper understanding of (patho-) physiological processes involved in cell proliferation and maturation as well as the characterisation of the systems of leukopoiesis, erythrocyte ageing and HbA1c formation. In future, the models can be used to scientifically interpret clinical results, guide the planning of clinical studies and improve existing and future therapy regimens in the indications of oncology and diabetes mellitus type 2.
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SeitenzahlXIV, 241 S.
Fachbereich/EinrichtungFB Biologie, Chemie, Pharmazie
Erscheinungsjahr2013
Dokumententyp/-SammlungenDissertation
Medientyp/FormatText
SpracheEnglisch
Rechte Nutzungsbedingungen
Tag der Disputation08.05.2013
Erstellt am24.05.2013 - 06:11:40
Letzte Änderung12.06.2013 - 11:29:21
 
Statische URLhttp://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000094322
URNurn:nbn:de:kobv:188-fudissthesis000000094322-8
Zugriffsstatistik
 

Dissertationen online der Freien Universität Berlin









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HaupttitelA validated animal model for the Serotonin Syndrome
TitelvarianteEin validiertes Tiermodell für das Serotoninsyndrom
AutorHaberzettl, Robert
Geburtsort: Berlin
GutachterProf. Dr. med. Heidrun Fink
weitere GutachterProf. Constance Scharff, PhD
Freie Schlagwörter5-HT enhancing drugs; animal model; mouse, rat; Serotonin; Serotonin syndrome; validity
DDC618 Experimentelle Medizin
ZusammenfassungThe serotonin syndrome (SS) is a potentially life-threatening disorder in humans which is typically induced by ingestion of an overdose or by combination of two or more serotonin (5-HT)-enhancing drugs. In mice, acute administration of direct and indirect 5-HT agonists also leads to behavioral and autonomic effects, but in literature the murine SS is not clearly defined as different responses are thought to be essential.
The first aim of this dissertation is thus the identification of core responses of the SS, which can serve as target parameters in a murine model of the SS. It is the second aim to evaluate the specificity of the responses of murine SS and to determine the validity of these responses. The third aim is to define the impact of the 5-HT1A and the 5-HT2A receptor for the different SS responses.
First an overview is provided in a review of the existing versions of the animal model of the SS. With a focus on studies in rats and mice, data was extracted on the behavioral and autonomic responses following administration of serotonergic drugs administered alone or in combination. Based on the analyses of the data, a distinct set of responses was identified that are consistently observed following administration of serotonergic drugs.
In order to determine in NMRI mice common SS responses induced by 5-HT-enhancing drugs independent of the mechanisms of action, the effects of the three serotonergic drugs with differing mechanism of action were studied. The following five responses consistently and dose-dependently occurred: flat body posture, hindlimb abduction, piloerection, tremor, and decreased rearings. Additionally, combinations of drugs lead to a drug potentiation effect. The specificity of these five responses was evaluated by comparing the effects of the three serotonergic drugs with drugs targeting other transmission systems.
Finally, the effect of agonists at the 5-HT1A and the 5-HT2A receptor on the murine SS was examined in NMRI mice. On the basis of the findings, the major relevance of the 5-HT1A receptor was confirmed. Additionally, it was revealed that the 5-HT2A receptor has more impact on the SS than previously suggested.
My findings demonstrate that the SS in NMRI mice is a suitable animal model for the SS in humans. It is a valuable tool to study serotonin-induced hyperactivity for both basic and preclinical research in order to identify drugs or drug combinations with potential risk to induce a serotonin syndrome in man. Further improvement is achieved by standardizing assessments of SS responses in rodents, which will increase the utility of animal models of the SS in translational studies. This research will be of importance in creating new effective therapeutic compounds, possibly with fewer side effects.
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SeitenzahlVI, 102 S.
Fachbereich/EinrichtungFB Biologie, Chemie, Pharmazie
Erscheinungsjahr2015
Dokumententyp/-SammlungenDissertation
Medientyp/FormatText
SpracheEnglisch
Rechte Nutzungsbedingungen
Anmerkungen des AutorsAus Copyrightgründen sind die Zeitschriftenartikel hier nicht online veröffentlicht.
Tag der Disputation24.06.2015
Erstellt am02.10.2015 - 09:30:34
Letzte Änderung05.10.2015 - 13:22:54
 
Statische URLhttp://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000100088
URNurn:nbn:de:kobv:188-fudissthesis000000100088-3
Zugriffsstatistik
 

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