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Study of the effect of mesenchymal stem cells in combination with immunosuppressive therapy on inflammatory response in in vivo model
Jabůrek, Filip ; Krulová, Magdaléna (advisor) ; Brdička, Tomáš (referee)
Immunosuppressive drugs have been used for many years for the treatment of autoimmune diseases and post-transplantation treatment. While these drugs have a lot of advantages, they also show several undesirable side effects. The most common side effects are higher blood pressure, lowered renal function and susceptibility to infections. Therefore, in recent years there has been a demand for other medical approaches that do not exhibit the above-mentioned adverse effects. Among one of the newly tested approaches is the application of mesenchymal stem cells (MSCs), which possess several advantages such as immunomodulatory abilities, safety and relatively easy isolation, however, stem cell use alone has not yet provided sufficiently strong immunomodulation. Only a small part of research of MSCs is focused on their use in the combination with immunosuppressive therapy. Therefore, in my thesis I focused on the model which allows to reduce the dose of immunosuppressive drugs in the combination with MSCs. Combined therapy is more advantageous than both monotherapies thanks to lower dosages of these drugs used. It enables to decrease negative side effects of immunosuppressive drugs, when combined with MSCs to provide sufficient immunomodulation in comparison to classical therapy. The aim of my work was to...
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Determination of related compounds in final dosage forms based on cyclosporine by HPLC with chemiluminescent detection specific for nitrogen.
Mrůzek, Zbyněk ; Klimeš, Jiří (advisor) ; Kastner, Petr (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Pharmaceutical Chemistry and Drug Control Candidate: Zbyněk Mrůzek Supervisor: prof. RNDr. Jiří Klimeš. CSc Consultant thesis: Ing. Pavel Blatný. Ph.D. Title of thesis: Determination of related substances in the dosage forms based on cyclosporine by HPLC with nitrogen specific chemiluminescence detection. Development of an HPLC method with chemiluminescent detection specific for nitrogen for related substances determination in cyclosporine final dosage forms is described in this work. The method is capable to determine cyclosporine impurities originated from cyclosporine substance and relevant degradation products except isocyclosporines. The method utilizes the stationary phase Zorbax SB-C18, particle size 1.8 µm, 150x2.1 mm and gradient elution at flow rate 0.15 ml.min-1 at column temperature 100řC. Mobile phases are Acetone: TBME: water: TFA (30: 5.5: 64.5: 0.01) and Acetone: TBME: water: TFA (49: 5.5: 45.5: 0.01). The work includes the verification of method validability in terms of specificity, linearity, limit of quantittion, accuracy, precision and robustness. The method can be used for determination of cyclosporine impurities in final dosage forms in pharmacetical QC laboratories. Keywords: cyclosporine....
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Structure and physiological role of the mitochondrial permeability transition pore
Eliáš, Jan ; Mráček, Tomáš (advisor) ; Kalous, Martin (referee)
Mitochondrial permeability transition pore (mPTP) is Ca2+ dependent channel localised in the inner mitochondrial membrane. One of its defining characteristics is inhibition by nanomolar concentrations of immunosuppressant cyclosporine A (CsA). Together with additional interacting proteins, which regulate its opening, mPTP forms a permeability transition protein complex. Persistent opening of mPTP is accompanied by mitochondrial swelling and a subsequent collapse of organelle, which precedes release of proapoptotic proteins and programmed cell death. Channel forming unit of mPTP remains unknown, despite intense and long-lasting study. Numerous proteins were proposed to play a role of channel forming subunit of mPTP, including complex of ANT and VDAC, ANT alone, PiC or even ATP synthase. Despite the fact, that molecular structure remains elusive, mPTP seems to play a role in a range of pathophysiological processes or diseases associated with them. Among others this includes ischemia/reperfusion injury, neurological and muscle dystrophies, or tumorigenesis. Keywords: mitochondria, mitochondrial permeability transition pore, cyclosporine A, programmed cell death, ATP synthase, oxidative phosphorylation apparatus.
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Study of the effect of mesenchymal stem cells in combination with immunosuppressive therapy on inflammatory response in in vivo model
Jabůrek, Filip ; Krulová, Magdaléna (advisor) ; Brdička, Tomáš (referee)
Immunosuppressive drugs have been used for many years for the treatment of autoimmune diseases and post-transplantation treatment. While these drugs have a lot of advantages, they also show several undesirable side effects. The most common side effects are higher blood pressure, lowered renal function and susceptibility to infections. Therefore, in recent years there has been a demand for other medical approaches that do not exhibit the above-mentioned adverse effects. Among one of the newly tested approaches is the application of mesenchymal stem cells (MSCs), which possess several advantages such as immunomodulatory abilities, safety and relatively easy isolation, however, stem cell use alone has not yet provided sufficiently strong immunomodulation. Only a small part of research of MSCs is focused on their use in the combination with immunosuppressive therapy. Therefore, in my thesis I focused on the model which allows to reduce the dose of immunosuppressive drugs in the combination with MSCs. Combined therapy is more advantageous than both monotherapies thanks to lower dosages of these drugs used. It enables to decrease negative side effects of immunosuppressive drugs, when combined with MSCs to provide sufficient immunomodulation in comparison to classical therapy. The aim of my work was to...
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Study of effect of immunosuppressive drugs on interaction of mesenchymal stem cells with immune cells
Heřmánková, Barbora ; Krulová, Magdaléna (advisor) ; Indrová, Marie (referee)
Mesenchymal stem cells (MSC) represent a heterogenous population of nonhematopoietic stem cells with multipotent differential potential. MSC can be isolated from various tissues of organism, the most common tissue are bone marrow or adipose tissue. MSC are good candidates for treatment of autoimmune diseases and possess the ability to prevent graft rejection or graft versus host disease. The immunosuppressive drugs are currently used for inhibition of unwanted immune reaction but they exhibit serious side effects. The use of MSC in therapy can reduce doses of immunosuppressive drugs and eliminate side effects. The study of MSC and immunosuppressant interactions should be detected before MSC can be used for clinical application. We aimed to analyze the interaction between MSC and immunosuppressive drugs and their effect on immune cells. Cyclosporine A and mycophenolate mofetil were used in our research. We demonstrated changes in the expression of surface molecules, production of interleukin 6 and in metabolic activity of MSC after treatment with immunosuppressive drugs. MSC are in organism, in cooperation with the number of other cells. Therefore we studied MSC cocultured with splenocytes in the presence of immunosuppressive drugs. Our results show the effect of MSC and immunosuppressive drugs on different...
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Determination of related compounds in final dosage forms based on cyclosporine by HPLC with chemiluminescent detection specific for nitrogen.
Mrůzek, Zbyněk ; Klimeš, Jiří (advisor) ; Kastner, Petr (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Pharmaceutical Chemistry and Drug Control Candidate: Zbyněk Mrůzek Supervisor: prof. RNDr. Jiří Klimeš. CSc Consultant thesis: Ing. Pavel Blatný. Ph.D. Title of thesis: Determination of related substances in the dosage forms based on cyclosporine by HPLC with nitrogen specific chemiluminescence detection. Development of an HPLC method with chemiluminescent detection specific for nitrogen for related substances determination in cyclosporine final dosage forms is described in this work. The method is capable to determine cyclosporine impurities originated from cyclosporine substance and relevant degradation products except isocyclosporines. The method utilizes the stationary phase Zorbax SB-C18, particle size 1.8 µm, 150x2.1 mm and gradient elution at flow rate 0.15 ml.min-1 at column temperature 100řC. Mobile phases are Acetone: TBME: water: TFA (30: 5.5: 64.5: 0.01) and Acetone: TBME: water: TFA (49: 5.5: 45.5: 0.01). The work includes the verification of method validability in terms of specificity, linearity, limit of quantittion, accuracy, precision and robustness. The method can be used for determination of cyclosporine impurities in final dosage forms in pharmacetical QC laboratories. Keywords: cyclosporine....
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