Browsing by Subject "in vitro"
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(2020)Statins are a commonly used group of drugs that reduce the cholesterol levels in blood and have been shown to reduce cardiovascular morbidity and mortality. However, a considerable percentage of patients experience adverse effects during statin treatment. Statin adverse effects have been associated with genetic polymorphisms and drug-drug interactions that affect the elimination and active transport of these drugs. A more comprehensive knowledge of statin metabolism may be a step towards better management of statin treatments. Statin metabolism both in vivo and in vitro has been subject of study for years. In vitro incubation conditions may considerably affect the observed clearance, and results obtained with different methods or in different laboratories may not be directly comparable to each other. No single in vitro study on a wide panel of statins has previously been conducted. Six statins and some of their metabolites, fourteen compounds in total, were included in the study. The intrinsic clearance (CLint) of these molecules was investigated in vitro on human liver microsomes (HLM) and a panel of eleven cytochrome P450 (CYP) enzymes recombinantly expressed in E. coli. Observed CLint values for each compound in HLM and for each compound-CYP pair with observed depletion were calculated. The percentual contributions of each CYP enzyme to the metabolism of the compounds was calculated. The results obtained with recombinant CYP enzymes (rcCYP) were complemented with studies on HLM with specific chemical inhibitors of CYP enzymes. In this study the metabolism of statin lactones seemed to be faster than the metabolism of the corresponding statin acids. Atorvastatin lactone, 2-hydroxy atorvastatin lactone, 4-hydroxy atorvastatin lactone and simvastatin were extensively metabolized. Atorvastatin, 2-hydroxy atorvastatin, 3R,5S-fluvastatin, 3S,5R-fluvastatin, pitavastatin lactone and simvastatin acid showed intermediate metabolism. 4-hydroxy atorvastatin, pitavastatin, pravastatin and rosuvastatin rates of metabolism were below quantification limit. CYP3A4 had a major role in the metabolism of atorvastatin and its metabolites, simvastatin and simvastatin acid. CYP3A4 also had activity towards pitavastatin lactone. CYP2C9 had a high activity towards both 3R,5S-fluvastatin and 3S,5R-fluvastatin. CYP2D6 may play a part in the metabolism of pitavastatin lactone. CYP2C8 may have some activity towards simvastatin and simvastatin acid. The data is mostly in agreement with previous in vitro and in vivo studies regarding both the metabolism rate of statins and the contributions by different CYP enzymes to the metabolism of statins. Due to the screening nature of the study and some methodological constraints, these data should be considered as preliminary and require confirmation in further studies.
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(2010)Parkinson's disease is a chronic progressive neurodegenerative disorder, characterized by muscle rigidity, hypokinesia, tremors and bradykinesia. The cause of symptoms in Parkinson's disease is loss of dopaminergic nerve cells in the substantia nigra, which attenuates the nigrostriatal dopaminergic signaltransmission. Oxidative stress, mitochondrial dysfunction, protein misfolding and aggregation, inflammation, excitotoxicity, apoptosis and other routes for cell death, and loss of neurotrophic factors have shown to be mechanisms in the pathogenesis of Parkinson's disease. Microglia might have a double role in the pathogenesis of Parkinson's disease. Microglia stimulated by Į- synuclein does not only produce toxic factors such as certain cytokines and reactive oxygen and nitrogen species, which contribute to the neuronal cell death but also produce anti-inflammatory cytokines and neurotrophic factors, which can be neuroprotective. Deeper knowledge of the mechanisms underlying Parkinson's disease is needed for developing restorative medicines. Three different neurotrophic factor families are known to be important in the research of Parkinson's disease. The GDNF-family consists of glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN). The neurotrophin-family consists of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophins NT3 and NT4/5. The most recently discovered family is the MANF-family, which consists of mesencephalic astrocyte-derived neurotrophic factor (MANF) and conserved dopamine neurotrophic factor (CDNF). In Parkinson's disease the neurotrophic factors could stop, slow or ideally even reverse the neurodegeneration in the dopaminergic system and decrease the functional decline of the neurons. Research has already shown that GDNF has both a neurorestorative and neuroprotective effect in animal models of Parkinson's disease. Clinical trials have however shown controversial results. The challenge with neurotrophic factors can be the administration to the brain through the blood-brain-barrier, sideeffects because of receptor binding in other organs or sites of the body and low diffusionrate. Research of both MANF and CDNF has shown promising neurorestorative and -protective results in vivo. Local diffusion of MANF has been shown to be better than of GDNF. In this Master's thesis research was done on whether MANF and CDNF have a neurorestorative effect on the dopaminergic nerve cells in mixed primary culture in vitro after 6-OHDA exposure. The aim of the study was to receive information about whether MANF and CDNF are as effective as GDNF at repairing celldamages caused by 6-OHDA in vitro in this experimental model. GDNF was used as a posivite control in this study. The results from this study suggest that MANF might have a neurorestorative effect, but this effect is much smaller than with the neurotrophic factor GDNF. The results show no neurorestorative effect with CDNF. Neither the dopamine uptake nor the tyrosine hydroxylase staining showed statistical significance.
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