Thesis (doctoral)--Universität Hamburg, 1979.

No description available.

Thesis (Ph.D.)--University of Adelaide, Dept. of Obstetrics and Gynaecology, 1999. / Errata is tipped in between leaf 9 & 10. Bibliography: leaves 209-235.

There were two aims in this thesis. Firstly, to investigate cholinesterase and its isoenzymes in the fetal mouse brain, and secondly to study drug-induced fetal damage with the following objectives in mind: (i) to examine new markers for the evaluation and prediction of the teratogenic potential of drugs, and (ii) to try and throw more light on pathogenic mechanisms of drug injury with particular reference to the developing fetal central nervous system. Acetylcholinesterase activity in brain homogenates was determined colorimetrically and the isoenzymes were separated by polyacrylamide gel electrophoresis. A cyanmethaemoglobin method was used to measure the contribution of acetylcholinesterase activity in blood to total brain esterase activity. Cholinesterase activity was estimated colorimetrically, and with the aid of enzyme inhibitors and polyacrylamide gel electrophoresis. The effects of three central nervous system teratogens, vitamin A, cyclophosphamide and sodium valproate when administered during embryonic development, on gross fetal parameters in C3H mice including embryolethality, gross morphological abnormalities, fetal weight, brain weight, brain acetylcholinesterase and its isoenzymes, and in some instances brain total protein content and choline acetyltransferase activity, were assessed. Preliminary studies were also performed with a view to future areas of research on (i) the effects of vitamin A when administered during the pre-implantation period on viability/esterase enzyme activity, cell number, mitotic index and chromosome structure in the 81h blastocyst; (ii) the influence of vitamin A on C3H fetal mouse brain proteins using high resolution two-dimensional electrophoresis; and (iii) the effects of cyclophosphamide and vitamin A on cephalic DNA damage utilising a DNA unwinding assay to detect DNA strand breaks. Substantial acetylcholinesterase activity of ± 3nmol/min/mg was present in 17-day to 19-day fetal mouse brains and 5 isoenzymes were present on electrophoresis. The contribution of acetylcholinesterase activity in blood was low at approximately 3%. Similarly, fetal mouse brain cholinesterase activity was found to be very low and the effect of teratogens on this enzyme was not assessed. A rise in the incidence of malformations and embryolethality with increase in dose, and after administration earlier in gestation occurred with all three teratogens. A growth-inhibitory effect was another feature although this was most pronounced after cyclophosphamide administration. Acetylcholinesterase activity was affected by the teratogen used and its time of administration as well as other factors such as growth inhibition, haemorrhage and repair processes. Vitamin A administration on day 10 of gestation was associated with a greater acetylcholinesterase activity compared with controls, which was not accompanied by a change in brain total protein content or choline acetyltransferase activity. Cyclophosphamide and sodium valproate administration during the embryonic period were associated with a lower acetylcholinesterase activity in near-term fetuses. However, in fetuses examined two days after cyclophosphamide administration there was a greater acetylcholinesterase activity associated with an increase in haemoglobin and a decrease in choline acetyltransferase. A higher acetylcholinesterase activity was also observed in exencephalic brains. Vitamin A administration was associated with a higher activity of isoenzyme 5 whereas cyclophosphamide and sodium valproate administration resulted in a lower peak height for band 4. When vitamin A was administered during the pre-implantation period 60h after copulation no effect on viability/esterase enzyme activity, cell number, mitotic index or chromosome structure was observed in 81h embryos. However, a striking incidence of abnormalities was noted in fetuses examined near term. This study suggested that teratogenic doses of vitamin A modified the brain protein pattern of the fetal mouse with a possible broad spectrum deletion of protein spots and the appearance of a limited number of new spots. There was no evidence of DNA strand breaks induced by vitamin A, which contrasted with obvious cephalic DNA damage after cyclophosphamide administration. The potential of these techniques in the prediction of the embryotoxicity of drugs, and progress in the understanding of underlying mechanisms are discussed.

Thesis (Ph. D.)--University of Wisconsin, Madison, 1974. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Errata is tipped in between leaf 9 & 10. / Bibliography: leaves 209-235. / 235 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Focusses specifically on the role of acetylcholine in the circadian timing system of mammals, using the rat as an animal model. / Thesis (Ph.D.)--University of Adelaide, Dept. of Obstetrics and Gynaecology, 1999

Thesis (M.Sc. (Tropical Medicine))--Mahidol University, 2003.

Hrušková M.: Alkaloids from the wood of the species Liriodendron tulipifera L. and their activity against human cholinesterase. Diploma thesis, Charles University, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Botany, Hradec Králové, 2018. Key words: Liriodendron tulipifera, alkaloids, biological activity. The alkaloids from the wood of the species Liriodendron tulipifera L. were isolated and their inhibitory activity against acetylcholinesterase, butyrylcholinesterase and propyl oligopeptidase, which are enzymes involved in the pathophysiology of Alzheimer's disease (AD), was investigated. The search and testing of new substances, which are used in AD treatment, is very relevant, as this disease cannot be casually treated yet. An alkaloid extract of Liriodendron tulipifera L. wood was tested in a preliminary testing for inhibitory activity against human cholinesterase. Because of the promising results, it was chosen for an isolation and identification of possible effective alkaloids. The extract was carried out by column chromatography with a step gradient elution. A preparative TLC was used to isolate alkaloids. The identification of alkaloids was done by structural analyses (NMR and MS). Optically active substances were measured for their optical rotation. A modified...

Magister Pharmaceuticae - MPharm / The cascade of neurotoxic events involved in the pathogenesis of Alzheimer's disease may explain the inefficacy of currently available treatment based on acetylcholinesterase inhibitors (AChEI - donepezil, galantamine, rivastigmine) and N-methyl-D-aspartate (NMDA) antagonists (memantine). These drugs were designed based on the "one-moleculeone- target" paradigm and only address a single target. Conversely, the multi-target drug design strategy increasingly gains recognition. Based on the versatile biological activities of tacrine, trolox and β-carboline derivatives, the attention they have received as lead structures for the design of multifunctional drugs for the treatment of Alzheimer's disease, and the topology of the active site of AChE, we have designed tacrine-trolox and tacrine-tryptoline hybrids with various linker chain lengths. The aim with these hybrids was to provide additive or synergistic therapeutic effects that might help overcome the limitation of current anti Alzheimer's disease drugs. All synthesized compounds were designed from lead structures (tacrine, tryptoline and trolox) to obtain cholinesterase (ChE) multisite binders and multifunctional AD agents. The study was rationalized by docking all structures in the active site of TcAChE using Molecular Operating Environment (MOE) software before proceeding with the synthesis. ChE inhibition was assessed in a UV enzyme inhibition assay using Ellman's method. Antioxidant activities were assessed using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH.) absorbance assay. The hybrids containing the trolox moiety (compounds 8a-e) showed moderate to high AChE inhibitory activity in the nano to micro molar range (IC₅₀: 17.37 - 2200 nM), BuChE inhibition was observed in the same range (IC₅₀: 3.16 – 128.82 nM), and free radical scavenging activities in micro molar range (IC50: 11.48 – 49.23 µM). These are comparable or slightly higher than their reference compounds donepezil (AChE IC₅₀ = 220 nM), tacrine (BuChE IC₅₀: 14.12 nM), and trolox (DPPH IC₅₀: 17.57 µM). The hybrids with longer linker chain lengths, 6 and 8 carbons (8d and 8e), showed better ChE inhibitory activity than the shorter ones, 2, 3, and 4 carbons (8a-c respectively). This correlates well with literature. Free radical scavenging activities, however, seems not to be significantly affected by varying linker chain lengths. The hybrid compound (14) containing the tryptoline moiety linked with a 7 carbon spacer displayed the best AChE and BuChE inhibitory activity (IC₅₀ = 17.37 and 3.16 nM) but poor free radical scavenging activity. Novel anti-Alzheimer's disease drugs with multi-target neuroprotective activities were thus obtained and hybrid molecules that exhibit good ChE inhibition (8d, 8e and 14) and anti-oxidant (8d and 8e) activity were identified as suitable candidates for further investigation. / National Research Foundation (NRF)

Kateřina Janská Evaluation of the kinetics of acetylcholinesterase inhibitors in vitro Diploma thesis Charles University in Prag, Faculty of Pharmacy in Hradec Králové Pharmacy Department of Biological and Medical Sciences Supervisor: Doc. MUDr. Josef Herink, DrSc. Consultant: PharmDr. Vendula Šepsová The aim of the thesis was to determine the type of an inhibition of newly synthesized AChEI and to find out if AChEI structure changes influence the type of an inhibition. Altogether 12 substances (7 tacrine hybrides and 5 7-methoxy- donepezil hybrids) were investigated. The inhibition potential of the tested substances was studied in vitro on the human recombinant AChE. Spectrophotometric Ellman method was utilized as the measurement tool. The noncompetitive type of an inhibition for substances EN 1-5, PC-25 and PC-33, mixed type of an inhibition for substances PC-48 and PC-49, uncompetitive type of an inhibition for substances EN-6, EN-7 and competitive type of an inhibition for the substance PC-37 was determined. The greatest inhibition potential according to Ki values were found for substances EN-7 and PC-37. Substances PC-37 and PC-48 were determined as substances with the biggest affinity to the AChE. The type of an inhibition has been influenced by a substituent position in PC substances and by...