No description available.

Th. 3e cycle--Pharmacol. moléculaire--Paris 5, 1982. N°: 44.

Th. 3e cycle--Pharm.--Paris 5, 1980. N°: 10.

Made available in DSpace on 2014-06-11T19:32:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-10-30Bitstream added on 2014-06-13T19:42:30Z : No. of bitstreams: 1 lima_v_dr_botib_parcial.pdf: 121964 bytes, checksum: f1b5442c2529b9fae052af629d1f7759 (MD5) Bitstreams deleted on 2015-02-04T11:39:28Z: lima_v_dr_botib_parcial.pdf,Bitstream added on 2015-02-04T11:40:13Z : No. of bitstreams: 1 000713861.pdf: 1384411 bytes, checksum: b955783a5a264cb6a8fe99236063aa37 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Agonistas induzem ou estabilizam diferentes conformações de receptores com 7 domínios transmembrana (7TMRs) levando à modulação diferencial das atividades desses receptor. Este fenômeno é conhecido como eficácia colateral ou pluridimensional, seletividade funcional ou agonismo tendencioso. Este trabalho investigou se drogas comumente utilizadas como agonistas de 1-adrenoceptores (as feniletilaminas noradrenalina, dopamina, fenilefrina e metoxamina; e as imidazolinas A61603, oximetazolina e nafazolina) apresentam agonismo tendencioso para a via proteína Gq-mobilização de Ca2+ intracelular ([Ca2+]i) ou para a internalização dependente de -arrestina em 1A- ou 1B-adrenoceptores humanos em células HEK293. O agonismo tendencioso foi determinado pela comparação equimolar e quantificado pela comparação das “razões de transdução” /KA ou razões das “eficiências de acoplamento” . Os métodos quantitativos de análise do agonismo tendencioso apontaram perfis semelhantes de seletividade funcional em 1A- e 1B-adrenoceptores. Em 1A-adrenoceptores, a dopamina apresentou agonismo tendencioso para a internalização, enquanto que a fenilefrina e o A61603 foram tendenciosos para a mobilização de [Ca2+]i. Todas as imidazolinas investigadas foram agonistas tendenciosos na internalização de 1B-adrenoceptores. Houve repercussões funcionais do agonismo tendencioso observado, uma vez que a oximetazolina promoveu taquifilaxia tanto em respostas mediadas por 1B-adrenoceptores nativos do baço do rato quanto em 1B-adrenoceptores recombinantes humanos indicando que a sua capacidade de induzir internalização de receptores não é restrita a receptores recombinantes. Além disso, houve forte correlação entre os log(/KA) de agonistas de 1-adrenoceptores em receptores nativos do rato e humanos recombinantes / Agonists induce or stabilize different conformations of 7 transmembrane domain receptors leading to differential modulation of receptor activities, a phenomenon known as collateral or pluridimentional efficacy, functional selectivity or biased agonism. This study investigates if some ligands commonly used as 1-adrenoceptors agonists (the phenylethylamines: noradrenaline, dopamine, phenylephrine and methoxamine; and the imidazolines: A61603, oxymetazoline and naphazoline) present biased signaling for Gq protein mediated intracellular calcium mobilization or -arrestin dependent receptor internalization in human recombinant 1A- and 1B-adrenoceptores expressed in HEK293 cells. The biased agonism was determined by equimolar comparison and quantified by transduction ratios (/KA) and coupling efficiency ratios (). Both methods for quantification of biased agonism discriminated similar profiles of functional selectivity in 1A- and 1B-adrenoceptores. In 1A-adrenoceptors, dopamine is biased for internalization, but phenylephrine and A61603 were biased for [Ca2+]i mobilization. On the other hand, all imidazolines were biased agonists for internalization of 1B-adrenoceptors. There are functional repercussions of the biased agonism presented by oxymetazoline, as this agonist induced tachyphylaxis in responses mediated by native 1B-adirenoceptors of the rat spleen and human recombinant 1B-adrenoceptors expressed in HEK293 cells, indicating that its ability to induce internalization is not restricted to recombinant receptors. In addition, there was a strong correlation between log(/KA) of 1-adrenoceptor agonists in rat native and human recombinant 1-adrenoceptors

Thesis (MTech (Radiography))--Peninsula Technikon, 2004 / The radiation risks associated with children are higher than the risk for adults. Children have growing organs and they have a longer life expectancy than that of adults. As a consequence the effects of damage from radiation could be greater than in adults. Children who receive radiation damage may pass genetic damage onto future generations. This study was carried out to investigate the optimal effective x-ray dose young children need to receive who have radiographic examination to the chest at Tygerberg Hospital, South Africa. Chest radiographs are documented as being the most common radiographic examination done on children. The age groups of children participating in this study were 0-1 year, 1-5 years and 5-10 years. A total of 67 children were involved and the absorbed doses for 134 views of the anterior-posteria (AP) chest and lateral chest were measured. Entrance surface dose (ESD) values were determined, and measured mean ESD (mGy) and the ESD range was reported for each age group. This was done by attaching thermolurninescent dosirneters (TLD pellets) to the patients skin at the entrance point of the x-ray beam. The results were compared to similar studies done in Ireland and Nigeria From the ESD values obtained the absorbed doses ofthe eyes, heart, liver, thyroid and genitals could be calculated by using the "Childdose" programme ofthe NRPB. The ESD dose levels for South Africa compare favourably with Ireland. However the Nigerian values differed greatly from those of Ireland and South Africa It was very encouraging to note the comparative results achieved at Tygerberg Hospital especially due to the fact that this was the first time such study had been conducted in the Tygerberg Hospital Radiology Department. The results also compare favourable with that achieved by a group working in the United Kingdom. This group does similar surveys every five years as part of their radiation protection programme. The results were also in line with the UNSCEAR document of2000. v This study could serve as a valuable source of reference to radiographers and radiologists when performing paediatric radiology especially as the radiation absorbed dose could be used as a baseline to create awareness of size of dose received, and to limit deleterious radiation doses to patients and to prevent unnecessary exposures. A second significant outcome of the study was the effect that added filters had on the x-ray beam generated. Experiments were done in which the filtration filters were added sequentially. It was found that if the filtration was increased to 2mmAl the dose to the patient decreased by more than 20%. At 50 and 60 kV the density of the x-ray image on film only increased by 2%. From these results it may be concluded that an increase in filtration thickness used for paediatric chest x-rays should be giVIng reduced dose readings and assisting with radiation protection ofthe patient.

Liposomes have important potential as drug delivery vehicles. However, in order to realize this potential, much basic research is required to elucidate the interactions experienced by liposomes in vivo. In this thesis two aspects of these interactions are investigated: the influence of vesicle size and lipid composition on the biodistribution observed in vivo; and the interaction of liposomes with plasma proteins. In order to determine the in vivo behavior of liposomal systems, a new vesicle marker is synthesized (¹²⁵I-tyraminyl-inulin, ¹²⁵ITI) and tested in vivo. It is shown that this probe satisfies the necessary criteria for an accurate marker of liposome behavior, and is superior to probes used by other workers in terms of accuracy, convenience, high specific activity, low tissue quenching and cost. The use of ¹²⁵ITI as a vesicle marker allows accurate measurements to be made with lower doses of liposomes than previously employed. The influence of vesicle size, composition, and dose on the blood residency times, leakage and tissue distributions of vesicles was therefore investigated at these lower doses, employing a cannulation procedure to monitor vesicles. It is demonstrated that the clearance of vesicles from the circulation exhibits biphasic kinetics. The relative number of vesicles cleared during the early phase (halflife <20 min) is decreased by increasing the vesicle dose or decreasing the size. The behavior of small vesicles produced by extrusion is also investigated, and the in vivo behavior of these systems is shown to be equivalent to conventional sonicated systems. The second part of this thesis investigates the binding of plasma proteins to vesicles in vitro. It is shown that vesicles bind a large number of plasma components and that the binding is strongly dependent on the surface charge of the vesicle. Some of the proteins have been tentatively identified with 2-D electrophoresis and several were positively identified via immuno- autoradiography. A hypothesis is advanced regarding the role of plasma proteins in the fate of liposomes in vivo. / Medicine, Faculty of / Biochemistry and Molecular Biology, Department of / Graduate

M.Cur. (General Intensive Nursing) / In South Africa, where the nurse is seen as an independent practitioner, she must take continuously accountability and responsibility for her actions. Only she can decide whether she is legally able, or knowledgeable and competent enough to accept a prescription or direction from a doctor. Once she has indicated acceptance, she has made an independent decision and accepts full responsibility and accountability for her decisions and actions. Accountability means that the nurse must be able to give a reason for her actions and or omissions. It is very important that she has enough knowledge of the effects, side-effects, indications and contra-indications of the medications that are prescribed by the doctor before she administers it. Knowledge of medications and the Nursing Act with related regulations that directs her practice, are very important to the nurse to ensure a high standard of nursing care. The nurse working in an intensive care unit must often make decisions in a crisis situation in connection with her legal accountability. So much more in the private sector where the intensive care nurse must .often rely on her own judgement and knowledge because a doctor is not always available. Two questions evolving from this is what is the nurse's responsibility with in the legal framework of medication administration in a intensive care unit and do nurses have enough knowledge of selected medications? These two questions have been answered by evaluation of the doctor's prescriptions and nursing actions, with the help of prelisted control lists and a questionnaire The results of the study showed that the doctor's prescriptions were not legally correct and nurse's actions and knowledge of the selected medications were not up to the expected standard in the chosen unit. Two recommendations evolving from this study are that inservice training to increase knowledge of medications that are frequently used in the unit should be presented monthly and that more time must be spent on pharmacology during the training of the intensive care nurse.

The aim of this research was to develop a solid dosage form containing 1.5 g of the pesticide cypermethrin. The dosage should be stable in a tropical climate. In addition, it is to disintegrate and disperse in 10 L of tap water within 3 minutes. Such dissolution should yield a 150 ppm dispersion of cypermethrin, stable for at least one week. This provides for a dip dispersion to treat ticks and fly infestation on livestock. A new solid dosage was formulated as the scope of this research. It is a gel-based solid dosage form. Polymer electrolyte ASP4 - a copolymer of methacrylic acid, ethyl acrylate and diethyl maleate, was used to produce the gel. Preliminary tests revealed that ASP4- based gel, on its own, failed to meet the required dissolution time of 3 minutes. Strong entanglements of ASP4 chains impeded rapid dissolution. These strong entanglements occurred owing to the use of a high concentration of ASP4. Reducing the concentration of ASP4 yielded a solution of high viscosity instead of a gel. It was therefore decided to Gel-based solid dosage form for pesticide delivery use a superabsorbent (Product Z1069) in conjunction with ASP4 to produce the gel. Product Z1069 is a cross-linked sodium polyacrylate. Before producing the gel, a 1:1.5 by mass oil/water (O/W) emulsion was prepared using the phase-inversion route. The water (W) phase comprised 85.9% distilled water, 3.9% ASP4 at 20% dispersion, 8.6% sodium carbonate (0.5 M) and 1.6% Emulsogen EL. All concentrations are indicated in mass %. The oil (O) phase consisted of 76.9% cypermethrin, 19.3% Solvesso S200 and 3.8% Phenyl Sulphonate CA, also by mass. This emulsion was gelled by adding the superabsorbent Product Z1069 (ca. 37.5% by mass relative to the W phase of the emulsion). The superabsorbent strongly absorbed water, depleting it from the emulsion. This resulted in an increase of the effective concentration of ASP4 in the water phase of the emulsion. This increase of the polymer electrolyte concentration brought about a gel-like state corresponding to the desired solid dosage form. Rheometry confirmed that the dosage form maintained a solid gel-like consistency at 50°C. The dosage contained 24.6% m/m cypermethrin. Thus, the required dosage of 1.5 g was achieved in pellets weighing ca. 6.1 g. Such pellets rapidly disintegrated with mild stirring in 10 L of tap water. Complete pellet disintegration and active dispersion occurred within 2.5 minutes at ambient temperature (25 ± 2°C). / Dissertation (MSc)--University of Pretoria, 2008. / Chemistry / unrestricted

Proton therapy with pencil beam scanning technique is a novel technique to treat cancer patients due to its unique biophysical properties. However, a small error in dose calculation may lead towards undesired greater uncertainties in planed doses. This project aims to create a simulation model of Varian ProBeam Compact using the GEANT4 Monte Carlo simulation tool kit. Experimental data from the first clinical ProBeam Compact system at South Florida Proton Therapy Institute was used to validate the simulation model. A comparison was made between the experimental and simulated Integrated Depth-Dose curves using a 2%/2mm gamma index test with 100% of points passing. The beam spot standard deviation sizes (s!) were compared using percent deviation. All simulated s! matched the experimental s! within 2.5%, except 70 and 80 MeV. The model can be used to develop a more comprehensive model as an independent dose verification tool and further investigate dose distribution. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

Poor dose optimization in cancer trials leads to poor patient outcomes in tumor suppression and drug tolerance as well as failures in the drug development process. Most phase I clinical cancer trials still use traditional dose-finding methods, which are inadequate for evaluating novel cancer therapies, such as molecularly targeted agents and immunotherapies. Traditional approaches include using rule-based designs instead of model-based designs, assuming one dose should be recommended to all patients, and assuming the higher the dose, the better. This dissertation aims to address each of the inefficiencies that exist in phase I trials to optimize patient and trial outcomes in oncology, specifically in settings where the patient population is heterogeneous, i.e., settings where eligibility criteria have been expanded or settings evaluating a therapy that targets multiple tumor types and mutations. In the first part of this work, we address the inefficiencies of rule-based designs and the barrier to implementation of model-based designs. We use published phase I trials that used the most common rule-based method, the 3+3 design, and compare the trial outcomes to those obtained with novel model-based designs. In the second part of the work, we propose a broadened eligibility dose-finding design to address the situation of unknown patient heterogeneity in phase I cancer trials where eligibility is expanded, and multiple eligibility criteria could potentially lead to different optimal doses for patient subgroups. Lastly, we address patient heterogeneity in efficacy by developing a dose-optimization design that accounts for patient-specific characteristics, toxicity, pharmacokinetic data, and efficacy to identify the target population and inform the optimal dose for each subpopulation. The findings in each work highlight the advantages of model-based designs, particularly when tailored for the therapy and patient population in question. Using published dose-finding trials, we show that novel designs would recommend different doses about 40% of the time and confirm the advantages of these designs compared with the 3 + 3 design, as suggested previously by simulation studies. When accounting for heterogeneity in toxicity, the broadened eligibility design identified when the expanded subpopulation should be recommended a lower dose due to their tolerance and identified the criteria affecting toxicity at least 60% of the time in simulation studies. The dose-optimization design, focusing on heterogeneity in efficacy, demonstrated that a model-based approach to identifying the target population can be effective. Further, in the presence of heterogeneity, patient characteristics relating to molecular tumor characteristics were identified correctly, and a different optimal dose was recommended for each identified target subpopulation. The simulation studies of all proposed designs show that accounting for heterogeneity, even when the source of heterogeneity is unknown, is beneficial. In addition, the simulation studies highlight the poor performance of a naive method that recommends one dose for all. Our findings in this dissertation reveal the large proportion of the patient population that will be incorrectly dosed if inappropriate dose-finding designs are used. While we cannot directly understand the effect of dose selection on cancer trial outcomes, it is likely that not handling characteristics of novel cancer therapies early on contributes to the high attrition rates of cancer trials and the toxicity burden encountered in later trials and post-approval studies.