Thesis. 1978. Ph.D.--Massachusetts Institute of Technology. Dept. of Mechanical Engineering. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ENGINEERING. / Vita. / Includes bibliographical references. / by Thomas H. Papanek. / Ph.D.

目的：抗精神病藥物是多功能的藥物。鼻腔給藥可提供高效的藥物遞送，但關於鼻腔遞送抗精神病藥物的研究仍十分有限。此外，有關鼻腔給藥後生成的活性代謝物於全身及中樞神經系統的分佈的報導亦很少。本研究的主要目的在於：1）篩選出適合鼻腔給藥的抗精神病藥物，以及2）研究被選定抗精神病藥物在鼻腔給藥後於中樞神經系統的藥代動力學和藥效學特徵，尤其關注藥物代謝在藥代動力學和藥效學中的作用。 / 方法：本研究系統地採用了in silico 評估及體外透過模型，篩選出具有較高鼻腔給藥發展潛力的抗精神病藥物。通過不同的鼻腔給藥動物體內模型，研究所選藥物全身及中樞神經系統的藥代動力學和藥效學特徵，並與口服和靜脈注射進行比較。 / 結果：第一階段的in silico篩選包括了二十二種抗精神病藥物。其中氯丙嗪、氟奮乃靜、丙氯拉嗪及洛沙平具有鼻腔給藥所需的良好的理化性質和臨床特點，因此被挑選到第二階段篩選。第二階段篩選採用體外Calu-3單層細胞模型研究藥物經鼻腔吸收的能力。Calu-3細胞模型的實驗結果表明，抗精神病藥物的表觀滲透係數與藥物的親脂性和總回收率呈負相關，其中洛沙平具有最高的透過性，並被選擇作進一步的體內研究。 / 我們建立了一種全新的可以同時測定大鼠腦內和血漿中洛沙平及其體內代謝產物（包括7-羥基-洛沙平）的液質聯用方法，並比較了在大鼠清醒及麻醉狀態下洛沙平鼻腔給藥後的藥代動力學。結果表明無論在大鼠清醒還是麻醉狀態下，鼻腔給藥均具有較高的絶對生物利用度（清醒狀態：~50%；麻醉狀態：~100%）。另外，研究發現麻醉和鼻腔手術對洛沙平及其代謝產物的體內處置具有很大影響，且這些影響依賴於給藥途徑。 / 本研究亦考察了洛沙平在鼻腔及口服給藥後，於大鼠中樞神經系統的藥代動力學和藥效學特徵。鼻腔給藥後，洛沙平迅速被吸收入血，隨即進入腦部，且15分鐘內在所有腦部區域達至最高藥物濃度。與之相反，口服給藥後僅有極少量的洛沙平吸收入血及腦部。但是，在鼻腔與口服給藥後，主要代謝產物7-羥基-洛沙平在腦內的濃度水平相當，且兩種給藥途徑對腦部紋狀體中多巴胺、5-羥色胺、和它們的代謝物水平的影響亦無差異。由於錐體外系癥狀乃抗精神病藥物常見的運動障礙性副作用，我們採用了大鼠僵直模型對大鼠在服用洛沙平後的運動障礙反應進行了評價。研究表明相比鼻腔給藥而言，口服洛沙平後誘發了大鼠更強的僵直反應。另外，當分別靜脈注射洛沙平及7-羥基-洛沙平後，7-羥基-洛沙平誘發的僵直反應比洛沙平更強；但同時注射洛沙平及7-羥基-洛沙平則降低了由7-羥基-洛沙平誘發的僵直反應。 / 結論：洛沙平有望進一步開發成為一種鼻腔遞藥，用於治療精神分裂症及其他中樞神經系統疾病。服用洛沙平後，錐體外系癥狀副作用很大程度上是由體內代謝產物7-羥基-洛沙平引起，而非洛沙平本身。藥物代謝對抗精神病藥物及鼻腔遞藥的臨床作用能產生很大的影響。 / Purpose: Antipsychotics are versatile drugs. Intranasal route could provide efficient delivery for certain therapeutic agents; however, studies on intranasal antipsychotics are limited. Moreover, the systemic and central nervous system (CNS) dispositions of active metabolites after intranasal drug administration are seldom investigated. The current project aims to 1) identify the antipsychotics that are more suitable to be developed into intranasal medications; and 2) characterize the CNS pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the selected antipsychotic delivered by intranasal route, with a special attention to the role of drug metabolism in PK and PD outcomes. / Methods: To select an antipsychotic with greater potential for intranasal delivery, a systematic approach was adopted to screen antipsychotic candidates with in silico evaluations and then in vitro permeability assays. The systemic and CNS PK and PD profiles of the selected antipsychotic would be investigated in different intranasal delivery models and compared to that after oral and intravenous (IV) administrations. / Results: Twenty two antipsychotics were included in the primary in silico screening. Chlorpromazine, fluphenazine, prochlorperazine, and loxapine, which possessed more favorable physicochemical and clinical properties required for intranasal delivery, were selected. Secondary screening in the Calu-3 cell monolayer model demonstrated that the apparent permeability coefficients (P[subscript app]) correlated inversely to the antipsychoitc’s lipophilicity and total recovery. Loxapine, which demonstrated the highest permeability, was selected for further in vivo investigations. / A novel LCMS/MS assay method was first developed for quantification of loxapine and its metabolites including 7-hydroxy-loxapine (7-OH-loxapine) in rat brain and plasma. The systemic PKs of loxapine in conscious and anesthetized rat models of intranasal delivery were then studied and compared. While intranasal loxapine achieved satisfactory absolute bioavailabilities in both conscious (~50%) and anesthetized (~100%) models, anesthesia and nasal surgery were found to exert profound effects on the systemic disposition of loxapine and its metabolites, and such effects were dependent on the administration route. / The CNS PK and PD outcomes after intranasal and oral loxapine administrations were characterized. Intranasally administered loxapine was efficiently absorbed into systemic circulation followed by entering brain, with a t[subscript max] less than 15 min in all the studied brain regions. In contrast, oral route delivered minimal amounts of loxapine to plasma and brain. Intranasal and oral loxapine achieved similar brain levels of 7-OH-loxapine, the major metabolite, and these two routes induced similar changes in the striatal levels of dopamine, serotonin, and their metabolites. Extrapyramidal symptoms (EPS), the motor side effects frequently associated with antipsychotics, were evaluated by the catalepsy models. The severity and incidence of catalepsy were consistently higher after oral than after intranasal loxapine administration. Individual IV injections of loxapine and 7-OH-loxapine to rats revealed that 7-OH-loxapine was even more cataleptogenic than the loxapine, while co-injection of loxapine tended to lower the catalepsy induced by 7-OH-loxapine. / Conclusion: Loxapine seems to be a promising antipsychotic for further development into intranasal medication. 7-OH-loxapine, rather than the parent loxapine, could be the culprit in EPS associated with loxapine treatment. Drug metabolism could have considerable contribution to the clinical effects of antipsychotics and intranasal drugs. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Wong, Yin Cheong. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 259-296). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese. / Table of contents --- p.I / Acknowledgements --- p.VII / Publications --- p.IX / Abstract --- p.XI / 摘要 --- p.XIII / List of Tables --- p.XV / List of Figures --- p.XVII / List of Abbreviations --- p.XX / Chapter Chapter One. --- Introduction --- p.1 / Chapter 1.1 --- Overview of antipsychotics --- p.1 / Chapter 1.1.1 --- Pharmacology --- p.1 / Chapter 1.1.2 --- Therapeutic applications --- p.7 / Chapter 1.1.2.1 --- Schizophrenic and other mental disorders --- p.7 / Chapter 1.1.2.2 --- Pain management --- p.9 / Chapter 1.1.3 --- Antipsychotic-induced extrapyramidal symptoms (EPS) --- p.11 / Chapter 1.1.3.1 --- Clinical manifestations --- p.11 / Chapter 1.1.3.2 --- Preclinical evaluation of EPS by catalepsy tests --- p.13 / Chapter 1.1.3.3 --- Role of active metabolites in EPS --- p.16 / Chapter 1.2 --- Overview of intranasal drug delivery --- p.20 / Chapter 1.2.1 --- Absorption of drug in nasal cavity --- p.21 / Chapter 1.2.1.1 --- Nasal anatomy --- p.21 / Chapter 1.2.1.2 --- Pathways from the nasal passages to the central nervous system --- p.25 / Chapter 1.2.2 --- Metabolite formation after intranasal drug application --- p.26 / Chapter 1.2.2.1 --- Nasal metabolisms --- p.27 / Chapter 1.2.2.2 --- Contribution of gastrointestinal absorption and metabolism --- p.27 / Chapter 1.3 --- Potentials of delivering antipsychotics via intranasal route --- p.33 / Chapter 1.3.1 --- Advantages and limitations of intranasal drug delivery --- p.33 / Chapter 1.3.2 --- Advantages of intranasal antipsychotics --- p.37 / Chapter 1.4 --- Research questions and hypotheses of current study --- p.40 / Chapter 1.5 --- Objectives and thesis outline --- p.42 / Chapter 1.6 --- Significance of the current study --- p.46 / Chapter Chapter Two. --- In silico screening of antipsychotic candidates for their intranasal delivery potential --- p.47 / Chapter 2.1 --- Introduction --- p.47 / Chapter 2.2 --- Methods --- p.49 / Chapter 2.2.1 --- Antipsychotic candidates included in the in silico screening --- p.49 / Chapter 2.2.2 --- Evaluation of physicochemical properties of the candidates --- p.49 / Chapter 2.2.3 --- Clinical development potential of the candidates --- p.51 / Chapter 2.2.3.1 --- Therapeutic uses in conditions other than chronic schizophrenia --- p.51 / Chapter 2.2.3.2 --- Previous reports on intranasal delivery of antipsychotics --- p.52 / Chapter 2.2.4 --- Set up of selection criteria for further in vitro investigations --- p.53 / Chapter 2.3 --- Results and discussions --- p.54 / Chapter 2.3.1 --- Selection based on physicochemical characteristics --- p.54 / Chapter 2.3.2 --- Selection based on therapeutic usage --- p.58 / Chapter 2.3.3 --- Antipsychotic candidates selected for further in vitro investigations --- p.61 / Chapter 2.4 --- Conclusion --- p.66 / Chapter Chapter Three. --- In vitro permeation studies of selected antipsychotic candidates using Calu-3 cell line model --- p.67 / Chapter 3.1 --- Introduction --- p.67 / Chapter 3.2 --- Materials --- p.70 / Chapter 3.2.1 --- Chemicals --- p.70 / Chapter 3.2.2 --- Materials for cell culture --- p.70 / Chapter 3.2.3 --- Instruments --- p.71 / Chapter 3.3 --- Methods --- p.71 / Chapter 3.3.1 --- Cell culture --- p.71 / Chapter 3.3.2 --- Cytotoxicities of the drug candidates on Calu-3 cells by MTS/PES assay --- p.72 / Chapter 3.3.3 --- Stabilities of the drug candidates in loading solutions --- p.74 / Chapter 3.3.4 --- Permeation studies of drug candidates using Calu-3 cell line model --- p.75 / Chapter 3.3.5 --- HPLC/UV assay development and validation for the drug candidates --- p.77 / Chapter 3.3.6 --- Data analysis --- p.79 / Chapter 3.4 --- Results and discussions --- p.80 / Chapter 3.4.1 --- HPLC/UV methods for the drug candidates --- p.80 / Chapter 3.4.2 --- Cytotoxicities of the drug candidates on Calu-3 cells by MTS/PES assay --- p.82 / Chapter 3.4.3 --- Stabilities of the drug candidates in loading solutions --- p.85 / Chapter 3.4.4 --- Permeation studies of drug candidates using Calu-3 cell line model . --- p.86 / Chapter 3.4.4.1 --- Permeability across Calu-3 cell monolayer --- p.86 / Chapter 3.4.4.2 --- Relationship between lipophilicity and permeability and cellular uptake of the antipsychotic candidates --- p.89 / Chapter 3.5 --- Conclusion --- p.93 / Chapter Chapter Four. --- LCMS/MS assay development for quantification of loxapine, amoxapine and their hydroxylated metabolites in rat brain tissues, plasma and CSF --- p.94 / Chapter 4.1 --- Introduction --- p.94 / Chapter 4.2 --- Materials and chemicals --- p.100 / Chapter 4.3 --- Methods --- p.100 / Chapter 4.3.1 --- Preparation of stock solutions, calibration standards and quality control (QC) samples --- p.100 / Chapter 4.3.2 --- Sample extraction procedure --- p.102 / Chapter 4.3.2.1 --- Plasma --- p.102 / Chapter 4.3.2.2 --- Brain tissue --- p.103 / Chapter 4.3.2.3 --- CSF --- p.103 / Chapter 4.3.3 --- LCMS/MS conditions --- p.104 / Chapter 4.3.4 --- Method validation --- p.106 / Chapter 4.3.4.1 --- Linearity and range --- p.106 / Chapter 4.3.4.2 --- Accuracy and precision --- p.106 / Chapter 4.3.4.3 --- Recovery and stability --- p.107 / Chapter 4.3.4.4 --- Assay selectivity and matrix effects --- p.107 / Chapter 4.3.5 --- Application to pharmacokinetic study of orally administered loxapine in rats --- p.108 / Chapter 4.4 --- Results and discussions --- p.110 / Chapter 4.4.1 --- Optimization of LC and MS conditions --- p.110 / Chapter 4.4.2 --- Extraction of loxapine and metabolites from biological matrices --- p.114 / Chapter 4.4.2.1 --- Plasma --- p.114 / Chapter 4.4.2.2 --- Brain tissue --- p.115 / Chapter 4.4.2.3 --- Sample cleanup by SPE --- p.115 / Chapter 4.4.3 --- Method validation --- p.119 / Chapter 4.4.3.1 --- Linearity and range --- p.119 / Chapter 4.4.3.2 --- Accuracy and precision --- p.120 / Chapter 4.4.3.3 --- Recovery and stability --- p.120 / Chapter 4.4.3.4 --- Assay selectivity and matrix effects --- p.121 / Chapter 4.4.4 --- Application to pharmacokinetic study of orally administered loxapine in rats --- p.124 / Chapter 4.4.4.1 --- Plasma pharmacokinetic profiles --- p.124 / Chapter 4.4.4.2 --- Brain distribution study --- p.126 / Chapter 4.4.4.3 --- CSF disposition --- p.128 / Chapter 4.4.5 --- Implications on the further investigations of low-dose loxapine --- p.128 / Chapter 4.5 --- Conclusion --- p.131 / Chapter Chapter Five. --- Pharmacokinetic profiles of loxapine and its metabolites after intranasal loxapine administration: comparison of conscious and anesthetized rat models --- p.132 / Chapter 5.1 --- Introduction --- p.132 / Chapter 5.2 --- Materials and chemicals --- p.135 / Chapter 5.3 --- Methods --- p.135 / Chapter 5.3.1 --- Animal surgery --- p.135 / Chapter 5.3.1.1 --- Conscious rat model --- p.135 / Chapter 5.3.1.2 --- Anesthetized rat model --- p.136 / Chapter 5.3.2 --- Loxapine administration through intranasal, oral and IV routes --- p.138 / Chapter 5.3.2.1 --- Preparation of drug solutions --- p.138 / Chapter 5.3.2.2 --- Drug administration in conscious rat model --- p.138 / Chapter 5.3.2.3 --- Drug administration in anesthetized rat model --- p.139 / Chapter 5.3.3 --- Blood and brain samplings --- p.139 / Chapter 5.3.4 --- Pharmacokinetic and statistical analyses --- p.142 / Chapter 5.4 --- Results and discussions --- p.143 / Chapter 5.4.1 --- Pharmacokinetics of loxapine and its metabolites in conscious model --- p.149 / Chapter 5.4.1.1 --- Plasma concentration versus time profiles --- p.149 / Chapter 5.4.1.2 --- Brain dispositions of loxapine and its metabolites --- p.150 / Chapter 5.4.2 --- Pharmacokinetics of loxapine and its metabolites in anesthetized model --- p.151 / Chapter 5.4.2.1 --- Plasma concentration versus time profiles --- p.151 / Chapter 5.4.2.2 --- Brain dispositions of loxapine and its metabolites --- p.153 / Chapter 5.4.3 --- Effects of anesthesia and nasal surgery on the pharmacokinetics of loxapine and its metabolites --- p.155 / Chapter 5.4.3.1 --- Effects of anesthesia and nasal surgery on loxapine absorption --- p.158 / Chapter 5.4.3.2 --- Effects of anesthesia and nasal surgery on distribution of loxapine and its metabolites --- p.161 / Chapter 5.4.3.3 --- Effects of anesthesia and nasal surgery on loxapine metabolism --- p.164 / Chapter 5.4.3.4 --- Effects of anesthesia and nasal surgery on elimination of loxapine and its metabolites --- p.167 / Chapter 5.4.3.5 --- Overall effects of anesthesia and nasal surgery on the pharmacokinetics of loxapine and its metabolites --- p.168 / Chapter 5.5 --- Conclusion --- p.172 / Chapter Chapter Six. --- CNS pharmacokinetics of loxapine and its metabolites and pharmacodynamic effects on catalepsy and neurotransmission after intranasal loxapine administration --- p.173 / Chapter 6.1 --- Introduction --- p.173 / Chapter 6.2 --- Materials and chemicals --- p.178 / Chapter 6.3 --- Methods --- p.178 / Chapter 6.3.1 --- LCMS/MS assay development for quantification of neurotransmitters and their metabolites in rat brain tissue --- p.178 / Chapter 6.3.1.1 --- Preparation of stock solutions, calibration standards and quality control samples --- p.178 / Chapter 6.3.1.2 --- Sample extraction procedure --- p.179 / Chapter 6.3.1.3 --- LCMS/MS conditions --- p.180 / Chapter 6.3.1.4 --- Method validation --- p.180 / Chapter 6.3.2 --- Experimental procedures --- p.182 / Chapter 6.3.2.1 --- Drug administration through nasal and oral routes --- p.183 / Chapter 6.3.2.2 --- Catalepsy tests --- p.184 / Chapter 6.3.2.3 --- Drug and neurotransmitter analyses --- p.185 / Chapter 6.3.3 --- Data analysis --- p.185 / Chapter 6.4 --- Results and discussions --- p.187 / Chapter 6.4.1 --- LCMS/MS assay for quantification of neurotransmitters and their metabolites in rat brain tissue --- p.187 / Chapter 6.4.2 --- Pharmacokinetics of loxapine and its metabolites --- p.192 / Chapter 6.4.2.1 --- Pharmacokinetic profiles of loxapine and its metabolites in brain --- p.192 / Chapter 6.4.2.2 --- Pharmacokinetic profiles of loxapine and its metabolites in plasma --- p.197 / Chapter 6.4.3 --- Effects of nasal and oral loxapine administrations on catalepsy --- p.202 / Chapter 6.4.4 --- Effects of nasal and oral loxapine administrations on neurotransmitter levels --- p.208 / Chapter 6.4.5 --- Comparison of the present study on intranasal loxapine with previous studies on intranasal delivery of CNS drugs --- p.215 / Chapter 6.4.5.1 --- Intranasal delivery of antipsychotic --- p.215 / Chapter 6.4.5.2 --- Metabolite disposition in brain after intranasal administration of CNS drugs --- p.218 / Chapter 6.4.6 --- Clinical significance of the present study --- p.221 / Chapter 6.5 --- Conclusion --- p.225 / Chapter Chapter Seven. --- Cataleptogenic effects of loxapine and its metabolites --- p..226 / Chapter 7.1 --- Introduction --- p.226 / Chapter 7.2 --- Methods --- p.229 / Chapter 7.2.1 --- Literature study on the cataleptogenicity of loxapine and its metabolites --- p.229 / Chapter 7.2.2 --- Cataleptogenic effects of loxapine and its metabolites given by IV route --- p.229 / Chapter 7.2.2.1 --- Cataleptogenic effect of individual compounds --- p.229 / Chapter 7.2.2.2 --- Effect of addition of loxapine on the cataleptogenic effect of 7-OH-loxapine --- p.230 / Chapter 7.2.3 --- Data analysis --- p.230 / Chapter 7.3 --- Results and discussions --- p.231 / Chapter 7.3.1 --- Literature study on the cataleptogenicity of loxapine and its metabolites --- p.231 / Chapter 7.3.2 --- Cataleptogenic effects of loxapine and its metabolites given by IV route --- p.236 / Chapter 7.3.2.1 --- Cataleptogenic effect of individual compounds --- p.236 / Chapter 7.3.2.2 --- Effect of addition of loxapine on the cataleptogenic effect of 7-OH-loxapine --- p.240 / Chapter 7.3.3 --- Clinical significance of the present study --- p.245 / Chapter 7.4 --- Conclusion --- p.252 / Chapter Chapter Eight. --- Overall Conclusion --- p.253 / References --- p.259

No description available.

Two different types of rhizomorphs were produced by A. luteobubalina in vitro conditions - aerial and submerged. They differed in growth rate, amount of mucilage, extent of peripheral hyphae, degree of pigmentation and in the structure of inner cortex. Otherwise they had a similar internal structure comprising 4 radial zones, namely, peripheral hyphae, outer cortex, inner cortex and medulla. Two membrane permeant symplastic fluorescent tracers, carboxy-DFFDA and CMAC which ultimately sequestered in vacuoles, behaved in a similar fashion in aerial and submerged rhizomorphs regardless of whether pigment was present in the outer cortical cell walls or in the extracellular material. Rhizomorphs appeared to be mostly impermeable to these probes with exception of a few fluorescent patches that potentially connected peripheral hyphae to inner cortical cells. In contrast, the apoplastic tracer HPTS which was applied to fresh material and its localisation determined in semi-thin (dry) sections following anhydrous freeze substitution appeared to be impeded by the pigmentation in cell walls and/or the extracellular material in the outer cortical zone. Structures identified as air pores arose directly from the mycelium and grew upwards into the air. A cluster of rhizomorph apices is initiated immediately beneath the air pores. As air pores elongated they differentiated into a cylindrical structure. Mature air pores became pigmented as did also the surface mycelium of the colony. The pigmented surface layer extended into the base of air pores, where it was elevated into a mound by tissue inside the base of the air pore. Beneath the pigmented surface layer there was a region of loose hyphae with extensive gas space between them. This gas space extended into the base of the air pore and was continuous with the central gas canal of rhizomorphs. Oxygen is conducted through the air pores and their associated rhizomorph gas canals into the oxygen electrode chamber with a conductivity averaging 679??68x10-12 m3s-1. The time averaged oxygen concentration data from the oxygen electrode chamber were used to compare three different air pore diffusion models. It was found that the widely used pseudo-steady-state model overestimated the oxygen conductivity. Finally, a model developed on the basis of fundamental transport equations was used to calculate oxygen diffusivities. This model gave a better comparison with the experimental data.

Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Soil Science,1993

Tight gas reservoirs are those reservoirs where the matrix has a low permeability range (k < 0.1 md). The literature documents laboratory experiments under restressed conditions that show stress dependent rock properties are more significant in tighter rocks. For gas reservoirs, real gas properties are also sensitive to variations of pressure, and the correct description of gas flow must include pressure-dependent gas properties. Under these circumstances the resulting equation for real gas flow is a second order, non-linear, partial differential equation. Non-linearities include pressure-dependence of gas viscosity, gas compressibility, reservoir permeability and reservoir porosity. This paper investigates dynamic permeability change as a function of net overburden stress in tight gas reservoirs. The gas reservoir simulator used for this work included pressure-dependent reservoir permeability. Radial flow cases are analyzed using this simulator. During this study we found that from analysis of production data alone, it is impossible to determine the correct permeability value for tight gas reservoirs with pressure-dependent permeability. For the cases studied, the transient performance was similar for both constant permeability and pressure-dependent permeability. This similarity causes constant permeability and pressure-dependent permeability to be indistinguishable, based on analysis of transient performance data. It was found that the productivity index decreases when pressure-dependent permeability is more significant. Finally, this study verified that the method of Ibrahim et al.28 under estimates original gas in place (OGIP) for tight gas reservoirs with pressure-dependent permeability.

Permeability estimation in tight and shale reservoirs is challenging because little or no flow will occur without hydraulic fracture stimulation. In the pressure falloff following a fracture calibration test (FCT), radial flow after the fracture closure can be used to estimate the reservoir permeability. However, for very low permeability, the time to reach radial flow can exceed any practical duration. This study shows how to use the reservoir pressure to estimate the maximum reservoir permeability when radial flow is missing in the after-closure response. The approach is straightforward and can also be used for buildup tests. It applies whenever the well completion geometry permits radial flow before the pressure response encounters a real well drainage limits. Recent developments have blurred the boundary between fracture calibration test analysis and classic pressure transient analysis. Adapting the log-log diagnostic plot representation to the FCT analysis has made it possible to perform before and after closure analysis on the same diagnostic plot. This paper also proposes a method for diagnosing abnormal leakoff behavior using the log-log diagnostic plot as an alternative method for the traditional G-function plot. The results show the relationship between reservoir permeability and pressure can be used effectively for both estimation of the permeability upper bound when there is no apparent radial flow and for confirming the permeability estimated from apparent late time radial flow. Numerous field examples illustrate this simple and powerful insight.

Abnormal pressures have been measured in the deep boreholes at the Bruce site, southern Ontario, where a deep geologic repository for low and intermediate level radioactive waste disposal has been proposed. The pressure regime in the stratigraphic units exhibits either higher than hydrostatic pressure (over-pressured) or lower than hydrostatic pressure (under-pressured) are considered to be abnormal. At the Bruce site, the Ordovician sediments are under-pressured while the underlying Cambrian sandstone and the overlying Guelph carbonate are over-pressured. Hypotheses have been documented in literature to explain the phenomenon of abnormal pressures. These hypotheses include osmosis, glacial loading and deglaciation unloading, exhumation of overlying sediments, crustal flexure and the presence of an immiscible gas phase. Previous work on the Bruce site has shown that the under-pressures in the Ordovician limestone and shales could not be explained by glaciation and deglaciation or by saturated analyses. The presence of a gas phase in the Ordovician formations has been determined to be a reasonable cause of the under-pressure developed in the Ordovician shales and limestones at the Bruce site. Support for the presence of a gas phase includes solution concentrations of methane, concentrations of environmental isotopes related to methane and estimates of water and gas saturations from laboratory core analyses. The primary contribution of this thesis is the sensitivity analyses performed on the hydrogeologic parameters with respect to a one dimensional two-phase flow model. First, a one dimensional two-phase air and water flow model was adopted and reconstructed to simulate the long-term evolution of the groundwater regimes at the DGR site. Then the hydrogeologic parameters which impact the presence of under-pressure in the groundwater are investigated. Data required to quantify the properties of geologic media and groundwater are adopted directly from borehole testing and laboratory testing results. The permeable boundaries of the domain are assumed to be water saturated and pressure specified (using hydrostatic conditions in the Guelph Formation and hydrostatic with 120 m over-pressure condition in the Cambrian and Precambrian). Isothermal conditions were assumed, thus constant water density and viscosity values are estimated for the average total dissolved solids (TDS) concentration of the modelled stratigraphic column. A constant diffusion coefficient (a diffusivity of $0.25\times10^{-8}$ m$^2$/s) of air in water is assumed with a saturation-dependent tortuosity. The air generation rate is assumed to simulate the gas phase generated in the Ordovician formations. The numerical simulation of up to 4 million years provides a means to explore the behaviour of gas phase dissipation due to partitioning into the water phase and diffusive transport in the solute phase. Results confirmed that the presence of a gas phase would result in the under-pressure in water.

The goal of this research was to determine whether precast prestressed bridge elements with congested reinforcement could be cast using self-consolidating concrete (SCC) without vibration and yet comply with all parameters of strength, no honeycombing, and void-free surface finish. Eight wall panels and eight BT-72 13-ft long girder sections were fabricated in two precast plants. A qualitative and quantitative evaluation of the surface finish, and homogeneity of the concrete throughout the specimens was performed. Strength, creep, shrinkage and chloride permeability of the SCC field mixes were investigated. Good quality SCC mixes were produced for the walls and the BT-72 girder sections, which completely filled the specimens without the need of internal or external vibration, and resulted in a superior surface finish and a homogenous distribution of the aggregate throughout the section.

Predicting rock permeability from well logs in uncored wells is an important task in reservoir characterization. Due to the high costs of coring and laboratory analysis, typically cores are acquired in only a few wells. Since most wells are logged, the common practice is to estimate permeability from logs using correlation equations developed from limited core data. Most commonly, permeability is estimated from various well logs using statistical regression. For sandstones, often the logs of permeability can be correlated with porosity, but in carbonates the porosity permeability relationship tends to be much more complex and erratic. For this reason permeability prediction is a critical aspect of reservoir characterization in complex reservoirs such as carbonate reservoirs. In order to improve the permeability estimation in these reservoirs, several statistical regression techniques have already been tested in previous work to correlate permeability with different well logs. It has been shown that statistical regression for data correlation is quite promising in predicting complex reservoirs. But using all the possible well logs to predict permeability is not appropriate because the possibility of spurious correlation increases if you use more well logs. In statistics, variable selection is used to remove unnecessary independent variables and give a better prediction. So we apply variable selection to the permeability prediction procedures in order to further improve permeability estimation. We present three approaches to further improve reservoir permeability prediction based on well logs via data correlation and variable selection in this research. The first is a combination of stepwise algorithm with ACE technique. The second approach is the application of tree regression and cross-validation. The third is multivariate adaptive regression splines. Three methods are tested and compared at two complex carbonate reservoirs in west Texas: Salt Creek Field Unit (SCFU) and North Robertson Unit (NRU). The result of SCFU shows that permeability prediction is improved by applying variable selection to non-parametric regression ACE while tree regression is unable to predict permeability because it can not preserve the continuity of permeability. In NRU, none of these three methods can predict permeability accurately. This is due to the high complexity of NRU reservoir and measurement accuracy. In this reservoir, high permeability is discrete from low permeability, which makes prediction even more difficult. Permeability predictions based on well logs in complex carbonate reservoirs can be further improved by selecting appropriate well logs for data correlation. In comparing the relative predictive performance of the three regression methods, the stepwise with ACE method appears to outperform the other two methods.