Pharmacy and Pharmaceutical Sciences Commons^™

Mechanistic Study Of P23-Mediated Aryl Hydrocarbon Receptor Expression, Beverly Pappas

University of the Pacific Theses and Dissertations

The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule which is involved in diverse biological functions ranging from cancer metastasis to immune regulation. This receptor forms a cytoplasmic complex with Hsp90, p23, and XAP2. We have previously reported that down-regulation of p23 triggers degradation of the AHR protein, uncovering a potentially dynamic event which controls the cellular AHR levels without ligand treatment. Here we investigate the underlying mechanisms for this p23 effect using wild-type HeLa and the p23 knockdown HeLa cells. Reduction of the Hsp90 and XAP2 contents, however, did not affect the AHR protein levels, implying that this …

Computational Methods In Biomolecules:Study Of Hydrophilic Interactions In Protein Folding & Constant-Ph Molecular Simulation Of Ph Sensitive Lipid Morc16, Wei Zhang

University of the Pacific Theses and Dissertations

Water molecules play a significant role in biological process and are directly involved with bio-molecules and organic compounds and ions. Recent research has focused on the thermal dynamics and kinetics of water molecules in solution, including experimental (infrared spectroscopy and Raman spectroscopy) and computational (Quantum Mechanics and Molecular Dynamics) approaches. The reason that water molecules are so unique, why they have such a profound influence on bio-activity, why water molecules show some anomalies compared to other small molecules, and where and how water molecules exert their influence on solutes are some of the areas under study. We studied some properties …

Influence Of The Estrous Cycle And Female Sex Hormones On Ghb Toxicokinetics, Hao Wei

University of the Pacific Theses and Dissertations

Gamma-Hydroxybutyrate (GHB) is an endogenous short-chain fatty acid formed from Gamma-aminobutyric acid (GABA). Clinically, GHB is marketed in the United States as Xyrem to treat narcolepsy with cataplexy and in Europe for the treatment of alcohol withdrawal and narcolepsy. However, the illicit use and abuse of GHB occurs due to its sedative/hypnotic and euphoric effects. Monocarboxylate transporters (MCTs and SMCTs) are integral membrane proteins that control the bidirectional transport of endogenous substrates including lactate, acetate and pyruvate. They have also been found to transport and mediate the clearance and distribution of GHB. MCTs demonstrate a wide tissue distribution, including brain, …

Synthesis Of Ag10 Analogs And Optimization Of Ttr Ligands For Half-Life Enhancement (Tlhe) Of Peptides, Raghavendra Jampala

University of the Pacific Theses and Dissertations

The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidosis, which is most commonly, caused by aggregation of Immunoglobulin (Ig) light chains or transthyretin (TTR) in the cardiac muscle, represent an important and often underdiagnosed cause of heart failure. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. AG10 is a potent and selective kinetic …

Fragment-Based Excitonic Coupled-Cluster Theory For Large Chemical Systems, Yuhong Liu

University of the Pacific Theses and Dissertations

Accurate energetic modeling of large molecular systems is always desired by chemists. For example, ligand-protein binding simulations and enzymatic catalysis studies all involve with a small energy difference. The energetic accuracy depends largely on a proper handling of electronic correlations. Molecular mechanics (MM) methods deliver a parameterized Newtonian treatment to these problems. They show great capability in handling large calculations but give only qualitatively good results. Quantum mechanics (QM) methods solve Schrödinger equations and exhibit much better energy accuracy, though the computational cost can be prohibitive if directly applied to very large systems.

Fragment-based methods have been developed to decompose …

Investigating Secondary Structure Features Of Yap1 Protein Fragments Using Molecular Dynamics (Md) And Steered Molecular Dynamics (Smd) Simulations, Ferdiemar Cardenas Guinto Jr.

University of the Pacific Theses and Dissertations

Molecular dynamics (MD) is a powerful tool that can be applied to protein folding and protein structure. MD allows for the calculation of movement, and final position, of atoms in a biomolecule. These movements can be used to investigate the pathways that allow proteins to fold into energetically favorable structures. While MD is very useful, it still has its limitations. Most notable, computing power and time are of constant concern.

Protein structure is inherently important due to the direct link between the structure of a protein and its function. One of the four levels of protein structure, the secondary structure, …

The Rational Investigation Of Anti-Cancer Peptide Specificity Using The Knob-Socket Model, Shivarni Patel

University of the Pacific Theses and Dissertations

Cancer has been a pervasive and deadly problem for many years. No treatments have been developed that effectively destroy cancer cells while also keeping healthy cells safe. In this work, the knob-socket construct is used to analyze two systems involved in cancer pathways, the PDZ domain and the Bcl-BH3 complex. Application of the knob-socket model in mapping the packing surface topology (PST) allows a direct analysis of the residue groups important for peptide specificity and affinity in both of these systems. PDZ domains are regulatory proteins that bind the C-terminus of peptides involved in the signaling pathway of cancer progression. …

Solubility Enhancement Of Model Compounds, Lavanya Pitani

University of the Pacific Theses and Dissertations

Solubility is the amount of solute in the solvent system at phase equilibrium with certain temperature and pressure. Many of the new chemical entities are lipophilic molecules that require techniques to enhance solubility. Solubility enhancement can be achieved by either physical and/or chemical modification of the drug. Various techniques are available for solubility enhancement of poorly soluble drugs include particle size reduction, salt formation, solid dispersions, use of surfactants, prodrug, crystal modification, etc.

In this study, the three model drugs belong to BCS class II and IV having low solubility with a certain range of physicochemical properties were studies in …

Clinical Factors Associated With Hepatitis C Treatment Selection In A Veterans Affairs Population, Carly Anne Ranson

University of the Pacific Theses and Dissertations

Background: Hepatitis C virus is currently the most common chronic blood borne pathogen in the United States, with only half of those infected aware of their condition. The cost for treatment is higher with Harvoni® (ledipasvir/sofosbuvir) than Viekira Pak® (ombitasvir/paritaprevir/ritonavir and dasabuvir). With finite resources available to treat patients, it is important to understand which clinical factors may influence treatment selection decisions.

Methods: The study is a 12-month medical record review within the Veterans Affairs (VA) system to evaluate significant relationships between selected clinical and sociodemographic factors and HCV treatment selection with either Harvoni® or Viekira Pak®. Clinical and demographic …

Liposome-Coated Magnesium Phosphate Nanoparticle For Delivery Of Cytochrome C Into Lung Cancer Cells A549, Weizhou Yue

University of the Pacific Theses and Dissertations

Proteins are large biomolecules that have great therapeutic potential in treating many human diseases. However, chemical/enzymatic degradation, denaturation, and poor penetration into cells are some of the challenges for clinical use of intracellular proteins.

Previously, our group has developed cationic lipid-coated magnesium phosphate nanoparticle (LP MgP NP-CAT) formulations to enhance the intracellular delivery of the negatively charged protein catalase. The goal of the current research is to develop a formulation to deliver cytochrome c (CytC), a positively charged protein into lung cancer cells A549. Specifically, this thesis research prepares and tests liposome-coated magnesium phosphate nanoparticle for delivery of cytochrome c …

Preclinical Evaluation Of Ag10 For Therapeutic Use Against Familial Amyloid Cardiomyopathy And Its Application In Various Other Technologies, Mark Russell Miller

University of the Pacific Theses and Dissertations

Transthyretin (TTR) amyloidosis is a progressive, fatal disease in which deposition of amyloid derived from either mutant or wild-type TTR causes severe organ damage and dysfunction. TTR cardiomyopathy is an infiltrative, restrictive cardiomyopathy characterized by progressive left and right heart failure. Familial amyloid cardiomyopathy (FAC) is driven by pathogenic point mutations in the TTR gene that destabilize the TTR tetramer, prompting its dissociation into dimers and monomers, with subsequent misfolding, aggregation and deposition of toxic TTR amyloid aggregates in the myocardium. The most prevalent mutation that causes FAC is the V122I variant, carried by 3.4% of African Americans, that increases …

Predicting Aqueous Solubility Of Pharmaceutical Agents By Solid Dispersion Prepared By Solvent Evaporation Method, Karthik Reddy Patlolla

University of the Pacific Theses and Dissertations

Solubility of active pharmaceutical agents is a crucial process that determines drug absorption and ultimately its bioavailability. Many of the new therapeutically beneficial compounds discovered are lipophilic requiring various solubility enhancement strategies to improve their solubility. Among these strategies, solubility enhancement using solid dispersions is a leading method. To obtain a desirable increase in the solubility of a poorly-soluble compound, a good understanding of the molecular descriptors influencing the enhancement of solubility is essential. Therefore, the major research objective was to determine the descriptors which significantly influence the solubility enhancement by solid dispersions. After enhancing the solubility of selected poorly-soluble …

Turning Stealth Liposomes Into Cationic Liposomes For Anticancer Drug Delivery, Vijay Gyanani

University of the Pacific Theses and Dissertations

Targeting the anticancer agents selectively to cancer cells is desirable to improve the efficacy and to reduce the side effects of anticancer therapy. Previously reported passive tumor targeting by PEGylated liposomes (stealth liposomes) have resulted in their higher tumor accumulation. However their interaction with cancer cells has been minimal due to the steric hindrance of the PEG coating. This dissertation reports two approaches to enhance the interaction of stealth liposomes with cancer cells. First, we designed a lipid-hydrazone-PEG conjugate that removes the PEG coating at acidic pH as in the tumor interstitium. However, such a conjugate was highly unstable on …

Optimization Of Porcine Buccal Mucosa For In Vitro Evaluation, Upendra D. Kulkarni

University of the Pacific Theses and Dissertations

Porcine buccal mucosa has been extensively used as in vitro model to study the permeability of drugs and assess their potential to deliver through buccal route. Porcine buccal mucosa is found to be very similar to human oral mucosa in structure and function. However, the in vitro permeation studies across porcine buccal mucosa show high variability which is mostly due to the various experimental and biological variables that are often overlooked while conducting such studies.

The precise nature of the permeability barrier offered by the various tissue layers of buccal mucosa was investigated in this study. It was observed that …

Evaluation Of 10-Fold Cross Validation And Prediction Error Sums Of Squares Statistic For Population Pharmacokinetic Model Validation, Shibani Harite

University of the Pacific Theses and Dissertations

It was the objective of the current study to evaluate the ability of 10-fold cross validation and prediction error sum of squares (PRESS) statistic to identify population pharmacokinetic models (PPKM) that were estimated from data without influence observations versus PPKMs from data containing influence observations. The evaluation of 10-fold cross validation and PRESS statistic from Leave-one-out cross-validation for PPK model validation was performed in 3 Phases. In Phase 1 model parameters (theta and clearance) were estimated for datasets with and without influence observations. It was found that influence observations caused an over-estimation of the model parameters.

Evaluating Cholesterol Screening In A Community Pharmacy, Osama Mohamed Ibrahim

University of the Pacific Theses and Dissertations

The purpose of this research project was to evaluate the role of the community pharmacist in screening, identifying, and referring ambulatory patients with high total blood cholesterol (TBC) in a community pharmacy. Fifty seven patients, out of 241 initially screened individuals, met the study inclusion criteria and were accepted into this study. Of these 57 patients, 51 patients completed the six month study period. The normal population group consisted of 164 participants with TBC < 200 mgjdL at the initial cholesterol testing (visit 1). The drop out group represented six patients who failed to continue attending the two follow up tests (visit 2 and 3). For screening purposes, a non-fasting whole blood sample was used to measure TBC using the Boehringer Mannheim Reflotron analyzer.

The project was evaluated based on mean TBC levels obtained during the initial screening and the two follow up tests, pre-test and post-test scores, behavior and …

Polyamine And Acetylpolyamine Levels During Phenylhydrazine-Induced Erythropoiesis In Mouse Spleen, Othman A. Alshabanah

University of the Pacific Theses and Dissertations

The phenylhydrazine-induced erythropoietic mouse spleen is used as a model system to demonstrate the relationship between tissue growth and polyamine metabolism. Phenylhydrazine produced significant changes in spleen weights, hematocrits and reticulocyte counts in Swiss-Webster mice. The average spleen weight went up from a control of 155 mg to 875 mg at 96 hours after phenylhydrazine administration, while a 49% reduction in the value of hematocrit was observed at 72 hours. Reticulocyte counts in peripheral blood went from 0.8 to 58% at 168 hours after treatment with phenylhydrazine. Phenylhydrazine at a dose of 40 mg/kg produced significant increases in the levels …

Investigation Of Physicochemical And Formulation Parameters For Transdermal Delivery Of Isoproterenol Hc1, Rajesh Arvindkumar Patel

University of the Pacific Theses and Dissertations

Effects of solubility, partition coefficient, pH and selected adjuvants (propylene glycol and Azone) on the percutaneous penetration of isoproterenol HC1 in vitro have been investigated using human cadaver skin. Preliminary stability studies demonstrated that isoproterenol HC1 was very stable (less than 1% decomposition) for 24 hours at 22(DEGREES) (+OR-) 0.5(DEGREES) in the pH range 1 to 7 in the following solvents: water, normal saline, propylene glycol and a series of propylene glycol-water mixtures (10,20,40 and 60% v/v). The rate of decomposition of the drug in aqueous solutions increased with pH beyond pH 8. In normal saline, the decomposition was significant …

Formulary Status Of Cephalosporins, Agnes J. Renault

University of the Pacific Theses and Dissertations

The primary purpose of this study is to analyze the formulary status of cephalosporins among a representative sample of hospitals in the United States. In addition, the research design attempts to determine the ranking of cephalsoporins in terms of acceptance to the hospitals' formulary and actual stocking of the cephaosoporin products. The study will attempt to ascertain the reasons for these rankings and the influence of DRG implementation, teaching status and hospital bed size on number of cephalosporins on formulary and in stock. This may yield insight into the strategies that hospitals are currently using to contain a significant proportion …

Design And Evaluation Of Theophylline Monitoring For Home Health Care Patients, May Naim Mikhail

University of the Pacific Theses and Dissertations

The purpose of this study was to design, evaluate, and determine the cost benefit of a pharmacokinetic service for home-based patients. Four randomly selected patient populations were used in evaluating the service for six months. The experimental group consisted of 17 patients who were under the care of family practice physicians in private practice and who received pharmacokinetic consultation and monitoring by a pharmacist as a home health care service. The retrospective control consisted of the same 17 patients of the experimental group whose past medical history for a period of six months was used. The concurrent control consisted of …

Opioid Receptor Effects Of Two Aminotetralin Derivatives In Guinea Pig Ileum Longitudinal Muscle And Mouse Vas Deferens Preparations, Francisca Fatima Matos

University of the Pacific Theses and Dissertations

Two substituted analogs of 3-amino-2,2-dimethyltetralin, namely 3-dimethylamino-7-hydroxy-2,2-dimethyl-1-tetralone HBr (J) and 3-dimethylamino-7-hydroxy-2,2-dimethyl-1-tetralol (MRSAL) were evaluated for opioid agonist and antagonist activity using the electrically-stimulated guinea pig ileum longitudinal muscle and mouse vas deferens preparations. The effects of these compounds in these tissues were compared to those induced by several opioid prototype agonists at mu, kappa and delta sites (normorphine, dihydromorphine, ethylketocyclazocine, U-50,488H, beta -endorphin, dynorphin 1-13, leu-enkephalin and DADLE) and one opioid antagonist (naloxone). The results of these experiments demonstrated that compound J inhibited contractions in a concentration-dependent manner as an opioid agonist and its effects were antagonized by naloxone in …

The Partial Purification And Characterization Of A Soluble Activator For The Sodium Adenosinetriphosphatase From Rat Cerebral Cortex And The Effect Of Cholinergic Agents, Thibaldo Javier Manrique Blanco

University of the Pacific Theses and Dissertations

In order for organisms to co-exist with nonliving matter, envelop to protect their delicate internal functions must be present. There are other reasons for this boundary to exist, e.g. to limit the volume occupied by the organism and to compartmentalize the contents of the organism so that certain critical concentrations may be easily maintained. Such envelopes are, of course, the cellular membranes. Membranes differ greatly between species, as well as within species. Given the complexity to which organisms have evolved, membranes have developed with a myriad of functions and components. It is easy to see differences between plant cellular membranes …

Factors Associated With The Clinical Outcome And Nephrotoxicity In Patients Treated With Gentamicin, Wen-Hwei Chen

University of the Pacific Theses and Dissertations

This study is designed to investigate via discriminant analysis the factors that are associated with the clinical outcome and nephrotoxicity in patients receiving gentamicin.

Computerized Formulation And Optimization Of Medicated Chewing Gum, Daniel J. Berky

University of the Pacific Theses and Dissertations

Sixty Four caffeinated chewing gum preparations were formulated by varying the amounts of (i) cinnamaldhyde, (0-0.75%), (ii) docusate (0-0.5%) and (iii) sucrose (40-60%). The gum base consisted of 33.33% yellow beeswax and 66.66% polyisobutylene MH, and was added, adjusting for a final weight of 2 grams per gum. The amount of caffeine was maintained at 100mg. The preparations were subjected to an in vivo release study as well as a hedonic survey with a panel of student volunteers.

Data were analyzed by using multiple linear regression on a mainframe computer. The resulting mathematical model was used to predict a theoretically …

Comparison Of Selected Radiopharmaceutical Chromatographic Quality Control Procedures, Lawrence Ray Andreatta

University of the Pacific Theses and Dissertations

The purpose of this study was to compare the accuracy and reproducibility of two commercially available chromatography kits with Instant Thin Layer Chromatography-Silica Gel (ITLC-SG) and Whatman Chromatography Paper. The two commercial kits evaluated were the- MAC Klt- produced-General Radioisotopes Products, and the TECH Kit by Ackerman Nuclear.

Pharmacognosy Of The Saururaceae : Microscopy Of Powdered Drugs, Prakash Vaman Mallya

University of the Pacific Theses and Dissertations

Plants of the family Sauruaceae are used in folk medicine in various parts of the world. Chemistry of some plants of this family and their chemotaxonomy has been investigated in our laboratory (12).

It is very difficult to establish identity and authenticity of commercially available crude drugs and powders of the Saururaceae because a detailed, collective study of microscopic features of these plants is not available. Original papers establishing plants of this family (see later) do not include microscopic features; they describe only gross morphologic and other classical features required for systematics. They are not useful for a pharmacologist in …

The Effect Of Selected Adjuvants On The In Vitro Percutaneous Penetration Of Benzocaine, See-Yan Lam

University of the Pacific Theses and Dissertations

This research project was designed to test whether the in vitro percutaneous penetration of benzocaine through human cadaver skin could be enhanced by dimethyl sulfoxide (DMSO), urea, polyoxyethylene (20) isohexadecyl ether and 1-dodecylazacycloheptan-2-one (Azone) in propylene glycol/water systems. Solubility and partitioning of benzocaine in propylene glycol/water systems was investigated. The adjuvant effects were studied in a 60/40 (V/V) propylene glycol/water co-solvent system. The well known drug penetration enhancer dimethyl sulfoxide did not enhance the penetration of benzocaine at any concentration level of DMSO under the conditions of the experiment. This lack of enhancement effect was probably due to increased solubility …

The Synthesis Of Various Substituted 3-Amino-7-Hydroxy-2,2-Dimethyltetralins And Their Opioid-Related Activities, David Alan Lippman

University of the Pacific Theses and Dissertations

A series of aminotetralones and aminotetralins were synthesized from the common intermediate F, 3-amino-2,2-dimethyl-7-methoxy- 1-tetralone. The final compounds derived from F were simple substituted and/or reduced analogues. The products would allow a progressive structure activity relationship to be drawn based on pharmacological testing.

The common intermediate F was synthesized utilizing a six step procedure starting with p-methoxyphenylacetic acid. The overall yield from the precursor to the F:HC1 was 25%. Compound F was either O-demethylated to form 3-amino-2,2-dimethyl-7-hydroxy-l-tetralone (I) or was dimethylated on the amine and subsequently O-demethylated to yield the 3-dimethylamino-7-hydroxy-2,2-dimethyl-l-tetralone (J). The last major modification was the reduction of …

Evaluation Of Drug Information Retrieval Services For Selected Investigational Antineoplastic Agents, Ali Al-Hasan A Al-Hefzi

University of the Pacific Theses and Dissertations

The availability of drug information that is useful to clinicians is an important need for those responsible for medication use in patients. Physicians, pharmacists, nurses, and patients routinely require access to relevant information related to rational drug therapy. The need for rapid access to relevant information has become increasingly important as the science, technology, and specialization within health care expand. Because of this expansion the literature has increased not only in size but also in complexity.

The term drug information (e.g., used in drug information service, drug information center or drug information specialist) is defined as "knowledge of facts or …

Regulation Of Protein Synthesis By Leucine And Amino Acid Balance., John Patrick Mcgowan

University of the Pacific Theses and Dissertations

The effects of a physiologically balanced mixture of amino acids on the synthesis of proteins has been investigated. The roles of leucine and tryptophan, both implicated in the regulation of protein synthesis, were also studied. The balance of amino acids is important under specific rate-limiting conditions; the physiological balance "protects" the protein synthesizing system from the stressed condition of leucine limitation. Leucine is an important regulator of protein synthesis and the tryptophan effect on translation is dependent on the concentration of leucine. Thus tryptophan is a secondary regulator. The relative concentration of amino acids, described as balance, alterned the synthesis …