Pharmacy and Pharmaceutical Sciences Commons^™

Small Molecules Binding To Serpins, Junaid Afridi

Theses and Dissertations

Serpins are a unique breed of proteins due to their enzymatic mechanism. Two systems were closely monitored during fluorescent binding studies, the ACT-CHY along with the AT:TRY interaction. Four different conformational variants of each system were studied including the native, cleaved, latent and complex forms. Three different fluorescent dyes were used to identify the conformations including ANS, TNS, and bis-ANS. SI studies and protease assays utilizing both Suc-AAPF-pNA and L-BAPNA were instrumental in determining conformations along with gel electrophoresis studies. The hydrophobic dyes bound to the different serpins with varying KD and ΔFmax due to structural variations among the conformers …

Green Engineering And Gate-To Gate Life Cycle Assessments For Pharmaceutical Products, Daniel Fichana

Theses and Dissertations

The research of this thesis focused on the environmental and processing metrics during the development of two different drugs. Previous research in life cycle assessments and green engineering have focused on other products and processes, but only a limited amount of studies have been conducted for pharmaceutical applications. This analysis concerned a gate-to-gate analysis of two distinct pharmaceutical products along with the development of a solvent selection table. The goal of this research was to determine how various processing and environmental metrics were affected by process improvements.

The first drug was the pravastatin, which was made via a fermentation route. …

Clinical Pharmacology Of Ms-275, A Histone Deacetylase Inhibitor, Milin R. Acharya

Theses and Dissertations

The goal of this escalating single-dose phase I research study was to determine the safety, tolerability, pharmacokinetics, pharmacodynamics as well as in vitro metabolism and plasma protein binding of MS-275, a novel histone deacetylase inhibitor, in patients with solid tumors and lymphomas. A validated LC/MS assay was developed to quantitate MS-275 in plasma, human liver microsomes and urine. The pharmacokinetic (PK) evaluation was done using a non-compartmental approach. In-vitro plasma protein binding profile of MS-275 was characterized by a validated micro-equilibrium dialysis method. In vitro phase I and phase II hepatic metabolism of MS-275 were evaluated using human liver microsomes. …

The Influence Of Direct-To-Consumer Advertising: Who Will Talk To Their Doctor As A Result Of Prescription Drug Advertisement?, Hai Dubo Chen

Theses and Dissertations

OBJECTIVES: To identify the types of patients who talk with their physicians as a result of Direct-to-Consumer (DTC) advertising. METHODS: Data were taken from a national survey, "Public Health Impact of Direct-to-Consumer Advertising of Prescription Drugs, July 2001- January 2002", conducted by researchers from Harvard Medical School. Participants (n = 3000) were interviewed by telephone. We constructed a conceptual framework consisting of outcomes (3 types of physician visits), intervention (DTC experience) and five groups of explanatory factors (health beliefs, demographics, health status, socioeconomic status and market factors). Data were analyzed with three multivariate stepwise logistic regressions. The three dependent variables …

Evaluation Of The Pharmacokinetic-Pharmacodynamic Relationship, Metabolism And Plasma Protein Binding Of The Novel Antitumor Agent, 2-Methoxyestradiol (2me2), Following Oral Administration In Patients With Solid Tumors., Nehal Jagdish Lakhani

Theses and Dissertations

The goal of this study was to determine safety, tolerability and pharmacokinetics of 2ME2 in patients with solid tumors and determine maximum tolerated dose (MTD). The following hypotheses were tested: 1) 2ME2 will be well tolerated in clinic when given orally and will have quantifiable effects on the ex vivo markers of angiogenesis and apoptosis; 2) 2ME2 will exhibit linear pharmacokinetics; 3) Plasma protein binding will be extensive and linear; 4) Sulfation will be the major metabolic pathway for 2ME2.This was a phase I dose escalation study. Twenty patients with refractory solid tumors were enrolled. 2ME2 was administered orally starting …

A Nomogram For Valproic Acid And The Effect Of Missed Doses, Alaa M. Ahmad

Theses and Dissertations

Background. Clinicians are divided on dosing recommendations when a dose is delayed or missed. For a neuropsychiatric agent like valproic acid (VPA), rational dosing recommendations are of particular importance. VPA is subject to therapeutic monitoring using total concentrations. Due to non-linear binding of VPA to plasma proteins, current dose titration schemes for VPA are empirical. The objectives of this research were to 1- study the effect of missed/delayed doses on steady state concentrations of VPA and 2-design a nomogram that can be used for dose titration based on total VPA concentrations. Methods. 1- A simulation study was conducted to test …

Kinetics And Mechanisms Of Macromolecular Disposition In The Rat Lung, Masahiro Sakagami

Theses and Dissertations

The kinetics and mechanisms of macromclecular absorption from the airways of the rat lung were studied in vivo and in vitro, following identical solute administration methods. The isolated perfused rat lung (IPRL) was used as an in vitro model, and the disposition of 7.4 and 4.3 kDa fluorophore-labeled polyhydroxyethylaspartamide (F-PHEA) and other small and macromolecular reference solutes was investigated across doses and in the presence of a variety of biochemical inhibitors.

Absorption profiles of F-PHEA, and the solute's lung distribution at different times after administration, were statistically identical in vivo and in vitro, showing that the IPRL possessed a viable …

Adenosine 3', 5'-Cyclic Monophosphate Activation Of Islet Chloride Channels, Anjali Varandani

Theses and Dissertations

The objective of this thesis was to understand the regulation of islet Cl⁻ current by cAMP. This current, known as I_cl,islet flew is the first Cl⁻ channel current characterized in pancreatic �� cells. I_cl,islet has been hypothesized to modulate insulin secretion through changes in islet electrical activity. Both 5 ��M forskolin and 100 ��M IBMX (3-isobutyl-1-methylxanthine), agents that increase intracellular cAMP, were shown to activate an outwardly-rectifying ionic current in HIT cells that closely resembled I_cl,islet. The current was blocked when iodide was substituted for external Cl⁻ or when the Cl⁻ channel blocker niflumic acid was …

Physical And Chemical Stability Of Spray Dried Sugars And Protein-Sugar Molecuiar Mixtures For Inhalation, Venkatesh Naini

Theses and Dissertations

The feasibility of producing inhalable microparticles of sugars and protein-sugar molecular mixtures using spray drying was investigated as an alternative to conventional micronization techniques. Four sugars; lactose (L), trehalose (T), sucrose (S) and mannitol (M) were spray dried using a commercial bench-top spray dryer and their physicochemical stability, with respect to particle size, moisture uptake and crystallinity changes, investigated after storage at 23%, 52%, 75% and 93% relative humidity (RH) and 25 °C for 30 days. Two crystalline size fractions (“coarse” = 125-212 μm and “fine” = 44-74 μm) of each sugar, were also characterized, as possible replacements for lactose …

Pharmacokinetics And Pharmacodynamics Of Ethanol In Healthy Volunteers: Effects Of Input-Rate And Degree Of Ethanol Exposure On Subjective And Objective Measures Of Impairment, Vijay A. Ramchandani

Theses and Dissertations

The goal of this project was to investigate the effect of input-rate (oral and intravenous) and degree of exposure on the pharmacokinetics of ethanol and on subjective and objective measures of impairment, as well as on the development of acute tolerance to the effects of ethanol in young, healthy volunteers.

The primary objective of this research was to test the following hypotheses: 1) the rate and degree of ethanol exposure (oral and intravenous) in normal healthy males and females affect the pharrnacokinetics (PK) and pharmacodynarnics (PD) of ethanol in a non-linear fashion; 2) the EEG changes after ethanol administration correlate …

Evaluation Of Cannabinoid Receptor Interaction Of Anandamide, The Endogenous Cannabinoid Receptor Ligand, Irma Bateman Adams

Theses and Dissertations

Recent evidence implicates anandamide as the endogenous ligand for the cannabinoid receptor. One purpose of this study was to determine the structural requirements for anandamide's receptor interaction and the influence of phenylmethylsulfonyl fluoride (PMSF), an enzyme inhibitor, on receptor affinity. A second objective was evaluation of the correlation between affinities of the analogs and in vivo pharmacological activities. The ability of anandamide and analogs to displace [3H]- CP 55,940 was determined by a filtration assay. Displacement curves for anandamide in the presence of PMSF produced a Ki of 89 ± 10 nM; without PMSF the Ki increased to 5400 ± …

Evaluation Of Quantitative Electroencephalography For Assessment Of Central Nervous System Stimulant Response, Patricia W. Slattum

Theses and Dissertations

The objective of this investigation was to evaluate quantitative electroencephalography (EEG) as a measure of CNS stimulation. The reproducibility and sensitivity of quantitative EEG was compared to neuroendocrine, mood, and psychomotor performance measures.

The study was conducted in two parts. The first part investigated the inter- and intra-individual variability associated with a series of pharmacological response measures under baseline (no drug) conditions. It was an open-label pilot study in which eight healthy male volunteers underwent a series of tests (EEG, visual continuous performance task (CPT), a finger tapping task, and self-rated mood scales) repeated eight times over a 12 hour …

A Procedure For Performance Assessment Of Drugs Hypothesized To Be Effective In Controlling Motion Sickness, Zainab N. Ahmed

Theses and Dissertations

The Air Force Institute of Technology (AFIT) is conducting research into the effectiveness of certain drugs for controlling motion sickness. If the drugs are found to be useful, they must still be proven to have no harmful effects on the operator's performance abilities. There are many methods for assessing performance effects of drugs but very little standardization exists. The Unified Tri-Services Cognitive Performance Assessment Battery (UTC-PAB) is a performance assessment method designed to be used by all military branches. This will encourage standardization of drug testing, exchange of data, and comparability of methods. Five tests were chosen from the UTC-PAB …

Development Of The Analytical Methodology For Pyrimethamine And Its Application To Studies Of Partitioning And Binding In The Subcompartments Of Blood, Anita C. Rudy

Theses and Dissertations

An original HPLC assay was developed for pyrimethamine (PYR) in plasma, RBCs, and buffer for the purpose of studying its plasma protein binding and RBC partitioning.

Equilibrium dialysis (ED) was used to study protein binding. Isotonic phosphate buffer used in ED did not prevent small volume shifts. The pH of the plasma affected the protein binding of PYR although it was not significant for the comparison of binding at pH 7.4 vs. 8.0. PYR at 1000 ng/ml averaged 93.1% bound to plasma proteins. Binding to pure human albumin was 86.5% at lower levels of albumin and PYR (350 ng/ml). There …

Alternative Pharmacokinetic Models In End Stage Renal Disease During Continuous Ambulatory Peritoneal Dialysis, Eugenio Cefali

Theses and Dissertations

An important principle of pharmacokinetic modeling is to use the least complicated model possible that adequately describes the process studied. Pharmacokinetic studies in peritoneal dialysis often attempt to describe the time course of drug concentration in the dialysate. Peritoneal dialysis patients are subjected to the inconvenience and risk of infection associated with sampling peritoneal fluid. Alternative pharmacokinetic models were used to study drug distribution during continuous ambulatory peritoneal dialysis (CAPD). Efficient pharmacokinetic models of distribution in the peritoneal cavity were described for three drugs and the classes they represent.

Procainamide pnarmacokinetics were determined in six CAPD patients. The time course …

Evaluation Of Analytical, Pharmacokinetic And Pharmacodynamic Methods For The Study Of Digoxin, Santosh John Vetticaden

Theses and Dissertations

The primary objective of the research was to investigate the pharmacodynamics of digoxin in dogs. Initially an assay specific for digoxin in the presence of its major metabolites, viz., digoxigenin, digoxigenin mono-digitoxoside, digoxigenin bis-digitoxoside and dihydrodigoxin was developed using HPLC-RIA. Methodology for non-invasive measurement of left ventricular ejection time (LVET) and other systolic time intervals (STI) in beagle dogs were developed. This involved surgery for exteriorization of the carotid artery in the dogs and subsequent measurements of LVET and STI after recovery. STI, heart rate (HR) and digoxin levels were monitored in normal beagle dogs administered 0.05 mg/kg or 0.025 …

Synthesis Of Mesoionic Nucleosides As Potential Antineoplastic Agents, Shanaz Mohammedali Tejani

Theses and Dissertations

During the past few decades, analogs of purine nucleosides have been described that are modified either in the heterocyclic base, sugar moiety or both, and many of these modified nucleosides display antiviral and/or antineoplastic activity. The Class II mesoionic purinones are isosteric with their non~mesoionic purinone counterparts. It is conceivable that the mesoionic purinone nucleosides might constitute an entirely novel class of modified nucleosides with potential chemotherapeutic activity. That the mesoionic heterobases are bioisosteric as well as isosteric with non-mesoionic purinones was realized by demonstrating that certain mesoionic xanthine derivatives, such as Anhydro-8-ethylw-5-hydroxy-7-oxo-l,3,4-thiadiazolo[3,2-a]pyrimidinium hydroxide and Anhydro-6-p-chlorobenzyl-8-ethyl-5-hydroxy-7-oxo—l,3,4—thiadiazolo [3,2-a]pyrimidinium hydroxide were comparable …

Synthesis Of 3-(Substituted-Aryl)-1,2,3,4-Oxatriazolium-5-Olates As Potential Hypotensive Agents, Mary Quinn Lund

Theses and Dissertations

Hypertension or high blood pressure is a major cause of illness and death in the United States today.^1,2 An estimated thirty-six million people suffer from this disease.³ Prolonged hypertension and its attendant strain on various organs may cause heart failure, brain stroke or kidney damage.⁴ Usually, a pressure of 140/90 mm Hg is taken to be the dividing line between normotension and hypertension.^5,6

The hypertensive condition is generally characterized as either primary (essential) hypertension or secondary hypertension.¹ A specific cause can be identified in secondary hypertensive patients, such as, pheochromocytoma or adrenal tumor. These causes …

Synthesis And Biological Evaluation Of Sparsomycin Analogues, Scherer Preston Sanders

Theses and Dissertations

In 1962, Owen, Dietz, and Camiener reported the isolation of a new antitumor antibiotic from the culture filtrate of Streptomyces sparsogenes. The structure of the crystalline antibiotic, named sparsomycin, remained elusive until 1970, when Wiley and MacKellar reported results of spectroscopic and degradation studies which elucidated the structure. In addition to the molecular structure, investigators have examined the mechanism of action, toxicity, and related analogues, striving to establish sparsomycin or a synthetic analogue's usefulness as an effective chemotherapeutic agent.

The initial pharmacological evaluation of sparsomycin revealed it possessed activity against KB human epidermoid carcinoma cells, a variety of gram-negative and …

Interactions Of Ethanol And Methadone, Vijay Aggarwal

Theses and Dissertations

The effects of ethanol administration on the antinociceptive activity, lethal properties and brain concentration of methadone, were investigated. The effect of ethanol on the antinociceptive activity of methadone was assessed by the hot-plate and tail-flick tests. Concentrations of methadone in the brain were determined by the use of 3H-methadone as well as by gas liquid chromatographic analysis. The study showed that moderate doses of ethanol did not alter tail-flick or hot-plate response by themselves. However, when combined with methadone, ethanol produced a significant increase in the antinociceptive effectiveness of methadone as measured by both a decrease in the ED50 of …

Prostaglandin Synthesis In The Feline Adrenal Cortex, Suzanne Gale Laychock

Theses and Dissertations

Studies were carried out on the feline adrenal gland to ascertain the role of prostaglandins in the mechanism of action of ACTH. Using tritiated arachidonic acid as a prostaglandin (PG) precursor , it was demonstrated by column and thin layer chromatography techniques that isolated trypsinized adrenocortical cells possess an active PG synthetase capable of synthesizing radiolabeled PGE, PGF, and PGA/B-like substances. Concentrations of ACTH (125 - 250 _μU) which stimulate steroidogenesis enhanced the conversion of radiolabeled arachidonic acid to PGE, PGF and the PGA/B products extracted from cortical cells and incubation media.

PG biosynthesis by isolated cortical cells was …

The Relationship Of The Sixteen Personality Factor Questionnaire Inventory To Clients Of A Methadone Maintenance Program, Margaret Ann Neale

Theses and Dissertations

An original study was undertaken to examine the relationship of clients of Project Jump Street, Inc., a methadone maintenance program, to changes in personality factors as measured by R.B. Cattell's Sixteen Personality Factor Inventory, to compare the national norms of drug addicts/methadone users to the result of the 16 PF of clients of Project Jump Street, Inc., and to determine if significant differences appear among treatment phase I, phase II, and phase III.

Twenty-one clients of the program, seven subjects in each of phases I, II, and III, were given the 16 PF by their counselors between September 10 and …

Synthesis And Evaluation Of Some Arylalkenyl And Arylepoxyalkyl Hydrogen Succinates And Hydrogen Glutarates As Inhibitors Of Rat Liver Β-Hydroxy-Β-Methylglutaryl Coenzyme A Reductase, Paul Emil Marecki

Theses and Dissertations

Atherosclerotic disease is an almost universal phenomenon and increases in severity and frequency with increasing age. Atherosclerosis may contribute to several disorders including bursting of an artery, blockage of an artery, or induction of arterial clotting. The culmination of these diseases is usually premature since at the time of death the unaffected organs are in reasonably satisfactory condition and could have operated for several more years. Among the many factors which act in concert to produce the disease, serum cholesterol levels play a central role. It has been suggested that the lowering of cholesterol levels will provide an effective means …

Inhibition Of Cell Division, Protein Synthesis And Nucleic Acid Synthesis In Escherichia Coli W By Tetracycline Antibiotics, George Henry Miller

Theses and Dissertations

Tetracyclines, originally isolated in the late 1940's and early 1950's from the mycelium of Streptomyces, have achieved major importance as therapeutic and prophylactic agents against a wide range of infections in human and veterinary medicine. They have also achieved great importance in agriculture where they are widely used to promote weight gain in livestock. Commercial production, during 1958 in the United States alone was 120 tons with a value of approximately $1 million per ton.

The clinical importance of these compounds has stimulated efforts to define their mode of action as inhibitors of bacterial reproduction. Antibiotics having as many functional …