Pharmacy and Pharmaceutical Sciences Commons^™

Dissolution Testing Of Prednisone And Salicylic Acid Calibrator Tablets At Different Tablet Locations, Anandhavalavan Arulmozhi

Theses

Dissolution testing is routinely carried out in the pharmaceutical industry to determine the rate of dissolution of solid dosage forms. This test is one of the several tests that pharmaceutical companies typically conduct on oral dosage formulations (e.g., tablets) to determine compliance. The USP Dissolution Testing Apparatus 2 is the most common of the apparatuses listed in the USP. However, it has been shown previously that the dissolution profile of a tablet undergoing dissolution in the USP Dissolution Apparatus 2 can be affected by the tablet location in the apparatus.

In this work, the dissolution rates of both non-disintegrating tablets …

Dissolution Of Disintegrating Solid Dosage Forms In A Modified Dissolution Testing Apparatus 2, Shrutiben Rameshbhai Parekh

Theses

Dissolution tests are routinely carried out in the pharmaceutical industry to determine the dissolution rate of solid dosage forms. Dissolution testing serves as a surrogate for drug bioavailability through in vitro–in vivo correlation (IVIVR), and it additionally helps in guiding the development of new formulations and in assessing lot-to-lot consistency, thus ensuring product quality. The United States Pharmacopoeia (USP) Dissolution Testing Apparatus 2 is the device most commonly used for this purpose. Despite its widespread use, dissolution testing using this apparatus remains susceptible to significant error and test failures. There is documented evidence that this apparatus is sensitive to several …

Transdermal And Transbuccal Delivery Of Lidocaine And Nicotine : Combined Effects Of Iontophoresis And Chemical Enhancers, Ran Wei

Theses

This study focused on the effects of iontophoresis and chemical enhancers on drug release. The transport of Lidocaine HCl (LHCl) and Nicotine Hydrogen Tartrate (NHT) through the skin and mucosa was evaluated for potential clinical applications. These two potential delivery routes have the advantage of avoiding first-pass effect. Samples were pretreated with enhancer solutions for one hour before the experiments. Passive or 0.3 mA iontophoresis-assisted drug diffusion was conducted for 8 hours to monitor the cumulative amount of drug released. Graphical methods and mathematical optimization techniques were implemented to analyze the data. The effects of chemical enhancers on the delivery …

Pharmacokinetic And Pharmacodynamic Studies Of A Novel Spectinamide Series Of Antituberculosis Agents, V. N. R. Pavan Kumar Vaddady

Theses and Dissertations (ETD)

Spectinamides are novel amide derivatives of the antibiotic spectinomycin that have emerged as a new class of agents to treat tuberculosis. These agents showed potent in vitro activity against Mycobacterium tuberculosis (MTB) compared to spectinomycin and in a preliminary in vivo study in interferon gamma (IFN‑γ) knockout mice, spectinamide Lee1329 reduced the lung bacillary load of TB comparable to streptomycin. We hypothesized that the application of an iterative pharmacokinetics and pharmacodynamics (PK/PD) guided approach would facilitate the optimization of these lead compounds suitable for further development.

A series of in vitro experiments including parallel artificial membrane permeability assay (PAMPA), microsomal …

Rna Interference For Improving The Outcome Of Islet Transplantation And Polymeric Micelle‑Based Nanomedicine For Cancer Therapy, Feng Li

Theses and Dissertations (ETD)

Ex vivo gene transfer has been used to improve the outcome of islet transplantation for treating type I diabetes. RNA interference is an effective approach for reducing gene expressions at the mRNA level. The application of RNA interference to improve the outcome of islet transplantation was reviewed in Chapter 2, where I summarized biological obstacles to islet transplantation, various types of RNAi techniques, combinatorial RNAi in islet transplantation, and different delivery strategies.

Upregulation of inducible nitric oxide synthase (iNOS) and subsequent product of radical nitric oxide (NO) impair islet β cell function. Therefore, we hypothesized that iNOS gene silencing could …

The Design And Synthesis Of Autotaxin Inhibitors And Analogs Of Lysophosphatidic Acid, Renuka Niranjan Gupte

Theses and Dissertations (ETD)

Lysophosphatidic acid (LPA) is a naturally occurring bioactive phospholipid. It has a wide array of biological effects like cell proliferation, survival, migration, apoptosis invasion, wound healing and angiogenesis. Autotaxin (ATX) was identified as an autocrine tumor cell motility factor from A2058 melanoma conditioned medium. ATX has lysophospholipase D enzyme activity and is responsible for the cleavage of lysophophatidylcholine (LPC) leading to the generation of LPA. Antagonists of Autotaxin would have a potential therapeutic application in cancer research. Chapter 1 is an introduction of LPA and autotaxin. It provides the background and significance of the research. Chapter 2 explores the synthesis …

Development And Evaluation Of Paclitaxel-Loaded Liposomal Formulations For Targeted Drug Delivery To Breast Cancer, Vinayagam Kannan

Theses and Dissertations (ETD)

The objective of this work was to develop and evaluate paclitaxel-loaded liposomal formulations for targeted drug delivery to breast cancer. The liposomal formulation was optimized to maximize drug loading and physical stability. Cholesterol and saturated lipid content showed a negative influence on paclitaxel loading. Short-term stability studies showed that optimum drug-lipid ratio is necessary for adequate physical stability. Biodistribution studies in mouse xenografts bearing MDA-MB-231 breast cancer using near infrared fluorescence imaging showed that the accumulation of tumor vasculature targeted long-circulating liposomes (LCL) in the tumor was significantly less than non-targeted LCL at 48 h. The accumulation of these liposomes …

Development And Evaluation Of Therapeutics In The Setting Of Radiation Injury, Karin Emmons Thompson

Theses and Dissertations (ETD)

The possibility of an incident involving radiation exposure is at the forefront of public attention in the current global environment. With a greater number of entities possessing nuclear weapons and increased demand for nuclear power, the concern for uncontained exposure to radiation is increasing. In light of these developments, the need for treatments that may be easily stored and administered to large numbers of people who have been exposed to high doses of total body irradiation (TBI) is more urgent than ever before.

Our goal was to identify and develop novel, drug-like small molecules that would exhibit radiomitigating activity for …

Design Of Lipid And Polymeric Carriers For Nucleic Acid Delivery, Lin Zhu

Theses and Dissertations (ETD)

The objectives of the study were to investigate and develop lipid and polymeric carriers for nucleic acid delivery. These included: i) to develop novel cationic lipids for plasmid, oligonucleotide, and siRNA delivery; ii) to develop a novel polymeric delivery system, polyethylene glycol (PEG) based bio–conjugate, for oligonucleotide delivery; iii) to develop a novel bio–conjugate delivery system for siRNA delivery.

In Chapter 2, we discussed the barriers and strategies of nucleic acid delivery, as well as summarized the commonly used lipids, polymers, and the corresponding carriers in terms of their characteristics, applications, advantages and limitations.

Cationic lipids are most commonly used …

Preliminary Studies Into Dna Binding Capabilities Of Ruthenium Nitro Nitrosyl As Anti-Tumor Pro-Drugs, Natasha Hansson

Seton Hall University Dissertations and Theses (ETDs)

The complex [Ru(bpy)z(NO)(N02)](PF6)2 was investigated as a potential anti­ tumor drug option. The nitrosyl group was displaced by reaction with azide ion in acetone to yield the solvento complex in situ. The products isolated from addition of a solution or slurry of guanine, adenine, cytosine or thiamine to the resulting [Ru(bpy)(N02)(acetone)t were investigated by electronic absorption spectroscopy, infra­ 1 red spectroscopy, H NMR spectroscopy and cyclic voltammetry. The results of the studies showed that guanine, adenine and thiamine form adducts with Ru(bpy)z(N02)(acetone)t. However, each base forms a unique complex as shown by electronic spectroscopy. Guanine is the strongest field ligand, …

Minimum Agitation Speed For Solid Suspension And Mixing Time In A Torispherical -Bottomed Pharmaceutical Stirred Tank Under Different Baffling Conditions, Dilanji Bhagya Wijayasekara

Theses

The minimum agitation speed, NS, required to just suspend solid particles dispersed in water was experimentally determined in this work for a glass-lined type of mixing tank provided with a torispherical bottom and agitated with a retreat-blade impeller under different baffling configurations. Ns for the same tank but equipped with a different agitation system, namely an axial impeller, was also experimentally determined for the purpose of comparing of performances of the two systems. The effect of impeller off- bottom clearance and the vessel's liquid level on the minimum agitation speed were also experimentally studied. Njs, was experimentally determined …

Discovery Of Quinic Acid Derivatives As Oral Anti-Inflammatory Agents, Kui Zeng

Theses and Dissertations (ETD)

Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. Cat’s claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB). Herein, we described the synthesis and biological testing of novel QA derivatives. Inhibition of NF-κB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-κB response element. A549- NF-κB cells were stimulated with TNF-α (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP activity. Amide substitution at …

Tdiscovery And Development Of Novel Therapeutic Agents For Advanced Melanoma, Zhao Wang

Theses and Dissertations (ETD)

Malignant melanoma is the most dangerous form of skin cancer and accounts for about 75% of skin cancer deaths. Once diagnosed at the metastatic stage, it has a very poor prognosis with a median survival rate of 6 months and a 5-year survival rate of less than 5%. In addition, melanoma has become an important public health hazard owing to its rising incidence, which has been well documented over the past 50 years. Currently there is no effective way to treat melanoma. It is highly resistant to existing chemotherapy, radiotherapy, and immunotherapy. Over the past 30 years, only two drugs …

Experimental Investigation Of Mixing Time In A Stirred, Torispherical-Bottomed Tank Equipped With A Retreat-Blade Impeller, Nonjaros Chomcharn

Theses

Glass-lined reactors are typically used in the pharmaceutical and specialty chemicals industries because of their material compatibility with most reactants and their cleanability. These reactors are typically equipped with a retreat-blade impeller placed close to the bottom of the tank a single baffle mounted from the top. The mixing performance of such reactors has not received significant attention in the literature, despite their ubiquitous presence in the pharmaceutical industry. In particular, mixing time, i.e., the time required by the system to achieve a predefined level of homogeneity, has not been studied to any significant degree.

In this work, the mixing …

Mixing Performance Of A Novel, Continuous Confined Impinging Jets Mixer Using Competitive Reactions, Han Zheng

Theses

In this work, a novel continuous flow apparatus featuring the impingement of fluid jet streams in the presence of ultrasonic energy provided by an ultrasonic probe was tested using competitive reactions in order to determine its mixing effectiveness. The ultrasonic energy enhances micromixing of the fluid jet streams, which results in an overall mixing effectiveness improvements in different physical and chemical processes.

In the competitive reactions system used here (third Bourne reaction), one stream containing sodium hydroxide was continuously fed to the first impinging jet, while an aqueous solution of hydrochloric acid and ethyl chloroacetate was fed to the second …

A Pharmacokinetics And Pharmacodynamics (Pk/Pd) Guided Approach To Lead Optimization Of Nitrofuranylamide Anti-Tuberculosis Agents, Nageshwar Rao Budha

Theses and Dissertations (ETD)

Currently used treatment strategies for tuberculosis (TB) involve administration of multiple drug combinations for a minimum of 6-9 months. However, these prolonged regimens do not always achieve sterilization, as evidenced by post-therapy relapse in a subgroup of treated individuals. In an effort to develop novel therapeutic agents for TB a new class of chemical agents, nitrofuranylamides, is being developed at the University of Tennessee Health Science Center. We hypothesized that the application of an iterative pharmacokinetics and pharmacodynamics (PK/PD) guided approach would facilitate the optimization of nitrofuranylamide lead compounds suitable for further development.

First, we examined the biopharmaceutic properties and …

Preparation Of Nanovehicles For Targeted Drug Delivery, Anagha Avinash Bhakay

Theses

Application of nanotechnology in pharmaceutical research has opened new frontiers for drug development and its efficient delivery. In recent years, the focus of the research has been on the engineering of nano/micro-particulate structures for efficient and targeted delivery of drugs for selective and enhanced absorption. This work throws light on the preparation of biodegradable and non-toxic nanoparticulate systems for targeted drug delivery. The drug vehicles were made by two different processes namely electrostatic interactions and desolvation process. The drug carriers made by these processes were found to be in the size range of 150-200nm which is necessary for cellular uptake …

Cytotoxic Effects Of Ruthenium Compounds On Human Cancer Cell Lines., Katie Beth Brown

Electronic Theses and Dissertations

Chemotherapy is the most common cancer treatment. Traditionally, platinum-based drugs are used in chemotherapy. More recently, researchers have focused on ruthenium based compounds as a substitute for the platinum compounds. Ruthenium-based compounds appear to be less toxic to healthy cells than traditional platinum-based compounds. In this study, 7 ruthenium-based compounds were tested on HT-29 (colon) and MCF-7 (breast) human cancer cell lines with the specific aim of determining whether or not any of the ruthenium-based compounds exhibited cytotoxic properties. In addition, levels of vascular endothelial growth factor (VEGF) production were tested in supernate from the cancer cells treated with various …

Controlled Release Of Insulin And Modified Insulin From A Novel Injectable Biodegradable Gel, Om Anand

Theses and Dissertations (ETD)

The objective of the study was to develop a controlled release dosage form of
insulin, which can provide basal concentrations of insulin in diabetic rats for 1 to 2 weeks after a single subcutaneous injection.
A biodegradable injectable drug delivery gel was prepared by dissolving a
biodegradable polymer, polylactic-co-glycolic acid (PLGA), in biocompatible
plasticizer(s), triethyl citrate (TEC) and/or acetyl triethyl citrate (ATEC). Insulin was
then loaded into the blank gel to form an insulin suspension in the polymer solution.
After the insulin-loaded gel was injected subcutaneously, the plasticizer(s) dissolved in the aqueous media and were gradually taken away from the …

Structure- And Ligand-Based Design Of Novel Antimicrobial Agents, Kirk Edward Hevener

Theses and Dissertations (ETD)

The use of computer based techniques in the design of novel therapeutic agents is a rapidly emerging field. Although the drug-design techniques utilized by Computational Medicinal Chemists vary greatly, they can roughly be classified into structure-based and ligand-based approaches. Structure-based methods utilize a solved structure of the design target, protein or DNA, usually obtained by X-ray or NMR methods to design or improve compounds with activity against the target. Ligand-based methods use active compounds with known affinity for a target that may yet be unresolved. These methods include Pharmacophore-based searching for novel active compounds or Quantitative Structure-Activity Relationship (QSAR) studies. …

Synthesis And Evaluation Of Tetramic Acids As Antimicrobial Agents, Jason B. Wilson

Theses and Dissertations (ETD)

As bacterial infectious diseases are a major cause of morbity and mortality throughout the world, and many causative organisms are resistant to currently available antibiotics, the motivation for the development of new drugs is readily apparent. A number of natural products exhibiting antimicrobial activity possess a tetramic acid (2,4-pyrrolidinedione) functional group. As their antibacterial mechanism of action is different from that of many of the currently available antibiotics, these compounds have potential to serve as a basis for a pharmacophore in synthetic compounds. However, toxicity to eukaryotic cells is frequently a problem with currently known tetramic acids. The purpose of …

Oxidative Stress-Mediated Anticancer Activity Of Novel Ahr Modulators Af & 5f203, Lancelot S. Mclean

Loma Linda University Electronic Theses, Dissertations & Projects

Estrogen receptor positive (ER+) breast cancer tends to respond to anti-estrogen agents such as Tamoxifen. Approximately 40% of ER+ breast cancer is resistant to these agents and those that initially respond often acquire resistance. Estrogen receptor negative (ER-) breast cancer remains largely unresponsive to these agents. It is therefore vital to discover drugs that are potent in both forms of breast cancer. Aminoflavone, (5-amino-2, 3-fluorophenyl)-6,8-difluoro-7-methyl-4H-l-benzopyran-4-one; AF; NSC 686288) and 5F203, (2-[-Amino-3-methy phenyl]-5-flurobenzothiazole) are novel anticancer candidate agents that display potent in vitro and in vivo anti-proliferative activity against select human tumor cells with a unique anticancer activity profile in the …

Experimental Investigation Of The Fluid Velocity Distribution In Stirred Tank Reactors Equipped With Retreat-Blade Impellers Using Laser Doppler Velocimetry, Deepak Rajesh Madhrani

Theses

Stirred tank reactors are commonly used in the pharmaceutical industry for synthesis of Active Pharmaceutical Ingredients (API's) and their intermediates. Typically, these vessels are glass-lined and are provided with a single retreat-blade glass-lined impeller and a single baffle. Despite their ubiquitous utilization in the pharmaceutical industry for at least the past 40 years, the mixing characteristics of these systems have not been studied to any great extent, making it difficult to predict mixing performance in any given operation.

In this work, the velocity distribution inside the typical glass-lined vessel/impeller system was experimentally quantified using Laser Doppler Velocimetry (LDV), which is …

Design, Synthesis, And Evaluation Of Small Molecules In The Discovery Of Novel Antimicrobial Agents, Kimberly D. Grimes

Theses and Dissertations (ETD)

The increasing prevalence of antibiotic-resistant bacteria, including Mycobacterium tuberculosis, Streptococcus pneumoniae, Staphylococcus aureus, and Enterococcus faecalis, pushes us to discover new antibacterial agents to maintain adequate patient coverage. This body of work highlights the use of medicinal chemistry methodologies that encompass cross-disciplinary fields of study. Chapter 1 gives an introduction to the antibacterial drug targets, resistance, and how scientists are working to overcome obstacles encountered with drug-resistant bacteria. It also details modern medicinal chemistry applications in antimicrobial drug discovery. Chapter 2 details the use of a structure-guided library approach to drug design, in which large virtual libraries against the target …

Flavonoids And Related Compounds As Nucleoside Transporter Inhibitors, Surekha Ravaji Pimple

Theses and Dissertations (ETD)

Mammalian nucleoside transporters can be classified into two main categories, namely, equilibrative nucleoside transporters (ENTs) and concentrative nucleoside transporters (CNTs). ENTs are ubiquitous, and mediate sodium-independent bi-directional facilitated diffusion nucleoside transport processes. CNTs on the other hand, are secondary active unidirectional transporters that are sodium-dependent. Both the equilibrative and the concentrative nucleoside transporters have several family members which are ENT1 to ENT4 and CNT1 to CNT6. Over the past two decades, important advances in the understanding of nucleoside transporter functions have been made. Identification and molecular cloning of the ENT and CNT families from mammals and protozoan parasites have provided …

Ultra-Fine Particle Formation Using Principle Of Rapid Expansion Of Supercritical Solutions`, Miraj Minesh Sheth

Theses

There are indications in the chemical and pharmaceutical industries that the reduction in size of a crystalline particle can lead to better performance of the drug compound, particularly for water insoluble drugs, in the final dosage form. Many particle formation techniques have been investigated in recent years by researchers to obtain desired particulate sizes and size distributions. Supercritical fluid technologies have been successfully investigated for particle formation due to its unique gas/liquid properties in the supereritical state. In this report, results of particle formation using the principles of Rapid Expansion of Supercritical Solutions (RESS) have been documented.

In the RESS …

Development And Evaluation Of Brain Tumor Targeted Liposome Delivery System For Paclitaxel, Murali Krishna Divi

Theses and Dissertations (ETD)

Primary brain tumors are a relatively common cause of cancer-related deaths. High-grade gliomas are the most common type of primary brain cancer, and the affected patients have a median survival of less than 1 year. Almost all malignant gliomas are incurable with the present standards of healthcare. Currently accepted therapeutic adjuvants to surgery, such as radiotherapy and chemotherapy, provide only a minor improvement in the disease course and life expectancy for patients diagnosed with malignant gliomas. Often, chemotherapy has failed to make any significant impact on the prognosis of disease because of significant local and systemic toxicity, problems with transport …

The Role Of Multi-Drug Resistance Associated Protein 4 And P-Glycoprotein In Resistance Of Neuroblastoma To Topotecan And Irinotecan, Patricia Kellie Turner

Theses and Dissertations (ETD)

High-risk neuroblastoma presents a significant therapeutic challenge because the 5-year survival rate remains less than 30% despite the use of surgery, multi-agent chemotherapy, radiation, and autologous bone marrow transplant. Novel therapeutic modalities are under development. The camptothecin analogs topotecan and irinotecan have been identified as successful cytotoxic agents. For topotecan, pharmacokinetically guided dosing to achieve a systemic exposure associated with preclinical anti-tumor activity in neuroblastoma xenograft models is feasible and has elicited favorable responses in children with high-risk neuroblastoma. However, some children with high-risk disease did not respond to the putatively effective topotecan systemic exposure. These children represent a subset …

Synthesis Of Novel Sulfonamide-Based Calpain Inhibitors And Their Potential As Anti-Tumor Agents, Jin Xu

Theses and Dissertations (ETD)

Calpain is a class of intracellular cytoplasmic cysteine proteases.1 The enzyme participates in different intracellular signaling pathways that are mediated by Ca2+.2 The two major isoforms of calpain universally distributed in most mammalian tissues are calpain 1 (µ-calpain) and calpain 2 (m-calpain). The exact in vivo function of the enzyme is not clear, but calpain has been implicated in a variety of physiological and pathological conditions,3 such as cancer, stroke, cardiac ischaemia, muscular dystrophy, cataract and Alzheimer’s disease. Calpain inhibitors are therefore of interest as therapeutic agents and as biomedical tools.

Several potent calpain inhibitors isolated from natural sources as …