Medicinal Chemistry and Pharmaceutics Commons^™

Multi-Component Microparticulate/Nanoparticulate Dry Powder Inhalation Aerosols For Targeted Pulmonary Delivery, Xiaojian Li

Theses and Dissertations--Pharmacy

The aim of the work was to design, manufacture, and characterize targeted multi-component dry powder aerosols of (non-destructive) mucolytic agent (mannitol), antimicrobial drug (tobramycin or azithromycin), and lung surfactant mimic phospholipids (DPPC:DPPG=4:1 in molar ratio). The targeted dry powder for inhalation formulation for deep lung delivery with a built-in rationale of specifically interfering several disease factors of chronic infection diseases in deep lungs such as cystic fibrosis, pneumonia, chronic bronchitis, and etc. The dry powder aerosols consisting of selected chemical agents in one single formulation was generated by using spray drying from organic solution.

The physicochemical properties of multi-component dry …

Phosphatidylinositol 3-Kinase (Pi3k) As A Therapeutic Target In Nsclc, Christopher W. Stamatkin

Theses and Dissertations--Pharmacy

Deregulated activation of phosphatidylinositol 3-kinase (PI3K) pathway is central to many human malignancies. The functions of this pathway are critical for normal cell metabolism, proliferation, and survival. In lung cancers, the PI3K pathway activity is often aberrantly driven by multiple mutations, including EGFR, KRAS, and PIK3CA. Molecules targeting the PI3K pathway are intensely investigated as potential anti-cancer agents. Although inhibitors of the pathway are currently in clinical trials, rational and targeted use of these compounds, alone or in combination, requires an understanding of isoform-specific activity in context. We sought to identify class IA PI3K enzyme (p110a/PIK3CA, p110b/PIK3CB, p110d/PIK3CD) activities using …

Β-Lactam Estrogen Receptor Antagonists And A Dual-Targeting Estrogen Receptor/Tubulin Ligand, Niamh O'Boyle, Jade K. Pollock, Miriam Carr, Andrew Js Knox, Seema M. Nathwani, Shu Wang, Laura Caboni, Daniela M. Zisterer, Mary Meegan

Articles

Twelve novel β-lactams were synthesised and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ERα and ERβ, were determined. β-Lactams 23 and 26 had the strongest binding affinities for ERα (IC₅₀ values: 40 and 8 nM respectively) and ERβ (IC₅₀ values: 19 and 15 nM). β-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G₂/M phase (mitotic blockade) and depolymerisation of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation …

Integrating Phage Therapy Into Western Medicine, Jacob B. Jaminet

Undergraduate Research Posters

The World Health Organization has described the rise of antibiotic use as a “global heath security emergency” (who.int). With the growing concern about antibiotic resistant bacteria, there has been an increased interest in bacteriophages. Bacteriophages are high-specific viruses that only infect bacteria. The use of bacteriophages medicinally to treat bacteria is called phage therapy. Research in phage therapy gained momentum until the introduction of antibiotics. While the USA and other Western countries accepted antibiotics, the Soviet Union and their satellite nations still continued to research phages. Since the funding for research was supplied by the Soviet military, the results of …

Dual Delivery Systems Based On Polyamine Analog Benspm As Prodrug And Gene Delivery Vectors, Yu Zhu

Wayne State University Dissertations

Combination drug and gene therapy shows promise in cancer treatment. However, the success of such strategy requires careful selection of the therapeutic agents, as well as development of efficient delivery vectors. BENSpm (N1, N11-bisethylnorspermine), a polyamine analogue targeting the intracellular polyamine pathway, draws our special attention because of the following reasons: (1) polyamine pathway is frequently dysregulated in cancer; (2) BENSpm exhibits multiple functions to interfere with the polyamine pathway, such as to up-regulate polyamine metabolism enzymes and down-regulate polyamine biosynthesis enzymes. Therefore BENSpm depletes all natural polyamines and leads to apoptosis and cell growth inhibition in a wide range …

Novel Compounds As Potential Alzheimer's Disease Therapeutics And Inhibitors Of The Nlrp3 Inflammasome, Jeremy E. Chojnacki

Theses and Dissertations

Alzheimer’s disease is a devastating neurodegenerative disorder and the leading cause of dementia. The disease manifests via several pathologies including neuroinflammation, oxidative stress, metal ion dyshomeostasis, and cell death. To address the multifaceted nature of this disorder, the design of several diverse compounds, targeting many pathological effects, was generated. First, a series of compounds based on curcumin and diosgenin were synthesized following the bivalent design strategy. Two compounds were discovered to have neuroprotective ability, anti-oxidative function, and anti-Aß oligomerization (AßO) properties. A second set of molecules was also designed, wherein a hybrid compound strategy was utilized. Three hybrids were to …

Studies On Two Polyherbal Formulations (Zpto And Zto) For Comparison Of Their Antidyslipidemic, Antihypertensive And Endothelial Modulating Activities, Nauman Aziz, Malik Hassan Mehmood, Anwarul Hassan Gilani

Department of Biological & Biomedical Sciences

Background

Cardiovascular disorders (CVDs) are the leading cause of disease burden worldwide. Apart from available synthetic drugs used in CVDs, there are many herbal formulations including POL-10 (containing 10 herbs), which have been shown to be effective in animal studies but POL-10 was found to cause tachycardia in rodents as its side effect. This study was designed to modify the composition of POL-10 for better efficacy and/or safety profile in CVDs.

Methods

To assess the antidyslipidemic, antihypertensive and endothelial modulatory properties of two herbal formulations, (ZPTO and ZTO) containing Z: Zingiber officinalis, P: Piper nigrum, T: Terminalia belerica and …

Investigation Of The Structure And Dynamics Of Regioisomeric Eu³⁺ And Gd³⁺ Chelates Of Nb-Dotma: Implications For Mri Contrast Agent Design, Benjamin Charles Webber

Dissertations and Theses

The detection of disease and abnormal pathology by magnetic resonance imaging (MRI) has been aided significantly by the use of gadolinium (Gd³⁺)-based contrast agents (CAs) over the past three decades. MRI and MRI CAs play a critical role in diagnosing tumors and diseases of the central nervous system. The agents used clinically have been shown to safely increase MRI contrast despite the toxicity of Gd³⁺, owing to the high kinetic and thermodynamic stability of these chelates. However, current CAs enhance contrast at a small fraction of what is theoretically possible. This leads to the necessity of …

Cytochrome P450 Family 1 Inhibitors And Structure-Activity Relationships, Jiawang Liu, Jayalakshmi Sridhar, Maryam Foroozesh

Faculty and Staff Publications

With the widespread use of O-alkoxyresorufin dealkylation assays since the 1990s, thousands of inhibitors of cytochrome P450 family 1 enzymes (P450s 1A1, 1A2, and 1B1) have been identified and studied. Generally, planar polycyclic molecules such as polycyclic aromatic hydrocarbons, stilbenoids, and flavonoids are considered to potentially be effective inhibitors of these enzymes, however, the details of the structure-activity relationships and selectivity of these inhibitors are still ambiguous. In this review, we thoroughly discuss the selectivity of many representative P450 family 1 inhibitors reported in the past 20 years through a meta-analysis.

Design, Synthesis And Development Of Transporter Targeting Agents For Image-Guided Therapy And Drug Delivery, Ning Tsao

Dissertations and Theses (Open Access)

The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with ^99mTc and ⁶⁸Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. In vitro stability assessment showed both ^99mTc-N4amG and ^99mTc-GP were stable up to 6 hours, whereas ⁶⁸Ga-GP was stable up to 2 hours. Cell culture studies …

Mechanisms Of Cytokine-Induced Metabolic Dysfunction Of The Pancreatic Beta-Cell, Abiy Mussa Mohammed

Wayne State University Dissertations

MECHANISMS OF CYTOKINE-INDUCED METABOLIC DYSFUNCTION OF THE PANCREATIC BETA-CELL

by

ABIY MUSSA MOHAMMED

August 2013

Advisor: Dr. Anjaneyulu Kowluru

Major: Pharmaceutical Sciences

Degree: Doctor of Philosophy

Type I diabetes is characterized by an absolute insulin deficiency due to loss of pancreatic â-cell mass by autoimmune aggression. During the progression of the disease proinflammatory cytokines such as IL-1â, TNFá and INFã are secreted by infiltrated and activated T-cells and macrophages which ultimately damage the pancreatic â-cell. However, the signaling mechanisms involved in cytokine-induced damage are only partially understood. Phagocyte-like NADPH oxidase [NOX2] has been shown to play regulatory roles in the …

Polymeric Nanocarriers And Their Oral Inhalation Formulations For The Regional Delivery Of Nucleic Acids To The Lungs, Denise Santos Conti

Wayne State University Dissertations

Gene therapy has attracted attention in the fields of medicine, pharmacy, and bionanotechnology due to the potential for treating a large number of medically relevant diseases. Oral inhalation (OI) is a promising route for the administration of therapeutics, including small molecules and biomacromolecules, such as nucleotides, peptides, and proteins, to (locally) and through (systemically) the lungs. The use of OI is especially attractive for the delivery of nucleic acids as it provides a direct and non-invasive route for targeting the lungs. Pressurized metered-dose inhalers (pMDIs), are the most commonly used OI in treatment of lung diseases and are thus promising …

Chlomid, Niki Smith

Natural Sciences Student Research Presentations

This poster details the use of Clomid and provides a chemical analysis.

Oligospermines For Non-Viral Sirna Delivery, Maha Elsayed

Wayne State University Theses

In this thesis, delivery systems for siRNA delivery are introduced with special attention to non-viral vectors. Many successful vectors used in vivo were reviewed. Our work focused on the effect of different architectures of oligospermine polmers on their suitability for siRNA delivery in lung cancer cells. Different archituctures showed different polyplex structures and variable transfection efficiencies. Moreover, we presented a review on nanoimprint lithography techniques with an outlook on possible biological applications in the field of gene and drug delivery.

The Antiinflammatory Action And Pharmacokinetics Of A Novel Glucosamine-Based Di-Peptide Aminosugar, Mohammad H. Gilzad-Kohan, Kamaljit Kaur, Fakhreddin Jamali

Pharmacy Faculty Articles and Research

Purpose. We have previously shown favorable in vitro gut permeability for three novel dipeptide esters of glucosamine (GlcN) likely facilitated by the peptide transporter 1 (PepT1). Herein, we report the development of a novel assay for the determination of bioavailability of the peptide ester of interest, the anti-inflammatory properties of a glycine-valine ester derivative of GlcN (GVG) as well as its pharmacokinetics under healthy and inflammatory conditions.

Methods. A pre-column derivatization (with 9-fluorenylmethoxycarbonyl) HPLC assay was developed to study bioavailability of GVG, GlcN or cleaved GlcN in the rats that were cannulated in their right jugular vein for …

Synthesis And Biochemical Activities Of Antiproliferative Amino Acid And Phosphate Derivatives Of Microtubule-Disrupting Beta-Lactam Combretastatins, Niamh M. O'Boyle, Lisa M. Greene, Niall O. Keely, Shu Wang, Tadhg S. Cotter, Daniela M. Zisterer, Mary J. Meegan

Articles

The synthesis and biochemical activities of novel water-soluble β-lactam analogues of combretastatin A-4 are described. The first series of compounds investigated, β-lactam phosphate esters 7a, 8a and 9a, exhibited potent antiproliferative activity and caused microtubule disruption in human breast carcinoma-derived MCF-7 cells. They did not inhibit tubulin polymerisation in vitro, indicating that biotransformation was necessary for their antiproliferative and tubulin binding effects in MCF-7 cells. The second series of compounds, β-lactam amino acid amides (including 10k and 11l) displayed potent antiproliferative activity in MCF-7 cells, disrupted microtubules in MCF-7 cells and also inhibited the polymerisation of …

Novel Cis-Restricted Β-Lactam Combretastatin A-4 Analogues Display Anti-Vascular And Anti-Metastatic Properties In Vitro, Seema M. Nathwani, Lisa M. Greene, Linda Hughes, Miriam Carr, Niamh O'Boyle, Susan Mcdonnell, Mary J. Meegan, Daniela M. Zisterer

Articles

No abstract provided.

Progress Towards Development Of Multifunctional, Dopamine D2/D3 Receptor Agonists As Symptomatic And Disease-Modifying Therapeutic Agents For Parkinson's Disease, Mark Andrew Johnson

Wayne State University Dissertations

Parkinson¡¯s disease (PD) is a progressive, neurodegenerative disorder that arises primarily through the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), resulting in a diminished level of the neurotransmitter dopamine in the nigrostriatal pathway and ensuing loss of motor function. Common symptoms of PD include resting tremor, muscular rigidity, bradykinesia (slowness and decreased amplitude of movement), along with postural instability and cognitive psychiatric complications. PD affects 1% of the population ¡Ý 65 and is the second most prevalent neurodegenerative disorder next to Alzheimer¡¯s disease (AD). Although the etiology of PD is not yet clear and may be …

Progress Towards Understanding Of Mechanisms Of Action Of Potent Multifunctional Disease Modifying Therapeutics For Parkinson's Disease & Investigating The Methamphetamine-Induced Striatal Microglia Activation., Mrudang M. Shah

Wayne State University Dissertations

PROGRESS TOWARDS UNDERSTANDING OF MECHANISMS OF ACTION OF POTENT MULTIFUNCTIONAL DISEASE MODIFYING

THERAPEUTICS FOR PARKINSON'S DISEASE.

by

MRUDANG MANOJKUMAR SHAH

December 2013

Advisor: Dr. Aloke Dutta

Major: Pharmaceutical Sciences

Degree: Doctor of Philosophy

Our long term goal is to design and develop potent multifunctional disease modifying therapeutics for Parkinson's disease. The objective of my dissertation was to understand the mechanisms of action of some potent small molecules (synthesized in our lab) as a disease modifying Parkinson's disease therapeutic. The objective was achieved by pursuing the following two specific aims:

1. Investigating anti-oxidant and neuroprotective effects of a lead molecule (D-512) …

Design, Synthesis, Biological Evaluation And Molecular Modeling Studies Of Novel Multifunctional Neuroprotective Drugs For The Treatment Of Parkinson's Disease: An Effort Towards The Improvement Of In Vivo Efficacy And Modulation Of Alpha Synuclein Aggregation Property Of The Neuroprotective Parent, Gyan Prakash Modi

Wayne State University Dissertations

DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION AND MOLECULAR MODELING STUDIES OF NOVEL MULTIFUNCTIONAL NEUROPROTECTIVE DRUGS FOR THE TREATMENT OF PARKINSON'S DISEASE: AN EFFORT TOWARDS THE IMPROVEMENT OF IN VIVO EFFICACY AND MODULATION OF ALPHA SYNUCLEIN AGGREGATION PROPERTY OF THE NEUROPROTECTIVE PARENT MOLECULE (D-264)

by

GYAN PRAKASH MODI

May 2014

Advisor: Dr. Aloke K. Dutta

Major: Pharmaceutical Sciences

Degree: Doctor of Philosophy

Parkinson's disease (PD) is a progressive age-related neurodegenerative disorder of the central nervous system that is characterized by gradual loss of dopaminergic neurons in the substantia nigra region of the brain. The research from the past two decades in PD area …