Medicinal and Pharmaceutical Chemistry Commons^™

Stribild: A Review Of Component Characteristics And Combination Drug Efficacy, Derek E. Murrell, Jonathan P. Moorman, Sam Harirforoosh

Pharmacy Faculty Articles and Research

BACKGROUND: Numerous methods have been devised to combat human immunodeficiency virus (HIV) replication and disease progression. Composed of an integrase strand transfer inhibitor, a pharmacoenhancer, and two reverse transcriptase inhibitors, Stribild is a relatively new combination HIV drug formulated for once-a-day dosing.

METHODS: Relevant information, original research articles and reviews, were gathered primarily through the use of the PubMed database. The search was conducted without date restrictions in order to collect both historical and recent information concerning HIV, individual drugs, and combinations for a thorough overview.

RESULTS: Stribild, when taken with food, provides therapeutic drug concentrations as …

Elaboration And Design Of Α7 Nachr Negative Allosteric Modulators, Osama I. Alwassil

Theses and Dissertations

α7 Neuronal nicotinic acetylcholine receptors are one of two major classes of receptors responsible for cholinergic neurotransmission in the central nervous system. The existence of α7 neuronal nAChRs in different regions of the nervous system suggests their involvement in certain essential physiological functions as well as in disorders such as Alzheimer’s disease (AD), drug dependence, and depression. This project was aimed toward the discovery and development of small–molecule arylguanidines that modulate α7 nAChR function with improved subtype-selectivity through an allosteric approach. Identifying the required structural features of these small molecules allowed optimization of their negative allosteric modulator (NAM) actions at …

Target-Directed Biosynthetic Evolution: Redirecting Plant Evolution To Genomically Optimize A Plant’S Pharmacological Profile, Dustin Paul Brown

Theses and Dissertations--Neuroscience

The dissertation describes a novel method for plant drug discovery based on mutation and selection of plant cells. Despite the industry focus on chemical synthesis, plants remain a source of potent and complex bioactive metabolites. Many of these have evolved as defensive compounds targeted on key proteins in the CNS of herbivorous insects, for example the insect dopamine transporter (DAT). Because of homology with the human DAT protein some of these metabolites have high abuse potential, but others may be valuable in treating drug dependence. This dissertation redirects the evolution of a native Lobelia species toward metabolites with greater activity …

Design, Synthesis, And Pharmacological Evaluation Of Three Series Of Lobelane Analogs As Inhibitors Of The Vesicular Monoamine Transporter (Vmat2), John P. Culver

Theses and Dissertations--Pharmacy

Methamphetamine (METH) abuse is a serious problem in the United States and worldwide. The reward experienced by METH users is due to the increase in extracellular dopamine (DA) concentrations caused by an interaction between METH and the DA transporter (DAT) as well as the Vesicular Monoamine Transporter-2 (VMAT2). The reward felt by users of METH leads to further use of the drug and subsequent abuse. The current project examined the ability of three novel series of lobelane analogs to interact with a binding site on the Vesicular Monoamine Transporter-2 (VMAT2) in an attempt to inhibit the effects of METH. Lobelane …

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

Celecoxib Or Diclofenac Hepatic Status In The Presence Or Absence Of Rebamipide, Derek E. Murrell, Yuyun Rahmasari, James W. Denham, Peter C. Panus, Sam Harirforoosh

Pharmacy Faculty Articles and Research

OBJECTIVE: Utilization of nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, can produce gastrointestinal ulceration. Thus, cyclooxygenase-2-selective inhibitors, such as celecoxib, and protective agents (e.g. rebamipide) have been employed to alleviate harmful NSAID effects. This study sought to explore the influence of rebamipide on the hepatic outcomes following administration of two commonly prescribed NSAIDs.

MATERIALS AND METHODS: Rats were given either vehicle or rebamipide (30 mg/kg) orally twice daily for two days, then on the third day respective groups were dosed with either vehicle, celecoxib (40 mg/kg), or diclofenac (10 mg/kg) in addition to a respective dose of vehicle …

Feasibility Of Integrating Tripterygium Wilfordii Into Modern Cancer Therapy For Increased Efficacy And Minimal Toxicity, Ngoc T. Vo

Undergraduate Research Posters

Cancer is the second leading cause of death in the U.S. and millions of novel cancer cases are being diagnosed each year. While chemotherapy and ionizing radiation are effective treatments against these malignant tumors, the adverse effects that accompany such treatments are devastating. In order to find alternative treatment methods with less side effects, we turn to Eastern herbal medicine. Recent scientific research has found that Tripterygium wilfordii, an herbal medicine traditionally used to treat inflammation in China, contains compounds (triptolide and celastrol) that prevent the growth of solid tumors, induce apoptosis, and prevent metastasis of developed tumors. Investigations …

Psychoactive Synthetic Cathinones (Or 'Bath Salts'): Investigation Of Mechanisms Of Action, Farhana Sakloth

Theses and Dissertations

Synthetic cathinones represent threatening and high abuse-potential designer drugs. These are analogs of cathinone (the b-keto analog of amphetamine (AMPH)) a naturally occurring stimulant found in the plant Catha Edulis. Methcathinone (MCAT) was the first synthetic analog of cathinone to be identified in 1987 by Glennon and co-workers and it exerted its action primarily through the dopamine transporter (DAT). Most central stimulants exert their action via monomaine transporters by causing either the release (e.g. cathinone analogs such as MCAT) or by preventing the reuptake (e.g. cocaine) of the neurotransmitter dopamine (DA) thus increasing the extracellular synaptosomal concentration of this …

Metal Organic Frameworks (Mofs) And Porous Organic Polymers (Pops) For Heterogeneous Asymmetric Catalysis, Youngran Ji

USF Tampa Graduate Theses and Dissertations

The administration of enantiopure drugs brings advantages such as improved efficacy, more predictable pharmacokinetics and reduced toxicity from the point of view of the pharmaceutical area.[1] For this reason, a tremendous amount of supply and demand for enantiomeric pure compounds has been shown not only in market, but industry and academia.[^2-4] According to the industry publication Genetic Engineering and Biotechnology News (GEN) in 2014, 22 billion dollars were accounted for enantiopure form of drugs such as Sovaldi® (Sofosbuvir), Crestor® (Rosuvastatin), and Advair® (fluticasone/salmeterol).

The fact that one enantiomer can be pharmacologically effective whereas the other enantiomer can be …

Effect Of Formulation Variables On Preparation Of Celecoxib Loaded Polylactide-Co-Glycolide Nanoparticles, Dustin L. Cooper, Sam Harirforoosh

Pharmacy Faculty Articles and Research

Polymer based nanoparticle formulations have been shown to increase drug bioavailability and/or reduce drug adverse effects. Nonsteroidal anti-inflammatory drugs (e.g. celecoxib) reduce prostaglandin synthesis and cause side effects such as gastrointestinal and renal complications. The aim of this study was to formulate celecoxib entrapped poly lactide-co-glycolide based nanoparticles through a solvent evaporation process using didodecyldimethylammonium bromide or poly vinyl alcohol as stabilizer. Nanoparticles were characterized for zeta potential, particle size, entrapment efficiency, and morphology. Effects of stabilizer concentration (0.1, 0.25, 0.5, and 1% w/v), drug amount (5, 10, 15, and 20 mg), and emulsifier (lecithin) on nanoparticle characterization were examined …

Top 10 Medicinal Plants And Their Groundbreaking Impact On Modern Medicine, Jordan N. Patterson, Joan Marie Lausier

Senior Honors Projects

This paper describes ten plants that having been groundbreaking drugs in the past century that were all derived from plants. I chose to do my project on this topic because of my family’s history with natural medicine. In 1999 my mother was diagnosed with Bile Duct cancer and the doctors gave her only a couple of weeks to live. The doctors recommended chemotherapy and radiation, but the results seemed negative for the situation. After some extensive research, my parents found St. Georges Medicinal Wellness Center located in the tiny village of Bad Aibling, Germany. This hospital along with offering traditional …

Computer-Aided Drug Design And Discovery, Screening And Synthesis Of Small Molecule Inhibitors Of Nucleoside Transporters, Hilaire Colleen Playa

Theses and Dissertations (ETD)

Using prior biological data, pharmacophore models were made for hCNT1, hCNT3, hENT1, and hENT4. The hCNT3 and hCNT1 pharmacophore were used to select compounds for biological testing. The NBMPR analogue and dipyridamole analogue hENT1 pharmacophores were compared to each other and to a combined pharmacophore for hENT1. The dipyridamole analogue pharmacophore better predicted non-nucleoside small molecule inhibitors, and as such appears to be the better tool for aiding in the design of new small molecule inhibitors. The hCNT3 pharmacophore failed to select active compounds and as such must be redesigned. The hCNT1 pharmacophore succeeded in identifying two moderately active compounds …

The Role Of Claudins In Bone Metabolism, Fatima Zakariya Alshbool

Loma Linda University Electronic Theses, Dissertations & Projects

Osteoporosis, a major public health problem in the U.S., is characterized by low bone mass and structural deterioration of bone tissue. Since the imbalance between bone formation and bone resorption during bone remodeling has been documented to be a major factor in the pathogenesis of osteoporosis, it is crucial to identify novel genes and/or novel functions of known genes that regulate the formation and activity of bone forming osteoblasts and bone resorbing osteoclasts. To this end, recent evidence suggests a significant role for caudins (Cldns), which comprise a major group of tight junction proteins, in bone biology and development. This …

Nucleoside Reverse Transcriptase Inhibitors Possess Intrinsic Anti-Inflammatory Activity, Benjamin J. Fowler, Bradley D. Gelfand, Younghee Kim, Nagaraj Kerur, Valeria Tarallo, Yoshio Hirano, Shoba Amarnath, Daniel H. Fowler, Marta Radwan, Mark T. Young, Keir Pittman, Paul Kubes, Hitesh Agarwal, Keykavous Parang, David R. Hinton, Ana Bastos-Carvalho, Shengjian Li, Testuhiro Yasuma, Takeshi Mizutani, Reo Yasuma, Charles Wright, Jayakrishna Ambati

Pharmacy Faculty Articles and Research

Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)–derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile …

Ho-1 Upregulation Attenuates Adipocyte Dysfunction, Obesity, And Isoprostane Levels In Mice Fed High Fructose Diets, Zeid Khitan, Mohit Harsh, Komal Sodhi, Joseph I. Shapiro Md, Nader G. Abraham

Pharmaceutical Science and Research

Background. Fructose metabolism is an unregulated metabolic pathway and excessive fructose consumption is known to activate ROS.HO-1 is a potent antioxidant gene that plays a key role in decreasing ROS and isoprostanes.We examinedwhether the fructosemediated increase in adipocyte dysfunction involves an increase in isoprostanes and that pharmacological induction ofHO-1would decrease both isoprostane levels and adipogenesis. Methods and Results. We examined the effect of fructose, on adipogenesis in human MSCs in the presence and absence of CoPP, an inducer of HO-1. Fructose increased adipogenesis and the number of large lipid droplets while decreasing the number of small lipid droplets (𝑃 < 0.05). Levels of heme and isoprostane in fructose treated MSC-derived adipocytes were increased. CoPP reversed these effects andmarkedly increasedHO-1 and theWnt signaling pathway. Thehigh fructose diet increased heme levels in adipose tissue and increased circulating isoprostane levels (𝑃 < 0.05 versus control). Fructose diets decreasedHO-1 and adiponectin levels in adipose tissue. Induction ofHO-1 by CoPP decreased isoprostane synthesis (𝑃 < 0.05 versus fructose). Conclusion. Fructose treatment resulted in increased isoprostane production and adipocyte dysfunction, which was reversed by the increased expression of HO-1.

Alternative Reaction Pathways To Metformin Hydrochloride, Mohammed S. Suleiman, Stephen A. Reeves, Jorge E. Gatica

Undergraduate Research Posters 2014

Metformin Hydrochloride is an important pharmaceutical used for the treatment of type 2 diabetes. The current manufacturing of this product involves a well-known and proven process. The process includes the dissolution and reaction, followed by the precipitation of Metformin Hydrochloride. Although reliable and effective, the current process relies on the use of a solvent; which later needs to be eliminated from the precipitates. The purpose of this project is the investigation of an alternative reaction pathway which will avoid the use of solvents and simplify the final purification stage. The anticipated benefits include reduced costs for the processing and a …

Inhibition Of The Thioesterase Activity Of Human Fatty Acid Synthase By 1,4- And 9,10-Diones, Herman H. Odens

Faculty Works

Fatty acid synthase (FASN) is the enzyme that synthesizes fatty acids de novo in human cells. Although FASN is generally expressed at low levels in most normal tissues, its expression is highly upregulated in many cancers. Consistent with this notion, inhibition of FASN activity has demonstrated potential to halt proliferation and induce cell death in vitro and to block tumor growth in vivo. Consequently, FASN is widely recognized as a valuable therapeutic target. In this report, we describe a variety of 1,4-quinones and 9,10- anthraquinones, including several natural compounds and some newly synthesized compounds, that potently inhibit the thioesterase (TE) …

Investigating Propargyl-Linked Antifolates In Inhibiting Bacterial And Fungal Dihydrofolate Reductase, Joshua Andrade

Honors Scholar Theses

Antimicrobial agents have been invaluable in reducing illness and death associated with bacterial infection. However, over time, bacteria have evolved resistance to all major drug classes as a result of selective pressure. The advancement of new drug compounds is therefore vital. The Anderson-Wright Lab has focused on developing potent and selective inhibitors of dihydrofolate reductase (DHFR), an enzyme key in cell proliferation and survival, in several pathogenic species. The lab has found that a set of compounds, known as propargyl-linked antifolates, are DHFR inhibitors that are both biologically effective and have strong pharmacokinetic properties.

The efficacy of novel propargyl-linked antifolates …

The Role Of Ape/Ref-1 In Hepatocellular Carcinoma Progression, Zhen Yang, Sun Yang, Bobbye J. Misner, Feng Liu-Smith, Frank L. Meyskens

Pharmacy Faculty Articles and Research

Hepatocellular carcinoma (HCC) is responsible for a third of the estimated cancer-caused deaths worldwide. To deeply understand the mechanisms controlling HCC progression is of primary importance to develop new approaches for treatment. Apurinic/apyrimidinic endonuclease-1/redox effector factor 1 (APE/Ref-1) has been uncovered elevated in various types of cancer, including HCC. Additionally, HCC progression is always correlated with elevated copper (Cu). Our previous data demonstrated that Cu treatment initiated APE/Ref-1 expression and its downstream targets. Therefore, we hypothesized that APE/Ref-1 may be involved in HCC progression through mediating the effect of Cu to its signaling cascades. Following different treatments, human HCC cell …

Exploring The Effect Of Solution Speciation On Crystallization Outcome, David M. Harvey, Arjun Kalra, Tonglei Li

The Summer Undergraduate Research Fellowship (SURF) Symposium

In the field of pharmaceuticals, the crystallization process significantly impacts the purity, morphology and polymorphism of active pharmaceutical ingredients (API), all of which are important in drug development. Polymorphism is the existence of more than one solid-state form of the same chemical entity. Tolfenamic acid (TFA), a Non-Steroid Anti-inflammatory drug (NSAID), has been shown to exhibit a unique physical phenomenon called concomitant polymorphism, whereby two polymorphs crystallize from the solution simultaneously. From previous work, it has been established that solution speciation i.e. the presence of monomers or dimers of TFA in solution is concentration and temperature dependent. This study correlates …