Pharmaceutics and Drug Design Commons^™

The Emerging Role Of Ticagrelor In Acute Coronary Syndromes, Jennifer Bauer, Brittany Dye, Kimberly Baucher, Megan Keller, David Bright, Karen L. Kier

Pharmacy and Wellness Review

Antiplatelet therapy has become a mainstay in the treatment of acute coronary syndromes (ACS). Until recently, options were somewhat limited when it came to individualizing drug selection. Plavix® (clopidogrel) has been successfully used for many years but requires activation by CYP enzymes. Depending on an individual patient's genetic makeup, function of these CYP enzymes may be altered, which may increase the risk for clots. The recent approval of Effient® (prasugrel) and Brilinta® (ticagrelor) has provided physicians and pharmacists with more options and may hopefully lead to improved clinical outcomes. Ticagrelor specifically exhibits clinically different pharmacologic characteristics that require twice daily …

Synthesis Of Bis(Imino)Pyridine Iron(Ii) Complexes And Development Of Bis(Imino)Pyridine Iron(Ii) Catalyzed Carbene Transfer Reactions, Ban Wang

Masters Theses & Specialist Projects

Metal catalysis of symmetric and asymmetric carbene transfer reactions has been widely applied in natural product synthesis and material science over years. Metal carbene can be easily generated from the extrusion of nitrogen under the catalysis of metal complexes to further undergo various organic reactions, O/N/C-H insertions, cycloadditions, and ylide formations. Currently, the dominant effective catalysts for carbene reactions are built with expensive precious metal, for example, rhodium, ruthenium, palladium, gold. Notably, the effective reactivity and enantioselectivity of the dirhodium(II) catalysts are researched and established over the decades. However, the use of precious metal catalysts is the major source of …

Sipuleucel-T (Provenge®): Therapeutic Use And Financial Implications, Courtney Porter, Joshua Ilenin, Lisa Berni, Ashley Overy, Karen L. Kier

Pharmacy and Wellness Review

Although mortality rates have been declining, prostate cancer accounts for a large percentage of cancer diagnoses around the world. Sipuleucel-T (Provenge®), an autologous cellular immunotherapy targeted against the antigen expressed in most prostate cancers, has been shown to increase the median survival rate of castration-resistant prostate cancer. Even so, the therapeutic risks and benefits, as well as financial implications, all currently play a role in the governmental decision to reimburse for this new therapy.

The Pharmacogenetics Of Opioid Pain Management, Maryanne Ventura, Lauren Desko, Kimberly Gathers, Ashley Overy, David Kisor

Pharmacy and Wellness Review

High rates of interpatient variability in drug metabolism and drug response for nearly all medications lead to the hypothesis that assessment of an individual patient's genotype with respect to their ability metabolize certain drugs can be a useful tool in predicting a patient's responsiveness to certain medications. Evaluating patients using pharmacogenomics as a basis for assessment could allow pharmacists to decide which treatment options would be most efficacious in a given patient and, thereby, have significant impact in the clinical setting. This holds true especially in the case of prodrugs, which require in vivo activation to an active or more …

Prescription Drug Manufacturer Attempts To Prevent Abuse Of Controlled Substances, Amanda R. Hoersten, Nathaniel Hedrick, Lacey Shumate, H. Paige Stewart, Caitlin Swann, Michael Milks

Pharmacy and Wellness Review

In the United States, prescription drug abuse is on the rise. This trend has impacted the makers of OxyContin®, as well as the manufacturers of other controlled substances,to reevaluate how they formulate their products, resulting in medications, that are more difficult to abuse. These abuse-deterrent formulations utilize physical, chemical and aversion barriers, specific delivery systems, and prodrug technology to prevent abuse. Additionally, some manufacturers have implemented the use of risk-management campaigns and education programs, to reduce the misuse of their products. Working together with prescription drug manufacturers, pharmacists play an important role in preventing abuse and educating patients on the …

Chemical Epitope Targeting: Review Of A Novel Screening Technology, Qurrat Ul-Ain, Rene Kandler, Dylan Gillespie, Arundhati Nag

Scholarly Undergraduate Research Journal at Clark (SURJ)

Chemical Epitope Targeting is a novel technology developed for designing peptide ligands with high affinity and specificity against specific regions of a protein that may be inaccessible to small molecules or antibodies. In this review, we summarize the key steps and significant applications of this technology. Operating on the same principles as antibody-antigen interactions, this technique involves chemically synthesizing the region of interest on the protein, called the epitope, as a polypeptide with a biotin detection tag and a strategically placed alkyne or azide presenting amino acid. The constructed epitope is screened against a comprehensive linear or cyclic One Bead …

Exploration Of The Inhibitory Properties Of The Nucleoside Antibiotic Salicyl-Ams And Analogues Targeting Siderophore Biosynthesis In Mycobacterium Tuberculosis, Glennon Bythrow

Dissertations, Theses, and Capstone Projects

Mycobacterium tuberculosis (Mtb) is a resilient, obligate bacterial pathogen responsible for pulmonary tuberculosis disease (TB), that has upheld a significant impact on global public health throughout history. The World Health Organization (WHO) approximates nearly 10 million new TB cases arose in 2017 alone, accounting for 1.6 million deaths. There has been a notable rise in TB cases produced by multidrug‑resistant (MDR) and extensively drug-resistant (XDR) strains of Mtb. This, along with the intrinsic resistance of Mtb to many standard drugs and poor patient compliance, is deeply impacting global control of TB. Among the several strategies currently in …

Design And Synthesis Of Pyrimidine Based Heterocycles As Potential Anti-Cancer Agents With Combination Chemotherapeutic Potential Or Targeted One Carbon Metabolism Inhibition And Anti-Opportunistic Agents, Arpit Doshi

Electronic Theses and Dissertations

This dissertation describes the design, synthesis and biological evaluation of monocyclic, bicyclic and tricyclic pyrimidine-based heterocycles as a) single agents with combination chemotherapy potential having dual antiangiogenic effects and cytotoxic effects or b) one-carbon metabolism inhibitors for targeted tumor therapy; or c) selective Pneumocystis jirovecii (pj) dihydrofolate reductase (pjDHFR) inhibitors for pneumocystis pneumonia (PCP) infection.

The work in this dissertation is centered on identifying structural features that are necessary for inhibition of tubulin polymerization or thymidylate synthase as well as for inhibition of one or more of the receptor tyrosine kinases (RTKs)- vascular endothelial growth factor receptor-2 (VEGFR2), epidermal growth …

A Quantitative Study Of Drug Recrystallization In Drug-In-Adhesive Transdermal Patches Using Vibrational Spectroscopy, Yi Li

Electronic Theses and Dissertations

Drug-in-adhesive (DIA) transdermal patches are an important type of transdermal drug delivery system (TDDS). The drugs used in the DIA system are frequently present in metastable forms, such as amorphous solids or supercooled liquids. These drug states are thermodynamically unstable and tend to undergo recrystallization. Recrystallization of the active pharmaceutical ingredient can adversely affect the efficacy of transdermal products. This dissertation demonstrates a systematic approach to quantify the crystalline content of the API in DIA systems. This approach uses a novel method of preparing calibration standards and a spectroscopic method to reliably predict crystalline content in DIA patches. Spectroscopic tools, …

Synthesis And Characterization Of Long-Acting Rilpivirine Prodrugs, James R. Hilaire

Theses & Dissertations

Antiretroviral therapy (ART) requires lifelong daily dosing to suppress viral replication, restore or maintain immune function and improve quality of life. As an alternative, long-acting (LA) antiretrovirals (ARVs) aim to deliver therapeutic drug concentrations over an extended period, ultimately requiring monthly or even more extended dosing intervals. Specifically, the success of recent clinical trials examining LA cabotegravir and rilpivirine (CAB and RPV LA) highlight the advent of these novel HIV-1 therapeutics. Further optimization of LA dosage forms are required and rests upon improving dosing frequency, injection volumes and tissue distribution to viral compartments. To this end, we report the synthesis …

New Vaccines In The Pipeline 2019, Michael Phan, Luma Munjy, Nicole Benipayo, Jeff Goad, Sun Yang

Pharmacy Faculty Articles and Research

"Before clinicians can administer a vaccine in the United States, the FDA must approve and license it. Investigators conduct extensive research leading up to this process, typically testing a vaccine in thousands of patients over 6 to 7 years or longer. Even with large sample sizes and rigorous study designs, rare adverse effects may be missed. For example, RotaShield, the first vaccine for rotavirus, was withdrawn from the market in 1999, despite being tested in more than 10,000 patients. Postmarketing surveillance demonstrated that a rare, yet serious, risk of intussusception was linked to the vaccine, and the FDA determined that …

Helsinn Healthcare S.A. V. Teva Pharmaceuticals Usa, Inc.: “Sale” Keeps Its Old Meaning Under The Leahy–Smith America Invents Act, Sherrie Holdman

Minnesota Journal of Law, Science & Technology

No abstract provided.

Alzheimer's Disease Drug Development Pipeline: 2019, Jeffrey Cummings, Garam Lee, Aaron Ritter, Marwan Sabbagh, Kate Zhong

School of Medicine Faculty Research

Introduction Alzheimer's disease (AD) has few available treatments, and there is a high rate of failure in AD drug development programs. Study of the AD drug development pipeline can provide insight into the evolution of drug development and how best to optimize development practices. Methods We reviewed clinicaltrials.gov and identified all pharmacologic AD trials of all agents currently being developed for treatment of AD. Results There are 132 agents in clinical trials for the treatment of AD. Twenty-eight agents are in 42 phase 3 trials; 74 agents are in 83 phase 2 trials; and 30 agents are in 31 phase …

Identifying The Enzyme Involved In Vacuolar Atpase Acetylation During Doxorubicin-Induced Cardiotoxicity, Rebecca Dang, Tianqing Peng

Western Research Forum

Doxorubicin is an established anticancer medication infamous for its bright colouration and extremely toxic side effects. Emerging studies support that the imbalance between acetylation and deacetylation disrupts the autophagic flux leading to doxorubicin-induced cardiotoxicity. Vacuolar ATPases are a family of electrogenic proton pumps present on the lysosomal membrane that create an acidic environment for proteases to degrade proteins. Our preliminary study found that acetylated Vacuolar ATPase subunit V₀ D1 levels increased in doxorubicin-injected mouse hearts. However, it is unknown how acetylation of subunit V₀ D1 is modulated and whether this modification plays a role in doxorubicin-induced cardiotoxicity.

The …

Investigating Trail Sensitivity In Platinum-Resistant Ovarian Cancer, Nicholas Pathoulas

All College Thesis Program, 2016-2019

Ovarian cancer is the deadliest gynecologic malignancy in the United States. While these tumors may have a promising initial response to platinum-based chemotherapies, the patient’s prognosis is commonly hindered by the development of platinum resistant cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been implicated as a potential treatment for many cancers based on its tumor selective nature. Combination therapies with TRAIL and platinum drugs have been shown to increase apoptosis and have been used in a variety of clinical trials, which have thus far failed to pass phase II.1 Researchers have not yet elucidated the complex mechanism(s) of TRAIL …

A Robust Delivery System For Rna Therapeutics, Suleyman Bozal

University Scholar Projects

The field of RNA therapeutics is currently undergoing both transformation and expansion. Specifically, research in lipid nanoparticle (LNP) based RNA therapeutics is gaining significant traction. Other research into mechanisms of gene regulation and manipulation, including siRNA and the CRISPR/Cas9 system have demonstrated the potential of RNA-based disease treatment. This work identifies a delivery system which can regulate expression of green fluorescent protein (GFP) in human embryonic kidney cells (HEK293) stably expressing GFP.

Analysis of siRNA-induced gene knockdown demonstrates that the current siRNA-LNP formulation is equally as effective as a commercially available transfection reagent, Lipofectamine RNAiMAX (RNAiMAX), which is designed specifically …

A Robust Delivery System For Rna Therapeutics, Suleyman Bozal

Honors Scholar Theses

The field of RNA therapeutics is currently undergoing both transformation and expansion. Specifically, research in lipid nanoparticle (LNP) based RNA therapeutics is gaining significant traction. Other research into mechanisms of gene regulation and manipulation, including siRNA and the CRISPR/Cas9 system have demonstrated the potential of RNA-based disease treatment. This work identifies a delivery system which can regulate expression of green fluorescent protein (GFP) in human embryonic kidney cells (HEK293) stably expressing GFP.

Analysis of siRNA-induced gene knockdown demonstrates that the current siRNA-LNP formulation is equally as effective as a commercially available transfection reagent, Lipofectamine RNAiMAX (RNAiMAX), which is designed specifically …

The Development Of Hybrid Process Control Systems For Fluidized Bed Pellet Coating Processes, Hanzhou Feng

Electronic Theses and Dissertations

The conventional basic control for pharmaceutical batch processes has several drawbacks. The basic control often uses constant process settings discovered by trial and error. The rigid process operation provides limited process understanding and forgoes the opportunities of process optimization. Product quality attributes are measured by the low efficient off-line tests, therefore these cannot be used to monitor and inform the process to make appropriate adjustments. Frequent reprocessing and batch failures are possible consequences if the process is not under effective control. These issues raise serious concerns of the process capability of a pharmaceutical manufacturing process.

An alternative process control strategy …

Modeling And Prediction Of Amorphous Solid Dispersion Formation Using A Molecular Descriptor, Kevin Deboyace

Electronic Theses and Dissertations

Poor aqueous solubility of an active pharmaceutical ingredient (API) is a significant hurdle during drug development. Delivering a drug in its amorphous solid-state is a potential method to overcome this issue, since the amorphous form has increased apparent aqueous solubility. However, the amorphous state is only metastable, and is thermodynamically driven to recrystallize. As a result, pure amorphous drugs are seldom used in marketed products. Intimately mixing a drug in its amorphous form with a polymer, known as an amorphous solid dispersion (ASD), has the potential to significantly extend the physical stability of the amorphous form, while maintaining the benefit …

Development Of Approaches Of Tumor Trapping Enhanced Bb2r-Targeted Radiopharmaceuticals For Prostate Cancer, Wenting Zhang

Theses & Dissertations

The Gastrin-Releasing Peptide Receptor (BB2r) has been intensively investigated as a cancer target over the years. Numerous diagnostic and therapeutic BB2r-targeted agents have been developed for various solid tumors, including prostate cancers, due to the high expression level of BB2r on neoplastic relative to normal tissues. The development of those targeted agents have mainly utilized the modified c-terminal of bombesin(BBN), a peptide that has nanomolar binding affinity to human BB2r. However, a major issue that hinders the clinical translational potential of low-molecular weight, receptor-targted agents, is their short residence time at tumor tissues due to the intrinsically high diffusion and …