Pharmaceutics and Drug Design Commons^™

Children With Cystic Fibrosis Can Lead Normal Lives; It All Started With The Nih, The Center For Integration Of Science And Industry

CISI Publication

Cystic fibrosis is a model of what can be accomplished with sustained support from the government, public, and biotechnology industry.

Our research shows that the NIH funded research underlying >99% of all drugs approved 2010-2024 with an average spending of $1.4 billion/drug approval.1-4 This research creates the foundational knowledge required for successful drug development by industry.

Avaren-Fc's Effects On Lymphoma Cells., Jacob Hahn

Electronic Theses and Dissertations

This thesis investigates the therapeutic potential of Avaren-Fc (AvFc), a novel lectin fusion protein that integrates the Fc region of human IgG1 with the engineered lectin Avaren, specifically targeting lymphoma. The study delineates the in vitro binding capabilities of Avaren-Fc with a human B-cell lymphoma cell line, a canine B-cell lymphoma cell line, healthy canine peripheral blood mononuclear cells (PBMCs), and healthy human PBMCs. AvFc was shown to exhibit significant binding to human lymphoma cells. Furthermore, the direct cytotoxicity of Avaren-Fc against canine lymphoma cells, canine lymphoma cells and healthy canine PBMCs was assessed. It was found that there is …

Mergers And Acquisitions (M&As) In Pharmaceutical Markets: Associations With Market Concentration, Prices, Drug Quantity Sold, And Shortages, J. Daniel Mcgeeney M.S., Aylin Sertkaya Ph.D., Leah Ross M.A., Fred Ledley M.D., Cody Hyman Ph.D.

CISI Publication

In recent decades, the pharmaceutical industry has become increasingly concentrated in the United States, in part due to mergers and acquisitions (M&As) between drug manufacturers. This consolidation from M&As has been cited as a key factor affecting drug prices and drug shortages (U.S. Federal Trade Commission, 2022). In this study, we assessed trends in pharmaceutical M&As during 2010–2023 and evaluated the characteristics of drugs and companies involved in those M&As. We considered the effects of M&As on market concentration, drug prices, drug quantity sold, and drug shortages. We also considered how these associations vary by drug characteristics, including brand drugs …

The Future Of Ai Regulation In Drug Development: A Comparative Analysis, Gabriela Lenarczyk, Timo Minssen, Nicholson Price, Arti Rai

Faculty Scholarship

As artificial intelligence (AI) transforms drug development, regulatory frameworks are evolving to oversee its implementation, particularly at the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This paper makes three contributions to understanding emerging regulatory approaches. First, we offer a comparative analysis of how these agencies have responded to AI-driven advances, incorporating new US executive orders and the European Union (EU)’s AI Act. Second, we propose a novel analytical framework to understand regulatory divergence: the FDA’s flexible, dialog-driven model contrasts with the EMA’s structured, risk-tiered approach, reflecting broader institutional and political-economic differences. While the former encourages …

Investigation Of Avaren-Fc's Therapeutic Potential Against Ovarian Cancer., Katarina Lee Mayer

Electronic Theses and Dissertations

This thesis describes the investigation of Avaren-Fc (AvFc), a novel lectin-based therapeutic fusion protein consisting of the recombinant Avaren lectin and the Fc region of human IgG1, against ovarian cancer. AvFc possesses selectivity toward tumor associated N-linked high-mannose-type glycans. The present study demonstrates AvFc’s in vitro activity against OVCA cell lines via antibody-dependent cell-mediated cytotoxicity and its ability to extend the survival of mice challenged with murine ID8 OVCA cells after repeated systemic administration. Furthermore, AvFc treatment in this model was found to increase the presence of peritoneal leukocytes, suggesting a shift toward an improved antitumor immune response. Another key …

Targeting Strategies To Optimize The Therapeutic Potential Of Gold Compounds Against Her2-Positive Breast Cancers, Afruja Ahad

Dissertations, Theses, and Capstone Projects

The overexpression of HER2 accounts for 20-30% of breast cancer tumors and not only serves as a marker for poor predictive clinical outcomes but also as a target for treatment. Antibody-drug conjugates (ADCs) combine the selectivity of monoclonal antibodies (mAbs) with the efficacy of chemotherapeutic drugs to provide targeted treatment without toxicity to normal tissue. Most of the ADCs currently in the clinic for cancer chemotherapy are based on complex organic molecules. In contrast, the conjugation of metallodrugs to mAbs has been overlooked when there is enormous potential in this area with the resurgence of metal-based drugs as prospective cancer …

Introducing Biosimilar Competition For Cell And Gene Therapy Products, Brian Canter, Sabine Sussman, Stephen Colvill, Nitzan Arad, Elizabeth Staton, Arti Rai

Faculty Scholarship

This article provides an early analysis of the potential for creating future biosimilar competition for cell and gene therapies (CGTs) to lower prices and improve patient access, building on a unique set of interviews with relevant experts. Our discussion addressed regulatory, manufacturing, intellectual property, and market size challenges. Due to CGTs’ complexity, meeting the regulatory requirement of ‘high similarity with no clinically meaningful differences’ will be difficult. Gene therapies are likely better candidates for biosimilar development than cell therapies. Biosimilarity should be met when gene therapy biosimilars contain the same genetic sequence as a reference product, and the variability in …

Tolfenamic Acid Derivatives: A New Class Of Transcriptional Modulators With Potential Therapeutic Applications For Alzheimer’S Disease And Related Disorders, Juanetta Hill, Karim E. Shalaby, Syed W. Bihaqi, Bothaina H. Alansi, Benjamin Barlock, Keykavous Parang, Richard Thompson, Khalid Ourarhni, Nasser H. Zawia

Pharmacy Faculty Articles and Research

The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs …

Spending On Phased Clinical Development Of Approved Drugs By The Us National Institutes Of Health Compared With Industry, Edward W. Zhou, Matthew J. Jackson, Fred D. Ledley

Natural & Applied Sciences Faculty Publications

The launch of the Advanced Research Projects Agency for Health to advance new cures and address public concern regarding drug prices has raised questions about the roles of government and industry in drug development.

This cross-sectional study examined NIH funding for published research reporting the results of phased clinical trials of drugs approved between 2010 and 2019 and compared the findings with reported industry spending estimates. Data analysis was performed between May 2021 and August 2022 using PubMed data from January 1999 through October 2021 and NIH Research Portfolio Online Reporting Tools Expenditures and Results data from January 1999 through …

Tech Note 2023-1 Nih Contribution To Phased Clinical Development Of Drugs Approved From 2010-2019, Edward Zhou, Matthew Jackson, Fred Ledley

CISI Publication

This report describes the methods and preliminary results for the manuscript titled, “Spending on Phased Clinical Development of Approved Drugs by the US National Institutes of Health Compared With Industry.”

Association Of Environmental Pollutants Exposure With Pulmonary Fibrosis: A Mini Review Of Molecular Mechanism Mediated, Soni Siswanto, Bantari W.K. Wardhani

Pharmaceutical Sciences and Research

Pulmonary fibrosis is a specific form of chronic progressive interstitial lung disease. Deposition of extracellular matrix, mainly collagen, is the pathogenic characteristic of pulmonary fibrosis. Many reports show that environmental pollutants, particularly asbestos, silica, mercury, cadmium, and benzo(a)pyrene, are contributed in the etiology of lung injury and a risk factor in the development of idiopathic pulmonary fibrosis (IPF) in humans. Based on its physicochemical properties, environmental pollutant-induced pulmonary fibrosis can be developed after a particular type or dose of exposure. To date, some studies have focused on variant pollutants that are induced. However, the molecular mechanism of various pollutants to …

Late-Stage Product Development And Approvals By Biotechnology Companies After Initial Public Offering, 1997-2016, Laura M. M. Mcnamee, Ekaterina Galkina Cleary, Sunyi Zhang, Usama Salim, Fred D. Ledley

Natural & Applied Sciences Faculty Publications

Purpose: This work describes the late-stage product portfolios of the biotechnology companies that completed initial public offerings (IPOs) from 1997 to 2016. We asked whether these emerging companies continue to develop innovative, biologic products and produce the innovation promised by the early biotechnology industry.

Methods: We identified therapeutic products that reached Phase III development from 1997 to 2016, the characteristics of the products, the dates of the initiation of Phase III and product approval, proxy indicators of the innovativeness of each product, and the contribution of each biotechnology company. Companies were characterized by IPO window and clinical status of the …

Foundational Research And Nih Funding Enabling Emergency Use Authorization Of Remdesivir For Covid-19, Ekaterina Galkina Cleary, Matthew J. Jackson, Zoë Folchman-Wagner, Fred D. Ledley

Natural & Applied Sciences Faculty Publications

Emergency Use Authorization for remdesivir months after discovery of COVID-19 is unprecedented. Typically, decades of research and public-sector funding are required to establish the mature body of foundational research requisite for efficient, targeted drug discovery and development. This work quantifies the body of research related to remdesivir’s biological target, RNA-dependent RNA polymerase (RdRp), or parent chemical structure, nucleoside analogs (NcAn), through 2019, as well as NIH funding for this research 2000–2019. There were 6,567 RdRp-related publications in PubMed, including 1,263 with NIH support, and 11,073 NcAn-related publications, including 2,319 with NIH support. NIH support for RdRp research comprised 2,203 Project …

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 …

Development Of A Lectin-Fc Fusion Protein With Antiviral And Anti-Cancer Activity., Matthew William Dent

Electronic Theses and Dissertations

This thesis describes the development of a novel lectin-Fc fusion protein and its antiviral and anti-cancer activity. The molecule, Avaren-Fc (AvFc), is a fusion of a variant of the actinomycete lectin actinohivin (Avaren) and the Fc region of human IgG1, and is selective for the terminal α1,2-mannose residues found at the ends of high-mannose-type glycans that can be found on the surface of certain heavily glycosylated viruses and cancer cells. Here, AvFc was found to be able to neutralize simian immunodeficiency virus as well as Hepatitis C virus with nanomolar IC₅₀ values. Furthermore, AvFc recognizes a number of cell …

The Morality Of Compulsory Licensing As An Access To Medicines Tool, Margo A. Bagley

Faculty Articles

This Article contemplates the validity of theft rhetoric in relation to the right of countries to grant compulsory licenses from an unconventional perspective; that of biblical teachings on what it means to steal.

Part I describes the use of theft rhetoric in relation to IP infringement broadly and drug-patent compulsory licenses in particular.

Part II challenges the contention, suggested by theft rhetoric, that compulsory licenses are morally wrong as a form of stealing, by considering the meaning of theft in the context of its Judeo-Christian origins.

Part III considers the cogency of the accusation that the issuance of compulsory licenses …

Cyclodextrin As A Drug Carrier Increasing Drug Solubility, Malka Silberberg

The Science Journal of the Lander College of Arts and Sciences

The development of a new drug requires research and evaluation before the drug is approved to enter the market. One of the factors determining the efficacy of a drug is the aqueous solubility of the drug. A current problem in today’s pharmaceutical industry is the low aqueous solubility of many useful drugs. A drug with a low aqueous solubility will not readily be absorbed by the body. The low aqueous solubility of a drug is often due to the drug’s hydrophobic character. Drug enhancement methods are necessary to avoid the obstacle of drug insolubility and many methods have been developed. …

Computational Pharmacology: Simulating Circuits Of The Brain For Drug Development, Patrick D. Roberts

Systems Science Friday Noon Seminar Series

The pharmaceutical industry is approaching unsustainable research costs to develop new drug therapies for mental disease because of the high failure rate in clinical trials. These failures are due to limitations of pre-clinical studies in animal models that fail to predict the efficacy of new drugs in human subjects. The gap between pre-clinical trials and clinical trials is particularly difficult in complex mental diseases such as schizophrenia because of the complex dynamics of the brain and the multiple chemical pathways that drugs can affect.

However, many biological mechanisms associated with schizophrenia are now understood, and computational power and methods have …

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 …