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Development Of Co-Processed Plasticized Cellulose Acetate For Sustained Release Matrix Tablets, Yinqi Zhou 2012 University of Tennessee Health Science Center

Development Of Co-Processed Plasticized Cellulose Acetate For Sustained Release Matrix Tablets, Yinqi Zhou

Theses and Dissertations (ETD)

Cellulose Acetate (CA) is a polymer extensively used in pharmaceutical applications. Because of the hydrophobic nature and good film properties of CA, it is a good polymer candidate for sustained release matrix tablets. Sustained release matrix tablets of cellulose acetate can be prepared by direct compression or wet granulation methods. However, previous studies showed that a large amount of CA was required to achieve the desired sustained release profile for a sparingly soluble drug and it was difficult to formulate a highly water soluble drug by using CA as the retarding agent. Some studies concluded that CA is very sensitive ...


Preclinical Study Of Potential Antiglioma Novel Tetrahydroisoquinoline Analogs: Pharmacokinetics And Mechanism Of Action, Fei Ma 2012 University of Tennessee Health Science Center

Preclinical Study Of Potential Antiglioma Novel Tetrahydroisoquinoline Analogs: Pharmacokinetics And Mechanism Of Action, Fei Ma

Theses and Dissertations (ETD)

Gliomas, the tumors of glial cells, account for 80% of primary malignant brain tumors. In 2011, there were about 18,300 new cases of maligant gliomas in the United States alone. Patients with glioblastoma multiforme or anaplastic astrocytoma, the two major types of malignant gliomas, have a median survival of 14 months or 2 to 3 years, respectively. Therefore novel treatments for malignant glioma are urgently needed.

A novel series of tetrahydroisoquinoline derivatives with antiglioma activity has been undergoing drug metabolism/pharmacokinetics (DMPK)-guided lead optimization. EDL-291 was result from structure modification of last generation compound EDL-155. Its preclinical pharmacokinetics ...


Investigations Of Pharmacokinetic Challenges In Premature Infants, Yi Zhang 2012 University of Tennessee Health Science Center

Investigations Of Pharmacokinetic Challenges In Premature Infants, Yi Zhang

Theses and Dissertations (ETD)

Premature infants (gestational age less than 37 weeks) are considered a vulnerable patient population due to their immaturity at birth. Currently, off-label prescribing is common in younger pediatric populations, especially in premature neonates and infants, which is a primary group receiving intensive care. Unique pharmacokinetic (PK) challenges—such as limited blood volume and frequency of blood sample collections, rapid growth and continuous developmental changes, complexity of pediatric studies as well as scientific, practical, and ethical concerns— lead to the current lack of PK information and empirical dosing in premature neonates and infants. In this research, several approaches were investigated to ...


Pharmacokinetic/Pharmacodynamic (Pk/Pd) Modeling Of Anti-Neoplastic Agents, Daniel Lexcen, Ahmed H. Salem, Walid F. Elkhatib, Virginia Haynes, Ayman Noreddin 2012 University of Minnesota

Pharmacokinetic/Pharmacodynamic (Pk/Pd) Modeling Of Anti-Neoplastic Agents, Daniel Lexcen, Ahmed H. Salem, Walid F. Elkhatib, Virginia Haynes, Ayman Noreddin

Pharmacy Faculty Books and Book Chapters

"Development of tumor resistance to chemotherapeutics is related to inherent tumor variations regarding sensitivity to chemotherapeutics and to sub-optimal dosing regimens, including variation in patient pharmacokinetics that result in suboptimal exposure of tumor cells to anti-neoplastic drugs [1, 2]. The rate and extent of drug efficacy depends on the extent of drug exposure at the tumor site and the time above the effective concentration [3]. In vitro models that incorporate these pharmacokinetic and pharmacodynamic (PK/PD) principles to optimize therapeutic response may be considered the method of choice for optimizing dosing schedules before translating data from static assays to animals ...


Application Of Pharmacokinetics/Pharmacodynamics (Pk/Pd) In Designing Effective Antibiotic Treatment Regimens, Ghada F. Ahmed, Ayman Noreddin 2012 University of Minnesota

Application Of Pharmacokinetics/Pharmacodynamics (Pk/Pd) In Designing Effective Antibiotic Treatment Regimens, Ghada F. Ahmed, Ayman Noreddin

Pharmacy Faculty Books and Book Chapters

"Designing antibiotic dosing regimens is often not optimal and the dose-response relationship for most antibiotics is not well-known1. Both Pharmacokinetics (PK) and Pharmacodynamics (PD) are characteristics of antimicrobial agents that should be considered in the development of effective antibiotic therapy. By linking the concentration time profile at the site of action to the drug effect (PK/PD), the effect of varying dosage regimens against pathogens could be simulated enabling the identification of effective dosage strategies. It is known that inadequate antibiotic dosing could not only lead to a therapeutic failure, but also to the development of bacterial resistance. Importantly, the ...


Doxorubicin Loaded Polymeric Nanoparticulate Delivery System To Overcome Drug Resistance In Osteosarcoma, Michiro Susa, Arun K. Iyer, Keinosuke Ryu, Francis John Hornicek, Henry J. Mankin, Mansoor M. Amiji, Zhenfeng Duan 2012 Massachusetts General Hospital

Doxorubicin Loaded Polymeric Nanoparticulate Delivery System To Overcome Drug Resistance In Osteosarcoma, Michiro Susa, Arun K. Iyer, Keinosuke Ryu, Francis John Hornicek, Henry J. Mankin, Mansoor M. Amiji, Zhenfeng Duan

Arun Iyer

Background: Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated ...


Inhibition Of Abcb1 (Mdr1) Expression By An Sirna Nanoparticulate Delivery System To Overcome Drug Resistance In Osteosarcoma, Michiro Susa, Arun Iyer, Keinosuke Ryu, Edwin Choi, Francis Hornicek, Henry Mankin, Lara Milane, Mansoor Amiji, Zhenfeng Duan 2012 Massachusetts General Hospital

Inhibition Of Abcb1 (Mdr1) Expression By An Sirna Nanoparticulate Delivery System To Overcome Drug Resistance In Osteosarcoma, Michiro Susa, Arun Iyer, Keinosuke Ryu, Edwin Choi, Francis Hornicek, Henry Mankin, Lara Milane, Mansoor Amiji, Zhenfeng Duan

Arun Iyer

Background: The use of neo-adjuvant chemotherapy in treating osteosarcoma has improved patients’ average 5 year survival rate from 20% to 70% in the past 30 years. However, for patients who progress after chemotherapy, its effectiveness diminishes due to the emergence of multi-drug resistance (MDR) after prolonged therapy. Methodology/Principal Findings: In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure resulting from MDR, we designed and evaluated a novel drug delivery system for MDR1 siRNA delivery. Novel biocompatible, lipid-modified dextran-based polymeric nanoparticles were used as the platform for MDR1 siRNA delivery; and the ...


Encapsulation And Controlled Release Of Rhu-Erythropoietin From Chitosan Biopolymer Nanoparticles, Cody Bulmer 2012 The University of Western Ontario

Encapsulation And Controlled Release Of Rhu-Erythropoietin From Chitosan Biopolymer Nanoparticles, Cody Bulmer

Electronic Thesis and Dissertation Repository

The objective of this research project was to develop a drug delivery system for recombinant human erythropoietin (rHu-EPO), a glycoprotein hormone used in the treatment of renal anaemia and chemotherapy induced anaemia, using the biopolymer chitosan as the base component. Two types of chitosan nanoparticles were produced through ionotropic gelation using flush mixing with either tripolyphosphate (TPP) or carrageenan polymer. Chitosan-TPP and chitosan-carrageenan nanoparticles were generated under a variety of conditions to evaluate the effects of chitosan concentration, chitosan to anion mass ratio and solution pH on the nanoparticle characteristics of particle diameter, surface charge and particle size distribution. A ...


A Glycosylated Recombinant Human Granulocyte Colony Stimulating Factor Produced In A Novel Protein Production System (Avi-014) In Healthy Subjects: A First-In Human, Single Dose, Controlled Study., Roslyn Varki, Ed Pequignot, Mark C Leavitt, Andres Ferber, Walter K Kraft 2012 Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 132 South 10th Street, 1170 Main Building, Philadelphia, PA 19107, USA

A Glycosylated Recombinant Human Granulocyte Colony Stimulating Factor Produced In A Novel Protein Production System (Avi-014) In Healthy Subjects: A First-In Human, Single Dose, Controlled Study., Roslyn Varki, Ed Pequignot, Mark C Leavitt, Andres Ferber, Walter K Kraft

walter k Kraft

BACKGROUND: AVI-014 is an egg white-derived, recombinant, human granulocyte colony-stimulating factor (G-CSF). This healthy volunteer study is the first human investigation of AVI-014. METHODS: 24 male and female subjects received a single subcutaneous injection of AVI-014 at 4 or 8 mcg/kg. 16 control subjects received 4 or 8 mcg/kg of filgrastim (Neupogen, Amgen) in a partially blinded, parallel fashion. RESULTS: The Geometric Mean Ratio (GMR) (90% CI) of 4 mcg/kg AVI-014/filgrastim AUC(0-72 hr) was 1.00 (0.76, 1.31) and Cmax was 0.86 (0.66, 1.13). At the 8 mcg/kg dose ...


Inhibition Of Adhesion And Invasion Of Pseudomonas Aeruginosa To Lung Epithelial Cells: A Model Of Cystic Fibrosis Infection, Ayman Noreddin, Ghada Sawy, Walid Elkhatib, Ehab Noreddin, Atef Shibl 2012 Chapman University

Inhibition Of Adhesion And Invasion Of Pseudomonas Aeruginosa To Lung Epithelial Cells: A Model Of Cystic Fibrosis Infection, Ayman Noreddin, Ghada Sawy, Walid Elkhatib, Ehab Noreddin, Atef Shibl

Pharmacy Faculty Books and Book Chapters

"Over their life time, CF patients experience multiple infections by various pneumoniacausing bacteria [6]. With more patients surviving to adulthood, chronic infections with Pseudomonas aeruginosa are coming to the forefront as a leading cause of death [7]. Problems presented by infected CF lung are multi-dimensional; the electrolyte balance and pH of the fluids are abnormal. The mucus is thick and of an alternative composition compared to normal lung and may contribute to colonization with Pseudomonas aeruginosa [2, 3, 5]. As such, research is multi-pronged and includes gene therapy to correct the defective protein, amelioration of inflammatory response and thinning of ...


Synthesis And Evaluation Of Human Phosphodiesterases (Pde) 5 Inhibitor Analogs As Trypanosomal Pde Inhibitors. 1. Sildenafil Analogs, Cuihua Wang, Trent D. Ashton, Alden Gustafson, Nicholas D. Bland, Stefan O. Ochiana, Robert K. Campbell, Michael P. Pollastri 2012 Northeastern University

Synthesis And Evaluation Of Human Phosphodiesterases (Pde) 5 Inhibitor Analogs As Trypanosomal Pde Inhibitors. 1. Sildenafil Analogs, Cuihua Wang, Trent D. Ashton, Alden Gustafson, Nicholas D. Bland, Stefan O. Ochiana, Robert K. Campbell, Michael P. Pollastri

Michael Pollastri

Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. In this report we describe target repurposing efforts focused on trypanosomal phosphodiesterases. We outline the synthesis and biological evaluation of analogs of sildenafil (1), a human PDE5 inhibitor, for activities against trypanosomal PDEB1 (TbrPDEB1). We find that, while low potency analogs can be prepared, this chemical class is a sub-optimal starting point for further development of TbrPDE inhibitors.


Synthesis And Evaluation Of Human Phosphodiesterases (Pde) 5 Inhibitor Analogs As Trypanosomal Pde Inhibitors. 2. Tadalafil Analogs, Stefan O. Ochiana, Alden Gustafson, Nicholas D. Bland, Cuihua Wang, Michael J. Russo, Robert K. Campbell, Michael P. Pollastri 2012 Northeastern University

Synthesis And Evaluation Of Human Phosphodiesterases (Pde) 5 Inhibitor Analogs As Trypanosomal Pde Inhibitors. 2. Tadalafil Analogs, Stefan O. Ochiana, Alden Gustafson, Nicholas D. Bland, Cuihua Wang, Michael J. Russo, Robert K. Campbell, Michael P. Pollastri

Michael Pollastri

In this report we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). We outline the synthesis and biological evaluation of analogs of tadalafil, a human PDE5 inhibitor currently utilized for treatment of erectile dysfunction, and report that these analogs are weak inhibitors of TbrPDEB1.


Identification And Characterization Of Kava-Derived Compounds Mediating Tnf-Α Suppression, Michael P. Pollastri, Adrian Whitty, Jamie Cassidy Merrill, Trent D. Ashton, Salomon Amar 2012 Boston University

Identification And Characterization Of Kava-Derived Compounds Mediating Tnf-Α Suppression, Michael P. Pollastri, Adrian Whitty, Jamie Cassidy Merrill, Trent D. Ashton, Salomon Amar

Michael Pollastri

There is a substantial unmet need for new classes of drugs that block TNF-α-mediated inflammation, and particularly for small molecule agents that can be taken orally. We have screened a library of natural products against an assay measuring TNF-α secretion in lipopolysaccharide (LPS)-stimulated THP-1 cells, seeking compounds capable of interfering with the TNF-α inducing transcription factor Lipopolysaccharide Induced TNF Alpha Factor (LITAF). Among the active compounds were several produced by the kava plant (Piper mysticum), extracts of which have previously been linked to a range of therapeutic effects. When tested in vivo, a representative of these compounds, kavain, was ...


The Challenge Of Developing Robust Drugs To Overcome Resistance, Celia Schiffer, Amy C. Anderson, Michael P. Pollastri, Norton P. Peet 2012 University of Massachusetts Medical School Worcester

The Challenge Of Developing Robust Drugs To Overcome Resistance, Celia Schiffer, Amy C. Anderson, Michael P. Pollastri, Norton P. Peet

Michael Pollastri

Drug resistance is problematic in microbial disease, viral disease and cancer. Understanding at the outset that resistance will impact the effectiveness of any new drug that is developed for these disease categories is imperative. In this Perspective, we detail approaches that have been taken with selected drug targets to reduce the susceptibility of new drugs to resistance mechanisms. We will also define the concepts of robust drugs and resilient targets, and discuss how the design of robust drugs and the selection of resilient targets may lead to successful strategies for combating resistance.


The Fit-Hansa Demonstrates Reliability And Convergent Validity Of Functional Performance In Patients With Shoulder Disorders, Prajyot Kumta, Joy C. MacDermid, Saurabh Mehta, Paul W. Stratford 2012 McMaster University

The Fit-Hansa Demonstrates Reliability And Convergent Validity Of Functional Performance In Patients With Shoulder Disorders, Prajyot Kumta, Joy C. Macdermid, Saurabh Mehta, Paul W. Stratford

Physical Therapy Faculty Research

Study

DesignPsychometric study design.

Objectives

To assess the test-retest reliability and convergent validity of the Functional Impairment Test-Hand and Neck/Shoulder/Arm (FIT-HaNSA) in patients with shoulder disorders.

Background

Performance tests that assess functional ability of patients with shoulder disorders can provide useful information for making clinical or return-to-activity decisions. No performance-based shoulder test has yet demonstrated sufficient relevance or clinical measurement properties. The FIT-HaNSA examines upper extremity performance during repetitive tasks that emphasize shoulder reaching and static postures and, therefore, has greater relevance for assessing performance.

Methods

Thirty-six patients with shoulder disorders and 65 healthy controls were recruited for ...


Structural Properties Of Thermoresponsive Poly(N-Isopropylacrylamide)-Poly(Ethyleneglycol) Microgels, J. Clara-Rahola, A. Fernandez-Nieves, B. Sierra-Martin, A. B. South, L. Andrew Lyon, J. Kohlbrecher, A. F. Barbero 2012 University of Almeria

Structural Properties Of Thermoresponsive Poly(N-Isopropylacrylamide)-Poly(Ethyleneglycol) Microgels, J. Clara-Rahola, A. Fernandez-Nieves, B. Sierra-Martin, A. B. South, L. Andrew Lyon, J. Kohlbrecher, A. F. Barbero

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The application of RNA interference to treat disease is an important yet challenging concept in modern medicine. In particular, small interfering RNA (siRNA) have shown tremendous promise in the treatment of cancer. However, siRNA show poor pharmacological properties, which presents a major hurdle for effective disease treatment especially through intravenous delivery routes. In response to these shortcomings, a variety of nanoparticle carriers have emerged, which are designed to encapsulate, protect, and transport siRNA into diseased cells. To be effective as carrier vehicles, nanoparticles must overcome a series of biological hurdles throughout the course of delivery. As a result, one promising ...


Bsa Nanoparticles For Sirna Delivery: Coating Effects On Nanoparticle Properties, Plasma Protein Adsorption, And In Vitro Sirna Delivery, Haran Yogasundaram, Markian Stephan Bahniuk, Harsh-Deep Singh, Hamidreza Montazeri Aliabadi, Hasan Uludag, Larry David Unsworth 2012 University of Alberta

Bsa Nanoparticles For Sirna Delivery: Coating Effects On Nanoparticle Properties, Plasma Protein Adsorption, And In Vitro Sirna Delivery, Haran Yogasundaram, Markian Stephan Bahniuk, Harsh-Deep Singh, Hamidreza Montazeri Aliabadi, Hasan Uludag, Larry David Unsworth

Pharmacy Faculty Articles and Research

Developing vehicles for the delivery of therapeutic molecules, like siRNA, is an area of active research. Nanoparticles composed of bovine serum albumin, stabilized via the adsorption of poly-L-lysine (PLL), have been shown to be potentially inert drug-delivery vehicles. With the primary goal of reducing nonspecific protein adsorption, the effect of using comb-type structures of poly(ethylene glycol) (1 kDa, PEG) units conjugated to PLL (4.2 and 24 kDa) on BSA-NP properties, apparent siRNA release rate, cell viability, and cell uptake were evaluated. PEGylated PLL coatings resulted in NPs with ζ-potentials close to neutral. Incubation with platelet-poor plasma showed the ...


Shaping The Operations Research Agenda For Antiretroviral-Based Prevention Products For Women: Gels And Rings, Martha Brady, C. Elizabeth McGrory 2012 Population Council

Shaping The Operations Research Agenda For Antiretroviral-Based Prevention Products For Women: Gels And Rings, Martha Brady, C. Elizabeth Mcgrory

HIV and AIDS

This report summarizes discussions from a two-day international experts consultation meeting in 2012 on preparing for the successful introduction of women-centered antiretroviral-based HIV prevention methods. It examines the limits and expectations of operations research in antiretroviral health technologies.


Confounding Issues In Estimation Of Patient-Specific Pharmacokinetic Parameters And Dosage Individualization Of Aminoglycosides, Reza Mehvar 2012 Chapman University

Confounding Issues In Estimation Of Patient-Specific Pharmacokinetic Parameters And Dosage Individualization Of Aminoglycosides, Reza Mehvar

Pharmacy Faculty Articles and Research

Aminoglycoside antibiotics are usually administered by multiple short intravenous infusions at fixed intervals. Today, equations reported 35 years ago by Sawchuk and Zaske are still the cornerstone of methods used for determination of patient-specific pharmacokinetic parameters of aminoglycosides and individualization of drug dosage regimens in many clinical settings. Additionally, these methods are included in many clinical pharmacology curricula in pharmacy and other related fields. However, there are a few issues with regard to the application and/or modification of this method in clinical settings, which may result in some confusion among novice clinicians. For example, serum samples collected from different ...


N-Myristoylglutamic Acid Derivative Of 3′-Fluoro-3′- Deoxythymidine As An Organogel, Bhupender S. Chhikara, Rakesh Tiwari, Keykavous Parang 2012 University of Rhode Island

N-Myristoylglutamic Acid Derivative Of 3′-Fluoro-3′- Deoxythymidine As An Organogel, Bhupender S. Chhikara, Rakesh Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

Designing microbicidal gels of anti-HIV drugs for local application to prevent HIV infection is a subject of major interest. 3′-Fluoro-3′-deoxythymidine (FLT), a nucleoside reverse transcriptase inhibitor (NRTI), was conjugated with a N-myristoylglutamate scaffold. The conjugate showed gelation at 1% (w/w) in different organic solvents, such as toluene, dichloromethane, and chloroform. The gels were opaque and stable at room temperature. The results indicate that myristoyl glutamate derivative of FLT can form an organogel. The gel could have potential application as a topical anti-HIV microbicidal agent.


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