Open Access. Powered by Scholars. Published by Universities.®

Articles 1 - 14 of 14

Full-Text Articles in Pharmaceutics and Drug Design

The Development Of Methods To Account For Physiologic Dynamic Changes And Their Effects On The Pharmacokinetics Of Therapeutic Monoclonal Antibodies And Other Therapeutics, Josiah Thomas Ryman May 2017

The Development Of Methods To Account For Physiologic Dynamic Changes And Their Effects On The Pharmacokinetics Of Therapeutic Monoclonal Antibodies And Other Therapeutics, Josiah Thomas Ryman

Theses and Dissertations (ETD)

Physiologic changes in the body can drastically affect the clearance of a medication, and therefore increase the variability in exposure to the medication. Physiologic changes that can have a profound effect on the exposure of a medication can stem from changes CYP enzymes, transport proteins, binding protein expression, organ function, immune reactivity, and health status to name a few; with the focus of this dissertation on the dynamic changes in the ontogeny of MRP2 (an apical liver transport protein) and the dynamic changes caused by an immune response to a therapeutic monoclonal antibody (mAb). Several approaches can be used to ...


Biosimilars In Rheumatology: What The Clinician Should Know, Gilberto Castaneda-Hernandez, Rodrigo Gonzalez-Ramirez, Jonathan Kay, Morton A. Scheinberg May 2016

Biosimilars In Rheumatology: What The Clinician Should Know, Gilberto Castaneda-Hernandez, Rodrigo Gonzalez-Ramirez, Jonathan Kay, Morton A. Scheinberg

Jonathan Kay

Biosimilars are now a reality in rheumatology. Although analytical and non-clinical procedures to establish similarity have evolved significantly, clinical trials demonstrating equivalent efficacy and safety are absolutely required for all biosimilars. The design of such trials, including equivalence and non-inferiority statistical approaches, are discussed. Clinical evidence on biosimilars that have been approved recently or are presently being developed for use in rheumatology is also reviewed and contrasted with that available for biomimics (or intended copies), which are non-innovator biologics that are marketed in several countries but have not undergone review according to a regulatory pathway for biosimilars.


Optimization Of Lead Spectinamide Compounds As Novel Anti-Tuberculosis Agents With A Pharmacometric Approach, Ashit Rasendu Trivedi Dec 2015

Optimization Of Lead Spectinamide Compounds As Novel Anti-Tuberculosis Agents With A Pharmacometric Approach, Ashit Rasendu Trivedi

Theses and Dissertations (ETD)

In an effort to combat the global Tuberculosis pandemic, Dr.Richard E. Lee and his group at St.Jude Children’s Research Hospital designed a novel series of anti-tuberculosis agents, spectinamides – semi-synthetic analogs of spectinomycin. Spectinamides are a potent inhibitor of mycobacterial ribosomes and overcome efflux mediated drug resistance in M. tb. Spectinamides have shown an excellent in vitro activity, which makes them well suited for further lead optimization and preclinical development. We hypothesized that through pharmacokinetic (PK) and pharmacodynamics (PD) model-based dosing optimization studies, we could strategically guide the selection and refinement of more potent and effective anti-TB spectinamides ...


Biosimilars In Rheumatology: What The Clinician Should Know, Gilberto Castaneda-Hernandez, Rodrigo Gonzalez-Ramirez, Jonathan Kay, Morton A. Scheinberg May 2015

Biosimilars In Rheumatology: What The Clinician Should Know, Gilberto Castaneda-Hernandez, Rodrigo Gonzalez-Ramirez, Jonathan Kay, Morton A. Scheinberg

Open Access Articles

Biosimilars are now a reality in rheumatology. Although analytical and non-clinical procedures to establish similarity have evolved significantly, clinical trials demonstrating equivalent efficacy and safety are absolutely required for all biosimilars. The design of such trials, including equivalence and non-inferiority statistical approaches, are discussed. Clinical evidence on biosimilars that have been approved recently or are presently being developed for use in rheumatology is also reviewed and contrasted with that available for biomimics (or intended copies), which are non-innovator biologics that are marketed in several countries but have not undergone review according to a regulatory pathway for biosimilars.


Effects Of Hepatic Ischemia-Reperfusion Injury On The P-Glycoprotein Activity At The Liver Canalicular Membrane And Blood-Brain Barrier Determined By In Vivo Administration Of Rhodamine 123 In Rats, M. K. Miah, Imam H. Shaik, Ulrich Bickel, Reza Mehvar Jan 2014

Effects Of Hepatic Ischemia-Reperfusion Injury On The P-Glycoprotein Activity At The Liver Canalicular Membrane And Blood-Brain Barrier Determined By In Vivo Administration Of Rhodamine 123 In Rats, M. K. Miah, Imam H. Shaik, Ulrich Bickel, Reza Mehvar

Pharmacy Faculty Articles and Research

Purpose To investigate the effects of normothermic hepatic ischemia-reperfusion (IR) injury on the activity of P-glycoprotein (P-gp) in the liver and at the blood-brain barrier (BBB) of rats using rhodamine 123 (RH-123) as an in vivo marker.

Methods Rats were subjected to 90 min of partial ischemia or sham surgery, followed by 12 or 24 h of reperfusion. Following intravenous injection, the concentrations of RH-123 in blood, bile, brain, and liver were used for pharmacokinetic calculations. The protein levels of P-gp and some other transporters in the liver and brain were also determined by Western blot analysis.

Results P-gp protein ...


The Pharmacokinetics Of Metal-Based Engineered Nanomaterials, Focusing On The Blood-Brain Barrier, Mo Dan Jan 2013

The Pharmacokinetics Of Metal-Based Engineered Nanomaterials, Focusing On The Blood-Brain Barrier, Mo Dan

Theses and Dissertations--Pharmacy

Metal-based engineered nanomaterials (ENMs) have potential to revolutionize diagnosis, drug delivery and manufactured products, leading to greater human ENM exposure. It is crucial to understand ENM pharmacokinetics and their association with biological barriers such as the blood-brain barrier (BBB). Physicochemical parameters such as size and surface modification of ENMs play an important role in ENM fate, including their brain association. Multifunctional ENMs showed advantages across the highly regulated BBB. There are limited reports on ENM distribution among the blood in the brain vasculature, the BBB, and brain parenchyma.

In this study, ceria ENM was used to study the effect of ...


Preclinical Study Of Potential Antiglioma Novel Tetrahydroisoquinoline Analogs: Pharmacokinetics And Mechanism Of Action, Fei Ma May 2012

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 ...


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

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 Apr 2012

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 ...


Hepatic Immunosuppressive Effects Of Systemically- Administered Novel Dextran-Methylprednisolone Prodrugs With Peptide Linkers In Rats, Imam H. Shaik, Hitesh K. Agarwal, Keykavous Parang, Reza Mehvar Jan 2012

Hepatic Immunosuppressive Effects Of Systemically- Administered Novel Dextran-Methylprednisolone Prodrugs With Peptide Linkers In Rats, Imam H. Shaik, Hitesh K. Agarwal, Keykavous Parang, Reza Mehvar

Pharmacy Faculty Articles and Research

The hepatic immunosuppressive activities of two novel dextran prodrugs of methylprednisolone (MP) containing one (DMP1) or five (DMP5) amino acids as linkers were studied in rats. At various times (02 weeks) after intravenous administration of single 5 mg/kg (MP equivalent) doses of each prodrug or MP succinate (MPS), livers were isolated and immunologically stimulated ex vivo with lipopolysaccharide. The concentrations of tumor necrosis factor (TNF)-a in the outlet perfusate were then quantitated to assess immune response. Additionally, the concentrations of DMP1, DMP5, and/or MP were measured in the liver. MPS, DMP5, or DMP1 injections caused a maximum ...


Preclinical Pharmacology Of The Mdm2 Antagonist Nutlin-3a, Fan Zhang Dec 2011

Preclinical Pharmacology Of The Mdm2 Antagonist Nutlin-3a, Fan Zhang

Theses and Dissertations (ETD)

Nutlin-3a is an MDM2-p53 interaction antagonist that is under investigation in preclinical models for a variety of pediatric malignancies, including neuroblastoma, retinoblastoma, leukemia, and rhabdomyosarcoma. In the current research, we conducted preclinical pharmacology studies of nutlin-3a to evaluate the synergistic effect of the nutlin-3a and topotecan combination on neuroblastoma cell growth, to assess the effect of nutlin-3a on breast cancer resistance protein (BCRP), and to characterize the disposition of nutlin-3a in the mouse plasma and multiple tissues.

Activating the p53 pathway might offer a new therapy for neuroblastoma. In the first part of the study, we assessed the effect of ...


Pharmacokinetic And Pharmacodynamic Studies Of A Novel Spectinamide Series Of Antituberculosis Agents, V. N. R. Pavan Kumar Vaddady May 2011

Pharmacokinetic And Pharmacodynamic Studies Of A Novel Spectinamide Series Of Antituberculosis Agents, V. N. R. Pavan Kumar Vaddady

Theses and Dissertations (ETD)

Spectinamides are novel amide derivatives of the antibiotic spectinomycin that have emerged as a new class of agents to treat tuberculosis. These agents showed potent in vitro activity against Mycobacterium tuberculosis (MTB) compared to spectinomycin and in a preliminary in vivo study in interferon gamma (IFN‑γ) knockout mice, spectinamide Lee1329 reduced the lung bacillary load of TB comparable to streptomycin. We hypothesized that the application of an iterative pharmacokinetics and pharmacodynamics (PK/PD) guided approach would facilitate the optimization of these lead compounds suitable for further development.

A series of in vitro experiments including parallel artificial membrane permeability assay ...


A Pharmacokinetics And Pharmacodynamics (Pk/Pd) Guided Approach To Lead Optimization Of Nitrofuranylamide Anti-Tuberculosis Agents, Nageshwar Rao Budha May 2009

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 ...


Dextran-Methylprednisolone Succinate As A Prodrug Of Methylprednisolone: Plasma And Tissue Disposition, Xiaoping Zhang, Reza Mehvar Dec 2001

Dextran-Methylprednisolone Succinate As A Prodrug Of Methylprednisolone: Plasma And Tissue Disposition, Xiaoping Zhang, Reza Mehvar

Pharmacy Faculty Articles and Research

Plasma and tissue disposition of a macromolecular prodrug of methylprednisolone (MP), dextran (70 kDa)–methylprednisolone succinate (DMP), was studied in rats. Single 5‐mg/kg doses of DMP or unconjugated MP were administered into the tail veins of different groups of rats (n  = 4/group/time point). Blood (cardiac puncture) and tissues (liver, spleen, kidney, heart, lung, thymus, and brain) were collected at various times after DMP (0–96 h) or MP (0–2 h) injections. Concentrations of DMP and MP in samples were analyzed by size‐exclusion chromatography (SEC) and reversed‐phase high‐performance liquid chromatography (HPLC), respectively. Conjugation ...