Browsing by Subject "Pharmacokinetics"

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Anxiolytic effects of exogenous intranasal testosterone in humans
(2019-07-29) Jin, Shuo; Josephs, Robert A.; Harden, Kathryn P; Pruessner, Jens; Smits, Jasper A
Higher levels of testosterone have been associated with fewer anxiety symptoms and greater psychological wellbeing. However, additional research is needed to advance the clinical use of testosterone in mental healthcare. This dissertation aims to investigate the anxiolytic effects of testosterone in men and women through three studies. The first study examines the pharmacokinetic profile of a novel testosterone nasal spray, designed for the safe and rapid delivery of exogenous testosterone in men and women. The second study leverages the utility of this novel spray preparation, and investigates the effect of intranasal testosterone on subjective anxiety during a psychosocial challenge. The final study extends the anxiolytic effects of exogenous testosterone in women, and explores the effect of intranasal testosterone on test anxiety and cognitive performance. Collectively, these three studies aim to contribute to a broader understanding of the anxiolytic effects of testosterone, and with it, the potential for testosterone to act as a novel pharmaceutical in the treatment of anxiety.
The development of an interactive simulation for pharmacokinetics learning
(2011-08) Li, Yin, master of arts in curriculum and instruction; Liu, Min, Ed. D.; Hughes, Joan
This report accounts the experience of a faculty member’s intention of creating an innovative interactive learning simulation in the field of pharmacokinetics to support the faculty member’s teaching and addresses his students’ learning needs. The report also describes the collaboration process between the faculty member and the instructional technology support units through the different phases of design, development, implementation and assessment on the simulation. It also discusses a faculty member’s role in using technology to enhance teaching and learning under university context.
Improved inhalation therapies of brittle powders
(2013-12) Carvalho, Simone Raffa; Williams, Robert O., 1956-
Advancements in pulmonary drug delivery technologies have improved the use of dry powder inhalation therapy to treat respiratory and systemic diseases. Despite remarkable improvements in the development of dry powder inhaler devices (DPIs) and formulations in the last few years, an optimized DPI system has yet to be developed. In this work, we hypothesize that Thin Film Freezing (TFF) is a suitable technology to improve inhalation therapies to treat lung and systemic malignancies due to its ability to produce brittle powder with optimal aerodynamic properties. Also, we developed a performance verification test (PVT) for the Next Generation Cascade Impactor (NGI), which is one of the most important in vitro characterization methods to test inhalation. In the first study, we used TFF technology to produce amorphous and brittle particles of rapamycin, and compared the in vivo behavior by the pharmacokinetic profiles, to its crystalline counterpart when delivered to the lungs of rats via inhalation. It was found that TFF rapamycin presented higher in vivo systemic bioavailability than the crystalline formulation. Subsequently, we investigated the use of TFF technology to produce triple fixed dose therapy using formoterol fumarate, tiotropium bromide and budesonide as therapeutic drugs. We investigated applications of this technology to powder properties and in vitro aerosol performance with respect to single and combination therapy. As a result, the brittle TFF powders presented superior properties than the physical mixture of micronized crystalline powders, such as excellent particle distribution homogeneity after in vitro aerosolization. Lastly, we developed a PVT for the NGI that may be applicable to other cascade impactors, by investigating the use of a standardized pressurized metered dose inhaler (pMDI) with the NGI. Two standardized formulations were developed. Formulations were analyzed for repeatability and robustness, and found not to demonstrate significant differences in plate deposition using a single NGI apparatus. Variable conditions were introduced to the NGI to mimic operator and equipment failure. Introduction of the variable conditions to the NGI was found to significantly adjust the deposition patterns of the standardized formulations, suggesting that their use as a PVT could be useful and that further investigation is warranted.
Improved prostate cancer therapeutics through KinetiSol® enabled amorphous solid dispersions of Abiraterone
(2019-12) Gala, Urvi Hasmukhlal; Williams, Robert O., III, 1956-; Miller, Dave A.; Smyth, Hugh D; Zhang, Feng
A majority of anticancer drugs have inherently poor water solubility, which limits their oral bioavailability and therapeutic potential. In Chapter one, the ability of amorphous solid dispersions (ASDs), to improve the dissolution, pharmacokinetics, efficacy and safety of anticancer drugs is demonstrated. Abiraterone is a poorly water soluble drug used in treatment of prostate cancer. Its commercial formulation Zytiga®, contains slightly more soluble prodrug, abiraterone acetate. Zytiga has poor oral bioavailability, high pharmacokinetic variability and high food effect, which limits its therapeutic potential. Abiraterone has a high melting point and limited solubility in organic solvents, which makes its ASD development difficult with conventional technologies. In Chapter two, KinetiSol® technology, which is a solvent free thermokinetic process, is utilized and an abiraterone ASD is developed for the first time. In addition to contemporary long-chain polymers, a short-chain oligomer is explored for development of binary and ternary KinetiSol processed ASDs (KSD) of abiraterone. Hydroxypropyl beta cyclodextrin (HPBCD) is identified as a suitable carrier for abiraterone KSD. In Chapter three, the impact of drug loading on abiraterone-HPBCD KSD properties is investigated. 10 to 50 % w/w drug loaded abiraterone KSDs are developed. The solid-state interaction studies revealed that abiraterone forms a complex with HPBCD in the KSD. Overall, as drug loading increased, the stability, in-vitro and in-vivo performance decreased. Thus, 10% drug loading is found to be optimum. In Chapter four, an optimal KSD of the prodrug abiraterone acetate is developed and compared with abiraterone KSD. A physicochemical stability study revealed, that the abiraterone acetate KSD is chemically unstable, while abiraterone KSD is both physically and chemically stable. Both KSDs have similar in-vitro and in-vivo performance. Thus, it is concluded that the active drug abiraterone’s KSD is more ideal and overcomes the issues associated with the prodrug use. In Chapter five, a preclinical prostate cancer xenograft model is developed to investigate the pharmacokinetic and pharmacodynamic performance of abiraterone KSD. This study demonstrated a statistically significant tumor growth inhibition of 33.1% by the abiraterone KSD. Thus, these studies suggest the potential for the abiraterone KSD formulation to improve therapeutic outcomes for prostate cancer patients.
Inhaled voriconazole formulations for invasive fungal infections in the lungs
(2011-12) Beinborn, Nicole Angela; Williams, Robert O., 1956-
Attention has begun to focus on the pulmonary delivery of antifungal agents for invasive fungal infections as inhalation of the fungal spores is often the initial step in the pathogenesis of many of these infections. Invasive fungal infection in the lungs in immunocompromised patients has high mortality rates despite current systemic (oral or intravenous) therapies. However, drug delivery of antifungal agents directly to the lungs could potentially result in high concentrations of drug in the lungs, a quicker onset of action, and reduction of systemic side effects. Voriconazole (VRC) is a second, generation triazole antifungal agent with increased potency, a broad spectrum of antifungal activity, and a fairly poor aqueous solubility. It is the recommended therapeutic agent for the treatment of Invasive Pulmonary Aspergillosis (IPA), and its use has improved therapeutic outcomes in immunocompromised patients with IPA. Still, systemic administration by oral or intravenous delivery is limited by high inter- and intra-patient pharmacokinetic variability, many potential drug interactions, and a narrow therapeutic index with many adverse effects, leading to clinical failures. Therefore, development of novel particulate formulations containing VRC for targeted drug delivery to the lungs is critical to improving therapeutic outcomes in patients with invasive fungal infections in the lungs. Within the framework of this dissertation, two particle engineering processes, thin film freezing (TFF) and advanced evaporative precipitation into aqueous solution (AEPAS), were investigated. The goal was to investigate microcrystalline VRC, nanocrystalline VRC, and nanostructured amorphous VRC formulations suitable for pulmonary delivery and to determine the effect of morphology on the in vivo deposition and distribution of inhaled particulate VRC formulations. TFF process parameters significantly affected the solid state properties and aerodynamic performance of the dry powder formulations containing VRC. Following dry powder insufflation into the lungs of mice, microstructured crystalline TFF-VRC achieved higher and more prolonged concentrations of VRC in the lungs with slightly lower systemic bioavailability than nanostructured amorphous TFF-VRC-PVP K25. AEPAS and TFF of template nanoemulsions did not lead to production of crystalline nanoparticles, as predicted. In particular, VRC proved to be a difficult molecule to stabilize in the nanocrystalline and nanostructured amorphous states. Ultimately, this body of work demonstrated that the particle engineering process, TFF, could be used to develop voriconazole formulations suitable for dry powder inhalation with more favorable pharmacokinetic parameters compared to inhaled voriconazole solution.
Peptide analysis by mass spectrometry : applications to pharmacokinetic analysis of opioid peptides
(1995-05) Márquez, Cristina del Valle; Not available
Pharmacokinetics and cytoprotective evaluation of Caffeic Acid Phenethyl Amide and fluorinated derivatives against oxidative stress
(2012-12) Yang, John; Stavchansky, Salomon; Bowman, Phillip D; Kerwin, Sean M; Williams, Robert O; McGinity, James W
Ischemic injury occurs when the flow of blood is reduced or blocked to an area of the body and can cause significant tissue damage by generation of reactive oxygen species (ROS), activation of apoptotic pathways and through induction of the inflammatory response. Restoration of blood flow and reperfusion of the blocked site, while essential, can generate a second injury that itself needs to be controlled. Together the two injuries are termed ischemia/reperfusion (I/R) injury. This type of injury is frequently encountered in medicine and is a major medical problem. Therapeutic strategies to combat I/R injury include the introduction of compounds that can scavenge ROS or can induce metabolic pathways with the effect of inhibiting apoptosis. Caffeic Acid Phenethyl Ester (CAPE), a polyphenolic compound found in propolis, has been shown to protect a variety of cells types against ROS in vitro and has also been shown to induce a variety of genes including hemeoxygenase 1 (HMOX-1) , an enzyme that has been implicated in a cytoprotective pathway. Despite showing significant cytoprotection of cells against oxidant stress in vitro, CAPE is readily hydrolyzed in plasma and is also quickly removed from circulation. This result may explain the limited cytoprotective effects of CAPE in vivo. We have synthesized a series of CAPE amide derivatives, including Caffeic Acid Phenethyl Amide (CAPA), with the aim of improving CAPE’s stability properties while maintaining the cytoprotective effects of the parent compound. We found that CAPA, in addition to 2 other amide derivatives, were able to protect human umbilical vein endothelial cells (HUVEC) against ROS to a similar degree as CAPE. In addition, we have observed significant improvement in plasma stability of CAPA over CAPE at multiple temperatures. The elimination half-life of CAPA from the systemic circulation was also seen to be significantly improved over CAPE following intravenous administration to male Sprague-Dawley rats. The longer residence time of CAPA over CAPE in circulation may potentially result in greater cytoprotection in vivo.
Repurposing niclosamide : oral and inhaled delivery of niclosamide using hot-melt extrusion and thin film freezing technologies
(2023-03-29) Jara Gonzalez, Miguel Orlando; Williams, Robert O., III, 1956-; Smyth, Hugh D; Zhang, Feng; Maniruzzaman, Mohammed; Morales, Javier O
This research aims to enable the repurposing of niclosamide as a viable pharmaceutical product for treating cancer and viral infections, including COVID-19. Niclosamide is a unique drug candidate because although it was approved for use over 60 years ago as an anthelmintic medication, several studies have shown its potential as a multi-targeted cancer therapy, broad-spectrum antiviral (including COVID-19), and antibacterial, among several others. There have previously been several attempts to repurpose niclosamide in clinical trials. Unfortunately, niclosamide is a poorly water-soluble molecule with low bioavailability, which has negatively affected the outcomes of these studies. To overcome this challenge, we developed two different niclosamide formulations based on the targeted disease state as well as the intended route of administration. We prepared an amorphous solid dispersion of niclosamide (Niclosamide ASD) as an oral therapy for prostate cancer and a dried powder inhaler to treat COVID-19 infection. Niclosamide ASD was manufactured using hot-melt extrusion. This ASD generates nanoparticles during its dissolution, increasing niclosamide’s apparent 5 solubility by more than 60-fold (i.e. from 6.6 ± 0.4 to 481.7 ± 22.2 μg/mL) and its oral bioavailability in Sprague–Dawley rats. This formulation generates amorphous nanoparticles during its dissolution, confirmed by cryo-TEM and Wide-angle X-ray scattering. Nevertheless, niclosamide ASD undergoes recrystallization in acidic media, and an enteric oral dosage form of niclosamide ASD was formulated without hindering the generation of nanoparticles while maintaining the increase in the niclosamide’s apparent solubility. The formulation successfully increased niclosamide’s plasma levels in dogs when compared to a niclosamide solution prepared using organic solvents. Niclosamide dried powder inhaler was prepared using the Thin Film Freezing technology (TFF). This formulation proved to be safe after an acute three-day, multi-dose pharmacokinetic study in rats, as evidenced by histopathology analysis. In addition, it achieved lung concentrations above the required IC90 levels of SARS-CoV-2 for at least 24 h after a single administration in Syrian golden hamsters. Efficacy studies confirmed that the formulation effectively reduces viral load in infected hamsters that had been inoculated 24 hours prior with intranasal SARS-CoV-2. This formulation was transferred to a pharmaceutical company and has successfully completed phase 1 clinical trials.