Pharmacology Commons^™

Development Of Long-Acting Antiviral Drug Nanoformulations, Denise Cobb

Theses & Dissertations

Antiretroviral therapy (ART) has improved the quality and duration of life for people living with human immunodeficiency virus (HIV) infection. However, opportunities to improve its profile abound. ART is limited by putative viral reservoir penetrance, emergence of viral mutations, inherent toxicities, and regimen non-adherence. These highlight the need improved drug delivery schemes. Previously, our lab has demonstrated that targeting mononuclear phagocytes for antiretroviral drug delivery extends drug half-life and improves penetrance into viral reservoirs, addressing these limitations of ART. Herein, we developed synthetic and biologic antiretroviral (ARV) drug nanocarriers improve the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ARVs through …

Development Of An Lc-Esi-Ms/Ms Method For Determination Of A Novel Pyrrolomycin (Mp-1) And Application To Pre-Clinical Adme Studies, Wafaa N. Aldhafiri

Theses & Dissertations

A rapid, selective, and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitation of a novel Pyrrolomycin (MP-1) in mouse plasma. MP-1 was extracted from plasma utilizing a structural analog (PL-3) as the internal standard (IS). Analyte separation was achieved using a Waters Acquity UPLC®BEH C18 column (1.7 µm, 100 x 2.1 mm) protected with Acquity UPLC C18 guard column. Mobile phase consisted of 0.1% acetic acid in water (10%) and methanol (90%) at a total flow rate of 0.25 mL/min. The mass spectrometer was operated at unit resolution in the multiple reaction …

Theranostics For Antiretroviral Biodistribution And Pharmacokinetics, Brendan M. Ottemann

Theses & Dissertations

RATIONALE: Our laboratories birthed the field of human immunodeficiency virus (HIV) theranostics. The new field allows simultaneous detection (diagnostics) and treatment (therapeutic) for the identification, treatment and inevitable elimination of virus in cell and tissue compartments. By employing theranostics, antiretroviral drugs (ARVs) can be tracked in lymph nodes, gut, spleen and liver. Cellular viral reservoirs including CD4+ T cell populations and mononuclear phagocytes (MP; monocytes, macrophages, microglia and dendritic cells) along with subcellular endosomal structures can now be targeted for drug delivery bringing therapeutics to areas where virus replicates. The overarching idea rests in improving precision targeted ARV delivery. …

Synthesis And Characterization Of A Long-Acting Emtricitabine Prodrug Nanoformulation, Ibrahim M. Ibrahim

Theses & Dissertations

The introduction of highly active antiretroviral therapy led to a paradigm shift in the management of HIV/AIDS changing a disease considered “a death sentence” to “a manageable chronic disease”. Nevertheless, challenges exist for successful treatment of HIV, including patient adherence to the complex daily regimens and the inability of current formulations to target viral sanctuaries. Introduction of nanoformulated antiretroviral therapy (ART) is a promising alternative to tackle these challenges. Our laboratory has been focusing on developing long-acting (LA) nanoformulated antiretrovirals and has succeeded in developing LA integrase inhibitors. However, challenges for this approach extend to a range of short-acting hydrophilic …

Development Of A Long-Acting Nanoformulation Of Dolutegravir For Prevention And Treatment Of Hiv-1 Infection, Brady Sillman

Theses & Dissertations

Dolutegravir (DTG) is a potent human immunodeficiency virus type 1 (HIV-1) integrase strand-transfer inhibitor (INSTI) with a high barrier to viral drug resistance. However, opportunities to improve its profile abound. These include extending the drug’s apparent half-life, increasing penetrance to “putative” viral reservoirs, and reducing inherent toxicities. These highlight, in part, the need for long-acting, slow effective release antiretroviral therapy (LASER ART) delivery schemes. A long-acting (LA) DTG was made by synthesizing a hydrophobic and lipophilic prodrug encased with poloxamer (P407) surfactant. This modified DTG (MDTG) reduced systemic metabolism and polarity, increased lipophilicity and membrane permeability, improved encapsulation, and formed …

Target Validation And Pharmacological Characterization Of Novel Nmdar Modulators, Kiran Sapkota

Theses & Dissertations

The N-methyl-D aspartate receptors (NMDARs) are ligand-gated ion channels, which play important roles in learning and memory. Excessive activity of NMDARs is implicated in damage due to stroke and neurodegenerative diseases, whereas hypoactivity of NMDARs contributes to schizophrenia. The initial goal of my dissertation is to evaluate the potential role of the GluN2D-containing NMDARs in neuropathological, behavioral and cognitive alterations associated with schizophrenia and characterize the pharmacology and mechanisms of action of NMDAR modulators which could potentially be used to modulate these receptors in schizophrenia.

A subanesthetic dose of the NMDAR antagonist ketamine elicits symptoms of schizophrenia. This property led …