Electronic Theses and Dissertations

Date of Award

1-1-2020

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

S Narasimha Murthy

Second Advisor

Michael A Repka

Third Advisor

Dhammika NP Nanayakkara

School

University of Mississippi

Relational Format

dissertation/thesis

Abstract

Safety of therapeutics is one of the primary concerns during the treatment of any ailments. Most of the toxic effects of drugs occurs due to accumulation of drug in organs, which is dependent on the dosage of the drug. The ideal therapy should minimize the risk of causing adverse events at the same time elicit intended therapeutic effects. Vigabatrin (VGB) is an antiepileptic drug used primarily in the treatment of infantile spasms and it acts by inhibiting gamma amino butyric acid (GABA) transaminase thereby increasing inhibitory neurotransmitter GABA levels. At therapeutic doses, VGB accumulates in retina leading to peripheral visual field defects and retinal degeneration. To alleviate retinal toxicity of VGB, different approaches have been explored to decrease the ocular accumulation of VGB and to protect retina from deleterious effects of VGB. Intranasal administration approach was investigated to deliver VGB directly to brain via olfactory region. The in vivo acute, sub-acute and pharmacodynamic studies were performed in Sprague Dawley rats by administering VGB through intraperitoneal and intranasal routes. The mechanism of VGB transport across blood retinal barrier was studied using retinal epithelial cells (ARPE-19) cells. The in vitro and in vivo studies were performed to evaluate the mechanism involved in retinal uptake of VGB and identify approach to decrease VGB retinal uptake. The effects of VGB on retinal neuronal (R28) and ARPE-19 cells were studied. The cytoprotective effect of silymarin and taurine on VGB induced retinal toxicity was investigated. The subacute intranasal administration decreased retinal VGB levels and histological changes compared to intraperitoneal administration. Intranasal pharmacodynamic study demonstrated smaller dose produced significant antiepileptic activity with prolonged duration of VGB action. The ARPE19 cellular transport studies showed Na+/Cl- dependent transporter, TauT was involved in retinal VGB uptake. Further, in vitro cell uptake and in vivo SD rat studies demonstrated TauT inhibitors decreased VGB retinal uptake, thus confirming role of TauT in retinal uptake of VGB. The in vitro cell toxicity studies demonstrated, VGB treatment produced cell death in ARPE19 and R28 cells are due to apoptosis and necrosis, respectively. Further, studies demonstrated antioxidants silymarin and taurine constituents decreased VGB induced cell toxicity. The study results demonstrate intranasal administration of VGB along with a safe TauT inhibitor and an antioxidant as a supplement would be beneficial to prevent the VGB induced retinal toxicity.

Available for download on Wednesday, August 31, 2022

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