Exploration of Hypotensive Effects of Novel Hydrogen Sulfide Donors: Mechanisms and Their Delivery

Glaucoma stands as a leading cause of irreversible blindness worldwide, largely influenced by increased intraocular pressure (IOP), which is the most critical modifiable risk factor. Existing therapies frequently focus on a particular pathway, which may limit their long-term effectiveness and reduce patient compliance. This study assessed a multi-targeted therapeutic approach utilizing hydrogen sulfide (H2S)-releasing donors, AMP and JDB, aimed at lowering the IOP through complementary mechanisms that involve H2S, nitric oxide (NO), and prostaglandins analog activity. Both compounds significantly reduced IOP in a normotensive rabbit model, with JDB demonstrating a more prolonged effect compared to AMP—probably because its amide-based structure provides enhanced stability. To better understand the mechanisms underlying the IOP lowering effects, mechanistic studies were conducted using aminooxyacetic acid (AOAA), an inhibitor of endogenous H2S synthesis, and glibenclamide (GLBN), a KATP channel blocker. These studies confirmed that both endogenous H2S production and the activation of KATP channels are crucial in mediating the observed effects, thereby supporting the biological significance of the donor’s design. To establish a connection between in vivo efficacy and release behavior, in vitro release profiling using amperometric biosensors was conducted. AMP demonstrated a quick, burst release, which aligns with its short-acting effect on IOP reduction, whereas JDB exhibited a slower, more sustained release over several days, corresponding to its extended activity in vivo. A controlled release microparticle formulation using solvent coacervation to improve ocular delivery was developed, acknowledging the therapeutic need for sustained drug action. Through the optimization of parameters including silicone oil viscosity, surfactant type, and sonication settings, a reproducible system characterized by well-dispersed and stable microparticles was established. This formulation is essential for sustaining therapeutic levels of the donor over time, minimizing dosing frequency and enhancing patient adherence. These findings highlight the potential of AMP and JDB as multi mechanistic agents for glaucoma therapy, emphasizing the critical role of formulation development in converting promising molecules into clinically viable treatments.

Grantor dc:publisher

Creighton University

Year dc:date.issued

2025

Author dc:creator

• Sahai, Pulkit

Advisors dc:contributor.advisor

• Opere, Catherine A.
• Singh, Somnath

Statement dc:rights

• Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.

Language dc:language.iso

en_US

Repository record dc:identifier.uri

https://cdr.creighton.edu/handle/10504/158612

OAI identifier oai:identifier

oai:cdr.creighton.edu:10504/158612