Local drug delivery for relaxation of the ureter

Abstract

Human ureteral contraction and relaxation is implicated in common physiologic situations. The success or failure of kidney stone expulsion and the body's pain response to ureteral stents placed during urologic surgery are affected significantly by ureteral contractions. The lifetime prevalence of kidney stones alone in the US is roughly 10% (of the entire US population), and annual health incidence and healthcare costs exceed 2.5M cases and $5bn. Worldwide, an additional IM ureteral stents are placed annually. The ability to decrease ureteral contractions has been shown to improve spontaneous stone passage rates and decrease ureteral stent pain. Several candidate oral medications have been tested but study outcomes are equivocal. Additionally, no oral therapy has been shown to be associated with substantial reproducible positive outcomes. There are currently no topical therapies available for ureteral relaxation.

The hypothesis of this thesis is that greater ureteral relaxation can be achieved with local administration of vasodilators compared with current standard oral therapy. This thesis reports the discovery and development of drugs and drug formulations that can be locally delivered to the ureter via an office-based approach. Representative drugs that can induce smooth muscle relaxation in the ureter were screened in vitro and potent hits were discovered. Nifedipine and rho-kinase inhibitors were found to be highly effective for relaxing ureteral smooth muscle cells at a micromolar dosage. Substantial drug synergy (increased relaxation) was also discovered when these two drugs were used in combination. The effect of these drugs were verified ex vivo. These drugs were ultimately compounded into a clinically deployable formulation for local delivery to validate effect and safety in vivo using pig studies.

Topical administration of this novel formulation reduced ureteral contraction amplitude and frequency by 90% and 50%, respectively, compared with placebo. Standard oral vasodilator therapy currently used for ureteral relaxation reduced contraction amplitude by 50% with minimal effect on frequency, compared with placebo. This thesis ultimately shows that using an office-based approach, high topical drug doses to induce greater ureteral relaxation can be delivered. These results have the potential to create a new class of therapeutics, topical ureteral relaxants, for common ureter- and urology-related conditions.