Identification and local delivery of vasodilators for the reduction of ureteral contractions.

Kidney stones and ureteral stents can cause ureteral colic and pain. By decreasing contractions in the ureter, clinically prescribed oral vasodilators may improve spontaneous stone passage rates and reduce the pain caused by ureteral stenting. We hypothesized that ureteral relaxation can be improved via the local administration of vasodilators and other smooth muscle relaxants. Here, by examining 18 candidate small molecules in an automated screening assay to determine the extent of ureteral relaxation, we show that the calcium channel blocker nifedipine and the Rho-kinase inhibitor ROCKi significantly relax human ureteral smooth muscle cells. We also show, by using ex vivo porcine ureter segments and sedated pigs that, with respect to the administration of a placebo, the local delivery of a clinically deployable formulation of the two drugs reduced ureteral contraction amplitude and frequency by 90% and 50%, respectively. Finally, we show that standard oral vasodilator therapy reduced contraction amplitude by only 50% and had a minimal effect on contraction frequency. Locally delivered ureteral relaxants therefore may improve ureter-related conditions.

Ovarian cancer spheroid shrinkage following continuous exposure to cisplatin is a function of spheroid diameter.

OBJECTIVE: Most ovarian cancer patients present with advanced-stage disease, disseminated in the peritoneal cavity. Standard treatment involves surgical resection of all visible tumor, followed by delivery of systemic therapy. Patients with advanced-stage disease may be candidates for intraperitoneal (IP) chemotherapy following surgical debulking. Recent clinical trials have created controversy regarding the benefits of this approach. Previous clinical trials report that patients with microscopic residual disease respond best to IP therapy. The goal of this study was to determine the relationship between tumor size and the efficacy of continuous chemotherapy. METHODS: Small and large ovarian cancer spheroids (derived from UCI101 and A2780 cell lines) were exposed to short-term high (modeling an IP injection, "IP") or prolonged, low cisplatin concentrations (modeling an implanted device, "device"), which have been previously shown to be less toxic. Spheroid diameter was measured at various time points via image analysis and used to quantify tumor shrinkage over the course of treatment. RESULTS: We show that "IP" doses more effectively shrink large spheroids when the same cumulative dose is administered with both treatments, but that both regimens similarly treat small spheroids. We also demonstrate that higher cumulative "device" doses are most effective at shrinking large spheroids. CONCLUSIONS: These results support the hypothesis that intratumoral drug distribution following IP treatment is diffusion-controlled. An implanted device that continuously delivers low doses of IP chemotherapy would, therefore, be maximally effective against microscopic tumors.