A New Application for Urethral Strictures: Tacrolimus-Eluting Stent

Dear Editor:

U rethral stricture is an important problem in urology practice. The primary treatment of disease is internal urethrotomy, but most of them recur (46–76%) within 2 years and their treatment involves an even greater risk of further recurrences. ¹ The main problem is how to prevent the edges of the cut stricture from adhering together and the scar shrinking. Permanent self-expanding metallic stents, temporarily placed biocompatible metallic stents, or polyurethane temporary stents have been used since the early 1980s, with much success in alleviating obstructive symptoms caused by stricture, to reduce recurrence rate and provide an open urethral passage. ¹ Although most of them are high-molecular-weight polymers of polylactic or polyglycolic acid, the tissue engineered or artificial synthetic biodegradable materials used have become a promising avenue of research. ²

After stent application into the urethra, several complications have been reported, such as migration, encrustation, infection, and irritative symptoms. ³ Some of the pharmacological agents and their local elution from the stent coatings have been investigated to prevent these problems and enhance stent performance. Urethral stent application induces reactive inflammation, epithelial hyperplasia, and fibrosis in the uroepithelium, and biodegradable stents alone do not prevent this pathology. ⁴ This is why the idea of developing drug-eluting properties in the biodegradable urethral stent materials has been suggested. Pharmacological agents targeting inflammation and cellular proliferation may be ideal candidates for stent-based therapies for the prevention of urethral restenosis. In a recent experimental study, Kotsar et al. ¹ reported the effects of indomethacin, dexamethasone, and ciprofloxacin on the biodegradation and biocompatibility of braided polylactide or polyglycolide stents in a rabbit urethral model.

The drug-eluting stents have shown significant potential to reduce restenosis development after vascular intervention. ⁴ For this aim, tacrolimus-eluting stents are being used in cardiology since a period of close to 10 years. Tacrolimus is a well-known cytostatic immunosuppressant with both antiproliferative and anti-inflammatory activity and is a metabolite of the actinomycete Streptomyces tsukubaensis. ^5,6 The drug was discovered in 1984 and approved by the Food and Drug Administration for use in management of liver transplantation and kidney allograft rejection. ⁵ Tacrolimus binds to the intracellular FK-binding protein and forms a complex that binds to calcineurin and inhibits the activation of calcineurin. Hamada et al. ⁶ showed in a porcine coronary artery model that tacrolimus-eluting stent decreases the proliferation of vascular smooth muscle cells and inhibits neointimal hyperplasia via calcineurin/nuclear factor of activated T-cell (NFAT) signaling. Further, Ebert et al. ⁷ reported long-term clinical results that the use of topical tacrolimus application was a safe therapy with no severe side effects in balanitis xerotica obliterans.

Taken together, these findings strongly support our hypothesis that tacrolimus-eluting stent may be useful for the management of recurrent urethral stricture. This theory might provide a novel approach and new treatment choice for this disease. In future studies, animal models are essential for better understanding of the results of tacrolimus-eluting stent application.