Bladder instillation of liposome encapsulated onabotulinumtoxina improves overactive bladder symptoms: a prospective, multicenter, double-blind, randomized trial.

PURPOSE: Cystoscopic intradetrusor injection of botulinum toxin has helped patients with refractory overactive bladder but with the increased risks of urinary tract infection and urinary retention. We assessed whether catheter instillation of 200 U onabotulinumtoxinA formulated with liposomes is safe and effective for the treatment of overactive bladder. MATERIALS AND METHODS: This 2-center, double-blind, randomized, placebo controlled study enrolled patients with overactive bladder inadequately managed with antimuscarinics. Patients were assigned to intravesical instillation of lipo-botulinum toxin (31) or normal saline (31). The primary end point was the mean change in micturition events per 3 days at 4 weeks after treatment. Additional end points included mean changes in urgency events, frequency and urinary urge incontinence, as well as changes in overactive bladder symptom scores and urgency severity scores. RESULTS: At 4 weeks after treatment lipo-botulinum toxin instillation was associated with a statistically significant decrease in micturition events per 3 days (-4.64 for lipo-botulinum toxin vs -0.19 for placebo, p = 0.0252). Lipo-botulinum toxin instillation was also associated with a statistically significant decrease in urinary urgency events with respect to baseline but not placebo. However, lipo-botulinum toxin instillation was associated with a statistically significant decrease in urgency severity scores compared to placebo (p = 0.0181). These observed benefits of lipo-botulinum toxin instillation were not accompanied by an increased risk of urinary retention. The effects of lipo-botulinum toxin on urinary urge incontinence were inconclusive. CONCLUSIONS: A single intravesical instillation of lipo-botulinum toxin was associated with decreases in overactive bladder symptoms without side effects. Intravesical instillation of liposomal botulinum toxin may be a promising approach to treat refractory overactive bladder.

Development of potential orphan drug therapy of intravesical liposomal tacrolimus for hemorrhagic cystitis due to increased local drug exposure.

PURPOSE: The potent immunosuppressive effect of systemic tacrolimus is limited by the high incidence of severe adverse effects, including nephrotoxicity and hypertension. Intravesical application of tacrolimus is hindered by its poor aqueous solubility, justifying the search for novel delivery platforms such as liposomes. We evaluated the pharmacokinetics of tacrolimus encapsulated in liposomes (lipo-tacrolimus), which is being developed as a potential orphan drug indication for hemorrhagic cystitis. MATERIALS AND METHODS: A single dose of lipo-tacrolimus was instilled in the bladder with the rat under anesthesia. Also, tacrolimus was instilled intravesically or injected intraperitoneally in other rat groups. The tacrolimus dose was constant in all formulations at 200 µg/ml. At different times blood, urine and bladder samples were collected and stored at -80C until analysis. Tacrolimus levels in samples were analyzed using microparticle enzyme immunoassay II. RESULTS: The AUC of lipo-tacrolimus in serum at 0 to 24 hours was significantly lower than that of tacrolimus instillation or injection. Noncompartmental pharmacokinetic data analysis revealed maximum concentration of lipo-tacrolimus and tacrolimus in serum and urine at 1 and at 2 hours, respectively. Urine AUC(0-24) after intravesical administration was significantly higher than in the intraperitoneal group (p <0.05). Bladder tacrolimus AUC(0-24) did not differ significantly between the groups. CONCLUSIONS: Single dose pharmacokinetics revealed that bladder instillation of liposome encapsulated tacrolimus significantly decreased systemic exposure to instilled tacrolimus as well as vehicle related toxicity. Intravesical liposomal tacrolimus may be a promising approach as an orphan drug indication for hemorrhagic cystitis.

Potential Effect of Liposomes and Liposome-Encapsulated Botulinum Toxin and Tacrolimus in the Treatment of Bladder Dysfunction.

Bladder drug delivery via catheter instillation is a widely used treatment for recurrence of superficial bladder cancer. Intravesical instillation of liposomal botulinum toxin has recently shown promise in the treatment of overactive bladder and interstitial cystitis/bladder pain syndrome, and studies of liposomal tacrolimus instillations show promise in the treatment of hemorrhagic cystitis. Liposomes are lipid vesicles composed of phospholipid bilayers surrounding an aqueous core that can encapsulate hydrophilic and hydrophobic drug molecules to be delivered to cells via endocytosis. This review will present new developments on instillations of liposomes and liposome-encapsulated drugs into the urinary bladder for treating lower urinary tract dysfunction.