Targeting P21-Activated Kinase-1 for Metastatic Prostate Cancer.

Metastatic prostate cancer (mPCa) has limited therapeutic options and a high mortality rate. The p21-activated kinase (PAK) family of proteins is important in cell survival, proliferation, and motility in physiology, and pathologies such as infectious, inflammatory, vascular, and neurological diseases as well as cancers. Group-I PAKs (PAK1, PAK2, and PAK3) are involved in the regulation of actin dynamics and thus are integral for cell morphology, adhesion to the extracellular matrix, and cell motility. They also play prominent roles in cell survival and proliferation. These properties make group-I PAKs a potentially important target for cancer therapy. In contrast to normal prostate and prostatic epithelial cells, group-I PAKs are highly expressed in mPCA and PCa tissue. Importantly, the expression of group-I PAKs is proportional to the Gleason score of the patients. While several compounds have been identified that target group-I PAKs and these are active in cells and mice, and while some inhibitors have entered human trials, as of yet, none have been FDA-approved. Probable reasons for this lack of translation include issues related to selectivity, specificity, stability, and efficacy resulting in side effects and/or lack of efficacy. In the current review, we describe the pathophysiology and current treatment guidelines of PCa, present group-I PAKs as a potential druggable target to treat mPCa patients, and discuss the various ATP-competitive and allosteric inhibitors of PAKs. We also discuss the development and testing of a nanotechnology-based therapeutic formulation of group-I PAK inhibitors and its significant potential advantages as a novel, selective, stable, and efficacious mPCa therapeutic over other PCa therapeutics in the pipeline.

Safety and efficacy of a patient-controlled bladder management system for treating urinary retention in men.

AIMS: The CymActive™ Bladder Management System (BMS) is a self-retaining, intraurethral catheter with a patient-controlled magnetic valve that allows cyclical bladder filling and emptying, without external appliances. We determined the safety and efficacy of the BMS in men with urinary retention who required catheterization for more than 7 days. METHODS: Men requiring continuous drainage, bladder capacity less than 300 ml, history of prostatic or urethral surgery, or urethral length outside of defined limits, were excluded. Data were collected from patient diaries and weekly visits during catheterization for up to 30 days. The primary composite endpoint assessed four outcomes: placement, post-void residual volume (PVR) of 75 ml or less, adverse device-related events requiring early removal, and removal. RESULTS: Nine of 23 patients met all four criteria: eight of 18 non-neurogenic (7/11 prior Foley users and 1/7 without Foley experience) and one of five neurogenic spinal cord injury (SCI) patients. Secondary outcomes in non-neurogenic patients included: 17/18 successful insertions; of these, 16/17 average PVR of 75 ml; successful valve openings and closings ≥ 95% of more than 1,400 voids; and minimal leakage. Four of five SCI patients discontinued within 7 days. Cystourethroscopy after removal revealed no marked inflammation or mucosal changes. CONCLUSIONS: This pilot study demonstrated the BMS is potentially useful, convenient, and safe for appropriate patients. A follow-up study will better define the characteristics of patients who benefit from this device and examine whether the use of antimuscarinic agents improves outcomes. Neurourol. Urodynam. 35:630-635, 2016. © 2015 Wiley Periodicals, Inc.

A 24-hour feasibility study of intraurethral valved catheter for bladder management in males with spinal cord injury.

This feasibility study was conducted to evaluate design features of the novel intraurethral valved catheter, Surinate (Urovalve, Inc; Newark, New Jersey). The device extends from the bladder neck to just beyond the external sphincter and contains a valve that can be activated by an external magnet for bladder emptying. Five patients were recruited from the Edward Hines Jr Department of Veterans Affairs Hospital spinal cord injury population. We conducted cystometry and cystoscopy to evaluate the lower urinary tract. Then, the device was inserted for 24 hours with careful monitoring. The catheter was removed from the first patient because he developed autonomic dysreflexia during implantation. The next four patients used the catheter overnight and tolerated it well: one with independent use and two with increased abdominal pressure. Emptying time was 208 +/- 99 s, residual was 42 +/- 33 mL, and the first-stream flow rate was 1.8 +/- 0.7 mL/s. The safety tether was used in three patients because the extraction device did not work. Results showed effective implantation and stability of the device in the urethra. However, objectives for use and extraction were not met. This feasibility study provided important information that will help guide design improvements for the intraurethral valved catheter.

Demonstration of dose response of flurbiprofen lozenges with the sore throat pain model.

The dose response of flurbiprofen lozenges (2.5, 5.0, and 12.5 mg) was evaluated in the treatment of sore throat. A refined version of the sore throat pain model showed that 12.5 mg flurbiprofen was significantly more effective than placebo at providing total pain relief and reducing throat soreness (p <.05). Flurbiprofen, 5.0 mg, was more effective than placebo for the reduction of throat soreness and the sensation of throat swelling (P <.05). The 2.5-mg flurbiprofen lozenge was indistinguishable from placebo. For every milligram of increase in the dose of flurbiprofen, there was an approximately 0.3-unit increase in total pain relief (P <.05). Flurbiprofen lozenges in all 3 dosages were well tolerated. Flurbiprofen lozenges are effective for sore throat at a dose between 5.0 mg and 12.5 mg; the sore throat pain model is a sensitive assay for demonstration of the dose-response relationship of an analgesic agent.