bxl628 and Urinary-Bladder--Overactive

To evaluate the efficacy and safety of elocalcitol in the treatment of women with overactive bladder and idiopathic detrusor overactivity.. The study was a multicenter, double-blind, randomized, placebo-controlled, parallel-group trial of women with overactive bladder symptoms recruited from 48 European tertiary referral centers. The participants were randomized to receive either placebo or elocalcitol, 75 μg/d or 150 μg/d for 4 weeks. A 3-day bladder diary, the Urgency Perception Scale, the Patient's Perception of Bladder Condition, and urodynamics were used before and after treatment. Vital signs, laboratory blood tests, 24-hour urine collection, and electrocardiography were also performed to assess the safety. The analysis of covariance test was used to compare the treatment groups. The primary objective was to evaluate the change in bladder volume at the first involuntary detrusor contraction from baseline.. A total of 308 women were studied. No significant change was seen in the urodynamic parameters between the placebo and elocalcitol groups, except for the bladder volume at the first desire to void. The frequency of incontinence episodes was significantly reduced in the elocalcitol group compared with the placebo group (P = .02). The Patient's Perception of Bladder Condition score improved significantly after treatment for the women receiving elocalcitol compared with those receiving placebo (P = .02). Treatment with both doses of elocalcitol was well tolerated, and no differences versus placebo were observed.. Although the primary endpoint was not achieved, elocalcitol appears to be an effective and well-tolerated drug for the treatment of women with overactive bladder and idiopathic detrusor overactivity. However, the multicenter setting for the use of urodynamics might have biased the results of our study.

Topics: Adolescent; Adult; Aged; Calcitriol; Double-Blind Method; Female; Humans; Middle Aged; Urinary Bladder, Overactive; Young Adult

To measure the effects of nonhypercalcemic vitamin D receptor agonist elocalcitol on bladder function in rats with cyclophosphamide-induced cystitis and on bladder function and sensory nerve activity in a mouse with acetic acid-evoked bladder irritation.. Female Wistar rats and male Balb/C mice were gavaged once daily with elocalcitol diluted in miglyol 812 (treatment group) or miglyol alone (control group). On experimental day 12, polyethylene tubing was implanted into the urinary bladder in all the animals. In the mice, a bipolar electrode was positioned under a single postganglionic bladder nerve. At 48 hours after surgery, bladder function was measured in awake, freely moving rats during bladder filling with 0.9% NaCl and both bladder function and sensory nerve activity was measured in awake, restrained mice during continuous intravesical infusion of 0.9% NaCl followed by 0.25% acetic acid.. In rats, the treatment group showed a significant increase in bladder capacity and decrease in number of nonvoiding bladder contractions. In mice, the filling pressure during saline infusion was similar in both groups; however, during acetic acid infusion, the average filling pressure was significantly increased (47%) in the control group but not in the elocalcitol treatment group. The firing rate at filling pressure for the treatment group was 3.6-fold and 2.7-fold lower than that in the control group during the saline and acetic acid infusion, respectively.. Oral treatment with elocalcitol suppressed signs of detrusor overactivity in both animal models and exerted strong suppressive effect on urinary bladder sensory signaling during filling in mice.

Topics: Acetic Acid; Animals; Calcitriol; Cyclophosphamide; Cystitis; Disease Models, Animal; Female; Male; Mice; Mice, Inbred BALB C; Muscle Contraction; Pressure; Rats; Rats, Wistar; Sensory Receptor Cells; Sodium Chloride; Urinary Bladder; Urinary Bladder, Overactive

Elocalcitol, which had been under development by BioXell SpA, is a synthetic derivative of vitamin D3 that regulates cell proliferation and apoptosis via its binding to the vitamin D receptor. In preclinical studies, elocalcitol inhibited the androgen-dependent and androgen-independent proliferation of benign prostatic hyperplasia (BPH) cells more potently than finasteride, a 5alpha-reductase inhibitor. In a phase IIb trial in patients with BPH, treatment with elocalcitol resulted in a significantly reduced prostate volume compared with placebo; irritative urinary symptoms (frequency, urgency and nocturia) and urodynamic parameters were comparable to the alpha1-adrenoceptor antagonist tamsulosin. In a phase IIa trial in patients with prostatitis, elocalcitol significantly reduced levels of IL-8 in semen, suggesting improved quality and forward motility of sperm. However, phase IIb trial data from patients with overactive bladder (OAB) were less promising: elocalcitol failed to meet the primary endpoint despite demonstrating good efficacy in a phase IIa trial. Based largely on these disappointing data, BioXell decided to terminate all further clinical development of elocalcitol, including an uncompleted phase IIa trial in patients with male infertility. Given the novel mechanism of action, efficacy profile and improved tolerability of elocalcitol over existing classes of drugs, the compound could have potentially added to the armamentarium in the expanding therapeutic markets of BPH, OAB and male infertility. This possibility appears to have been negated by BioXell's recent decision to terminate all further development of elocalcitol.

Topics: Animals; Apoptosis; Calcitriol; Cell Proliferation; Clinical Trials, Phase II as Topic; Female; Humans; Infertility, Male; Male; Prostatic Hyperplasia; Receptors, Calcitriol; Urinary Bladder, Overactive