Safety, tolerability and pharmacokinetics of single and multiple doses of a novel sigma-1 receptor antagonist in three randomized phase I studies.

AIM: To assess the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy subjects of a novel, highly selective, sigma-1 receptor antagonist (S1RA). METHODS: Three randomized, double-blind, placebo-controlled trials evaluated single oral doses (5-500 mg, study 101; 500-800 mg, study 106) and multiple doses (50-400 mg once daily for 8 days, study 102) of S1RA. Safety and tolerability were assessed by adverse event reporting, clinical laboratory, physical examinations, vital signs and electrocardiography, including Holter monitoring. Pharmacodynamic assessments included computerized cognitive testing. Plasma samples were analyzed using validated HPLC-MS/MS methods. RESULTS: One hundred and seventy-five subjects were enrolled. Single and multiple doses were safe and well tolerated, with no serious adverse events. The most common side effects were headache and dizziness. The highest single doses were associated with some mild to moderate transient CNS effects. The maximum tolerated dose was not reached. There were no clinically significant changes in the electrocardiogram (ECG), 24 h Holter monitoring, or in vital signs and laboratory assessments. Subjective CNS pharmacodynamics evaluations showed no relevant differences vs. placebo. Cognitive testing showed no effects on visual memory, executive function, attention or somnolence, while revealing some transient slowing of response for simple reaction time and choice reaction time at 2 h following the administration of higher doses. A fast absorption, rapid distribution and slow elimination were observed (t(max) 0.75-2.0 h, t(1/2) compatible with once a day administration) and steady-state was reached. No gender differences were observed. CONCLUSIONS: S1RA exhibited an acceptable safety, tolerability, pharmacodynamic and pharmacokinetic profile in healthy subjects over the dose range studied.

Cizolirtine citrate is safe and effective for treating urinary incontinence secondary to overactive bladder: a phase 2 proof-of-concept study.

BACKGROUND: Antimuscarinic agents currently dominate medical treatment for urinary incontinence secondary to overactive bladder (OAB). Alternatives to improve their risk-benefit ratio are welcomed. OBJECTIVE: To demonstrate the efficacy and safety of oral cizolirtine citrate in this indication. DESIGN, SETTING, AND PARTICIPANTS: A randomised, double-blind, placebo- and active-controlled, phase 2 multicentre clinical trial performed by urologists or gynaecologists at referral centres. A sample was composed of 135 outpatients with signs of lower urinary tract dysfunction and urodynamically documented detrusor overactivity; 20 patients left the study prematurely, chiefly (n=10) because of adverse events. INTERVENTION: Allocation to treatments was asymmetrical (2:2:1) to cizolirtine citrate 800 mg/d, placebo, or oxybutynin 15 mg/d. Treatments were given for 12 wk. MEASUREMENTS: Efficacy measures included a bladder diary, filling- and voiding-phase urodynamic evaluations, and measure of quality of life (QoL). Adverse events were systematically recorded. Statistical procedures included analysis of covariance, chi(2) tests, and calculation of 95% confidence intervals. RESULTS AND LIMITATIONS: Most patients (92.6%) were female, and their mean age was 51.8 yr. Bladder diary variables improved significantly with active drug over placebo: The average number of voidings per 24 h was reduced by 33.4%, 17.0%, and 34.3% (p=0.001) in the cizolirtine citrate, placebo, and oxybutynin groups, respectively. The mean estimated voided volume per voluntary micturition increased by 17.8%, 0%, and 14.5% (p=0.002) in the cizolirtine citrate, placebo, and oxybutynin groups, respectively. The proportions of patients achieving fewer than eight voidings per 24 h, complete dryness, or both were also superior with active drugs over placebo. Only cizolirtine showed significant superiority over placebo to improve urodynamic parameters, although the asymmetrical allocation played against oxybutynin in the inferences. Cizolirtine citrate caused fewer antimuscarinic but more gastrointestinal (nausea) and neurologic (headache and vertigo) adverse events than oxybutynin. CONCLUSIONS: Cizolirtine citrate is a promising agent in the treatment of OAB with urinary incontinence.

Cizolirtine citrate, an effective treatment for symptomatic patients with urinary incontinence secondary to overactive bladder: a pilot dose-finding study.

BACKGROUND: A dose-finding study was performed as the first step in the clinical development of the new drug, cizolirtine citrate. OBJECTIVE: To assess the efficacy and safety of cizolirtine citrate in overactive bladder with urinary incontinence. DESIGN, SETTING, AND PARTICIPANTS: Seventy-nine outpatients with clinical overactive bladder and/or urodynamic diagnosis of detrusor overactivity were randomized in a multicentre, 12-wk, double-blind, pilot trial. INTERVENTIONS: Patients received cizolirtine citrate 400 mg bid (C400), cizolirtine citrate 200 mg bid (C200), or placebo. MEASUREMENTS: Patients recorded efficacy variables in 7- and 14-d bladder diaries: urinary incontinence episodes, voluntary micturitions, and urgency episodes. The primary efficacy endpoints were changes from baseline to week 12 in average 24-h frequencies of the efficacy variables. RESULTS AND LIMITATIONS: Average 24-h frequency of urinary incontinence episodes decreased by a median of 1.14 in C400 versus 0.21 in placebo (p=0.08). Urgency episodes decreased by a median of 3.00 in C400, by 1.29 in C200 and by 0.43 in placebo (p=0.004; C400 vs placebo). Cizolirtine showed a clear improvement regarding the percentage of patients free from urinary incontinence episodes at the end of the study, being 68.75% in C400, 45% in C200, and 30% in placebo (p=0.04; C400 vs placebo). The global efficacy assessment reported by patients showed a clearly favourable opinion ("excellent" or "good") given by 80% of the patients in C400 and 60% in C200 versus 39% in placebo. Patients reporting adverse events (AEs) were 37% in placebo, 68% in C200, and 81% in C400. The majority of AEs had mild to moderate severity and none was serious. CONCLUSIONS: The therapeutic potential of cizolirtine citrate 400mg bid in overactive bladder has been evidenced.

Comparison of cizolirtine citrate and metamizol sodium in the treatment of adult acute renal colic: a randomized, double-blind, clinical pilot study.

BACKGROUND: Renal colic causes excruciating pain that provides a good clinical model of acute pain for the development of new analgesics. OBJECTIVE: The purpose of the study was to compare the analgesic efficacy and tolerability of cizolirtine citrate and metamizol sodium in adult acute renal colic. METHODS: This Phase II, randomized, double-blind, clinical pilot study was conducted in the emergency departments of 6 general hospitals in the Czech Republic between October 2000 and February 2001. Male and female patients aged 18 to 65 years and presenting with hematuria and moderate to severe pain due to suspected renal colic starting within the 24 hours before presentation were eligible. Patients were randomized to receive a single IV dose of cizolirtine 350 mg or metamizol 2,500 mg, administered by slow infusion over 15 minutes. Both doses were maximal for the respective drugs to attain adequate analgesia. Use of rescue medication with butorphanol was allowed 30 minutes after study drug administration. Pain intensity was assessed at various time points during the following 360 minutes using a 100-mm visual analog scale (VAS) and a verbal categoric scale. In addition, a specific verbal categoric scale was used to rank pain relief. Physical examinations, laboratory tests, and questioning for adverse events addressed drug tolerability. RESULTS: Sixty-four patients (50 men, 14 women; mean [SD] age, 44.21 [12.29] years; mean [SD] body mass index, 25.97 [3.38] kg/m(2)) were enrolled. Physical examination findings and mean VAS pain intensity scores at baseline (mean [SD], 79.42 [7.89] mm and 82.59 [10.50] mm in the cizolirtine and metamizol groups, respectively) were similar in both groups. After 30 minutes, the mean (SD) scores were 33.84 (25.15) mm and 25.41 (24.51) mm, respectively. This difference was not statistically significant, and the noninferiority of cizolirtine with respect to the comparator could not be established. However, the proportion of patients that showed satisfactory pain relief (ie, decrease of > or = 50% in VAS pain intensity score compared with baseline) at 30 minutes in the cizolirtine group was fairly high (64.5%), which means relevant analgesic activity. Both treatments were well tolerated; 6 adverse events were reported in 5 patients (7.8%), and all were considered as not treatment related. CONCLUSIONS: Although this limited pilot study did not include an internal measure of sensitivity, relevant pain reduction was shown in the population of patients with suspected renal colic undergoing treatment with cizolirtine, suggesting the presence of analgesic activity. However, the efficacy of cizolirtine was found to be similar to that of metamizol. Treatments were well tolerated.