A randomized, open-label, 5-period crossover study evaluating the pharmacokinetics and safety of a single dose of intranasal dihydroergotamine (DHE) powder (STS101), intramuscular DHE mesylate, and liquid nasal spray DHE in healthy adults.

OBJECTIVE: To compare the safety and pharmacokinetics (PK) of dihydroergotamine (DHE) after administration of intranasal DHE powder (STS101), liquid nasal spray (LNS) DHE mesylate, and intramuscular (IM) DHE mesylate injection in healthy participants. BACKGROUND: DHE is an effective acute migraine treatment; however, self-administration difficulties have prevented its broader role in the management of migraine. METHODS: This randomized, active-controlled, five-period crossover study was conducted over 5 weeks separated by 1-week washout periods. Three STS101 dosage strengths (5.2, 7.0, 8.6 mg), and one dose each of LNS DHE 2.0 mg, and IM DHE 1.0 mg, were administered to 36 healthy participants. Liquid chromatography, tandem mass spectrometry was used to determine DHE (including its 8'OH-DHE metabolite) plasma levels and to calculate PK parameters (Cmax , Tmax , AUC0-2h , AUC0-last , AUC0-inf , and t1/2 ). Safety was evaluated by monitoring adverse events (AEs), vital signs, electrocardiograms, nasal examinations, and laboratory parameters. RESULTS: Thirty-six participants (mean age 36 years; 19% Hispanic Black and 81% Hispanic White) were enrolled. DHE plasma concentrations rose rapidly after STS101 5.2, 7.0, and 8.6 mg and IM DHE injection, with mean concentrations greater than 2000 pg/mL for all STS101 dose strengths at 20 min. All STS101 dose strengths showed approximately 3-fold higher Cmax , AUC0-2h , and AUC0-inf , than the LNS DHE. The mean AUC0-inf of STS101 7.0 and 8.6 mg were comparable to IM DHE (12,600 and 13,200 vs. 13,400 h × pg/mL). All STS101 dose strengths showed substantially lower variability (CV%) compared to LNS DHE for Cmax (35%-41% vs. 87%), and AUC0-inf (37%-46% vs. 65%). STS101 was well tolerated, and all treatment-emergent AEs were mild and transient. CONCLUSION: STS101 showed rapid absorption and was well tolerated with mild and transient treatment-emergent AEs. Achieving effective DHE plasma concentrations within 10 min, STS101 displayed a favorable PK profile relative to the LNS with higher Cmax , AUC0-2h , and AUC0inf , and with greater response consistency. The AUC0-inf was comparable to IM DHE.

Dihydroergotamine and triptan use to treat migraine during pregnancy and the risk of adverse pregnancy outcomes.

Migraine is prevalent during pregnancy. Antimigraine medications such as dihydroergotamine (DHE) and triptans have been associated with adverse pregnancy outcomes in individual studies but lack of consensus remains. We compared the risk of prematurity, low birth weight (LBW), major congenital malformations (MCM), and spontaneous abortions (SA) associated with gestational use of DHE or triptans. Three cohort and one nested-case-control analyses were conducted within the Quebec Pregnancy Cohort to assess the risk of prematurity, LBW, MCM, and SA. Exposure was defined dichotomously as use of DHE or triptan during pregnancy. Generalized estimation equations were built to quantify the associations, adjusting for potential confounders. 233,900 eligible pregnancies were included in the analyses on prematurity, LBW, and MCM; 29,104 cases of SA were identified. Seventy-eight subjects (0.03%) were exposed to DHE and 526 (0.22%) to triptans. Adjusting for potential confounders, DHE and triptans were associated with increased risks of prematurity, LBW, MCM, and SA but not all estimates were statistically significant. DHE was associated with the risk of prematurity (aRR: 4.12, 95% CI 1.21-13.99); triptans were associated with the risk of SA (aOR: 1.63, 95% CI 1.34-1.98). After considering maternal migraine, all antimigraine specific medications increased the risk of some adverse pregnancy outcomes, but estimates were unstable.

A Phase 1, Randomized, Open-Label, Safety, Tolerability, and Comparative Bioavailability Study of Intranasal Dihydroergotamine Powder (STS101), Intramuscular Dihydroergotamine Mesylate, and Intranasal DHE Mesylate Spray in Healthy Adult Subjects.

OBJECTIVE: To investigate and compare the safety and the pharmacokinetics of dihydroergotamine (DHE) after administration of intranasal DHE powder (STS101), intranasal DHE spray (Migranal® ), and intramuscular (IM) DHE injection in healthy subjects. METHODS: This was a 2-part, active-controlled, 3-period crossover study over 3 weeks, separated by 1-week washout periods. In part 1, 3 ascending dosage strengths of STS101 (1.3, 2.6, and 5.2 mg) were administered to 15 healthy subjects with no history of migraine. In part 2, 27 healthy subjects were administered 1 dose each of STS101 5.2 mg, Migranal DHE Mesylate Liquid Nasal Spray 2.0 mg, and IM DHE Mesylate 1.0 mg in a randomized order. Liquid chromatography, tandem mass spectrometry was used to determine plasma levels of DHE and its major metabolite, 8'OH-DHE. Pharmacokinetic parameters (Cmax , Tmax , AUC0-2 h , AUC0-48 h , AUC0-inf , and t1/2 ) for DHE and metabolite were calculated. Geometric means and 90% confidence intervals of log-transformed data were calculated and the ratio of means compared. Safety was evaluated by monitoring adverse events, vital signs, electrocardiograms, subjective and objective assessments of nasal signs and symptoms, and changes in laboratory parameters. The study is registered as NCT03874832. RESULTS: Forty-three subjects were enrolled and received study medication. Forty completed all study activities, 14 in part 1 and 26 in part 2. In part 1, DHE plasma levels showed a dose-dependent increase, with STS101 5.2 mg reaching a mean Cmax of 1870 pg/mL with a Tmax of 23 minutes. In part 2, STS101 5.2 mg showed rapid absorption, achieving mean DHE plasma concentrations of 1230 and 1850 pg/mL at 10 and 15 minutes after administration, respectively. In comparison to Migranal, STS101 5.2 mg showed approximately 2-fold higher Cmax (2175 vs 961 pg/mL), AUC0-2 h (2979 vs 1316 h × pg/mL), and AUC0-inf (12,030 vs 6498 h × pg/mL), respectively. The mean AUC0-inf of STS101 5.2 mg was comparable to IM DHE (12,030 vs 13,650 h × pg/mL). STS101 5.2 mg showed substantially lower variability compared to Migranal for Cmax (41% vs 76%), AUC0-2 h (39% vs 75%), and AUC0-inf (39% vs 55%). The incidence of treatment emergent AEs (TEAEs), all mild and transient, reported in parts 1 and 2 combined was 9/15 (60%), 5/15 (33%), and 16/41 (39%) of the subjects after 1.3, 2.6, and 5.2 mg STS101, respectively, and 4/26 (15%) and 5/27 (19%) of the subjects after IM DHE and Migranal, respectively. CONCLUSION: STS101 showed rapid absorption, achieving effective DHE plasma concentrations within 10 minutes. It achieved substantially higher Cmax , AUC0-2 h and AUC0-inf , compared to Migranal suggesting potentially better efficacy than Migranal. Its variability was better than Migranal, thus offering improved consistency of response. AUC0-inf was comparable to IM DHE, suggesting prolonged action and low recurrence. Additionally, the Cmax was sufficiently low to avoid any significant nausea reported with IV DHE. Thus, STS101 is an easy to administer, non-injected, acute treatment for migraine, with a favorable tolerability profile and is expected to provide rapid and consistent freedom from pain and associated migraine symptoms without recurrence.

Pharmacokinetics of Tecarfarin and Warfarin in Patients with Severe Chronic Kidney Disease.

Chronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis (n = 13) were matched to healthy volunteers (HVs) (n = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug. PK parameters were measured following each drug. Mean plasma concentrations of (S)-warfarin and (R,S)-warfarin were higher (44 and 27%, respectively) in the subjects with CKD than in the healthy subjects. Both of these values fell outside of the 90% confidence interval of equivalence. For tecarfarin, the difference was less than 15% higher. Elimination half-life (t1/2) increased by 20% for (S)-warfarin and by 8% for (R,S)-warfarin and decreased by 8% for tecarfarin. The mean plasma concentration for tecarfarin's inactive metabolite ATI-5900 increased by approximately eightfold. CKD increased the effect of CYP2C9 genetic variation on (S)-warfarin and (R,S)-warfarin metabolism. Tecarfarin exposure was similar between the HVs and the CKD subjects regardless of CYP2C9 genotype. There were neither serious adverse events (SAEs) nor treatment-emergent adverse events (TEAEs) for any subject in the study. CKD inhibits metabolism of (S)-warfarin and (R,S)-warfarin, but not tecarfarin. The safety of repeated dosing of tecarfarin in CKD patients remains unknown. However, if the PK findings of this single-dose study are present with repeated dosing, tecarfarin may lead to dosing that is more predictable than warfarin in CKD patients who require anticoagulation therapy.

Pharmacokinetics and pharmacodynamics of tecarfarin, a novel vitamin K antagonist oral anticoagulant.

Tecarfarin is a vitamin K antagonist (VKA) with reduced propensity for drug interactions. To evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety of tecarfarin, we performed single ascending dose (SAD) (n=66), multiple ascending dose (MAD) (n=43), and tecarfarin versus warfarin (n=28) studies in human volunteers. In the SAD, tecarfarin was administered to 5 of 6 subjects (1 received placebo) in each of 11 cohorts. AUC0-∞ exhibited linearity and dose proportionality. Elimination T1/2 ranged from 87-136 hours (h) across all doses. In the MAD, tecarfarin was administered to 5 of 6 volunteers in each of 7 cohorts. The starting dose was continued until the subject's INR reached the target range (TR) of 1.7 to 2.0. Dosing was down-titrated if the TR was achieved. Elimination T1/2 ranged from 107-140 h. Doses <10 mg had insignificant effect on INR. Higher doses raised INRs and required down-titration to maintain the TR. Steady state INR dosing was 10-20 mg. INR declined promptly after discontinuation. In the comparative study, subjects received tecarfarin or warfarin and dose titrated to a TR of 1.5-2.0. Mean dose after TR was achieved was 13.9 mg (range 10.0-25.5 mg) for tecarfarin and 5.3 mg (range 2.5-9.0 mg) for warfarin. At similar INR levels, the concentration of coagulation factors II, VII, IX, and X were similar for tecarfarin and warfarin. Tecarfarin was tolerated well without serious adverse events in all three studies.

A randomised, double blind comparison of tecarfarin, a novel vitamin K antagonist, with warfarin. The EmbraceAC Trial.

Tecarfarin is a novel vitamin K antagonist that is metabolised by carboxyl estererase, thereby eliminating the variability associated with cytochrome-mediated metabolism. EmbraceAC was designed to compare the quality of anticoagulation with tecarfarin and warfarin as determined by time in therapeutic range (TTR). In this phase 2/3 randomised and blinded trial, 607 patients with indications for chronic anticoagulation were assigned to warfarin (n=304) or tecarfarin (n=303). Dosing of study drugs was managed by a centralised dose control centre, which had access to genotyping. The primary analysis tested superiority of tecarfarin over warfarin for TTR. Patients were recruited between May 12, 2008 and May 12, 2009. TTR with tecarfarin and warfarin were similar (72.3 % and 71.5 %, respectively; p=0.51). In those taking CYP2C9 interacting drugs, the TTR on tecarfarin (n=92) was similar to that on warfarin (n=87, 72.2 % and 69.9 %, respectively; p=0.15). In patients with mechanical heart valves, the TTR of tecarfarin (n=42) was similar to that of warfarin (n=42, 68.4 % and 66.3 %, respectively; p=0.51). The same was true for the TTR in patients with any CYP2C9 variant allele and on CYP2C9-interacting drugs (tecarfarin, n=24, 76.5 % vs warfarin, n=31, 69.5 %; p=0.09). There was no difference in thromboembolic or bleeding events. In conclusion, superiority of tecarfarin over warfarin for TTR was not demonstrated. The TTR with tecarfarin was similar to that with well-controlled warfarin and tecarfarin appeared to be safe and well tolerated with few major bleeding and no thrombotic events. Favourable trends in certain subpopulations make tecarfarin a promising oral anticoagulant that deserves further study.

A Phase 1 dose-ranging study examining the effects of a superabsorbent polymer (CLP) on fluid, sodium and potassium excretion in healthy subjects.

BACKGROUND: CLP is an orally administered, non-absorbed, superabsorbent polymer being developed to increase fecal excretion of sodium, potassium and water in patients with heart failure and end-stage renal disease. This study was conducted to evaluate the safety of CLP, and to explore dose-related effects on fecal weight, fecal and urine sodium and potassium excretion, and serum electrolyte concentrations. METHODS: This Phase 1, open-label, dose-escalation study included 25 healthy volunteers, who were administered CLP orally immediately prior to four daily meals for 9 days at doses of 7.5, 15.0, and 25.0 g/day (n = 5/group). An additional dose group received 15.0 g/day CLP under fasting conditions, and an untreated cohort (n = 5) served as control. Twenty-four-hour fecal and urinary output was collected daily. Samples were weighed, and sodium, potassium, and other ion content in stool and urine were measured for each treatment group. Effects on serum cation concentrations, other standard laboratory values, and adverse events were also determined. RESULTS: At doses below 25.0 g/day, CLP was well tolerated, with a low frequency of self-limiting gastrointestinal adverse events. CLP increased fecal weight and fecal sodium and potassium content in a dose-related manner. Concomitant dose-related decreases in urinary sodium and potassium were observed. All serum ion concentrations remained within normal limits. CONCLUSIONS: In this study, oral CLP removed water, sodium and potassium from the body via the gastrointestinal tract in a dose related fashion. CLP could become useful for patients with fluid overload and compromised kidney function in conditions such as congestive heart failure, salt sensitive hypertension, chronic kidney disease and end stage renal disease. TRIAL REGISTRATION: NCT01944007.

A double-blind, randomized, parallel, placebo-controlled study examining the effect of cross-linked polyelectrolyte in heart failure patients with chronic kidney disease.

AIMS: This double-blind, randomized, parallel, placebo-controlled investigation evaluated the effects of cross-linked polyelectrolyte (CLP) on serum potassium and measures of congestion in patients with heart failure (HF) and chronic kidney disease (CKD). METHODS AND RESULTS: The primary endpoint was change in serum potassium over time. Exploratory endpoints included: weight, physician and patient assessment of exertional dyspnoea, effect on N-terminal pro brain natriuretic peptide (NT-proBNP) levels, New York Heart Association (NYHA) classification, 6 min walk test (6MWT), and quality of life by Kansas City Cardiomyopathy Questionnaire (KCCQ). Serum potassium was similar in CLP (n =59) and placebo (n =52) groups throughout the 8-week study. Weight loss was greater in the CLP than in the placebo group at Weeks 1 (P =0.014) and 2 (P =0.004), and this trend continued until the end of the study. After 8 weeks, by physician assessment, the percentage of patients experiencing marked or disabling dyspnoea tended to be lower in the CLP than in the placebo group (7.3% vs. 23.9%, P =0.128). Fewer patients in the CLP than in the placebo group had NT-proBNP levels >1000 pg/mL at Week 4 (P =0.039) and Week 8 (P =0.065). The proportion of patients improving by at least one NYHA functional class over the study was higher in the CLP than in the placebo group (48.8% vs. 17.4%; P =0.002). Effects on 6MWT at Week 8 (p =0.072) and quality of life (overall KCCQ score) at Week 4 (p =0.005) and 8 (P =0.062) all favoured the CLP cohort. Four treatment-unrelated deaths occurred in the CLP group and none in the placebo group (P =0.056). CONCLUSION: In advanced, symptomatic HF with CKD, CLP is associated with beneficial clinical effects without significant serum potassium changes. TRIAL REGISTRATION: NCT01265524.

Efficacy and safety of oxybutynin in children with detrusor hyperreflexia secondary to neurogenic bladder dysfunction.

PURPOSE: We evaluated the efficacy and safety of oxybutynin in children with detrusor hyperreflexia due to neurological conditions. MATERIALS AND METHODS: Study 1--A prospective, open label trial of 3 formulations of oxybutynin (tablets, syrup and extended release tablets) was conducted for 24 weeks in children 6 to 15 years old with detrusor hyperreflexia who used oxybutynin and clean intermittent catheterization. The effect of treatment on average urine volume per catheterization and on secondary urodynamic outcomes was evaluated. Study 2--The efficacy and safety of oxybutynin syrup were evaluated urodynamically in an open label study of children 1 to 5 years old with detrusor hyperreflexia who used oxybutynin and clean intermittent catheterization. RESULTS: Study 1--Mean urine volume per catheterization (+/- SEM) increased by 25.5 +/- 5.9 ml (p <0.001). Maximal cystometric capacity increased by 75.4 +/- 9.8 ml (p <0.001). Mean detrusor and intravesical pressures were significantly decreased by -9.2 +/- 2.3 (p < or =0.001) and -7.5 +/- 2.5 cm H2O (p <0.004), respectively, at week 24. Of 61 children with uninhibited detrusor contractions 15 cm H2O or greater at baseline 34 did not have them at week 24 (p <0.001). Improvements in bladder function were consistent across all oxybutynin formulations. Study 2--Mean maximal cystometric capacity increased significantly by 71.5 +/- 21.99 ml (p = 0.005). At study end only 12.5% of patients had uninhibited detrusor contractions 15 cm H2O or greater compared with 68.8% at baseline (p = 0.004). Oxybutynin was well tolerated in both studies. There were no serious treatment related adverse events. CONCLUSIONS: All 3 formulations of oxybutynin are safe and effective in children with neurogenic bladder dysfunction.

Effect of controlled-release delivery on the pharmacokinetics of oxybutynin at different dosages: severity-dependent treatment of the overactive bladder.

OBJECTIVE: To assess the pharmacokinetics of a controlled-release formulation of oxybutynin (OROS-O, ALZA Corp., Mountain View, CA) at different dosages, compared with immediate-release oxybutynin (IR-O), and to determine the pharmacodynamic properties in the severity-dependent reduction of urge urinary incontinence (UUI). PATIENTS AND METHODS: In all, 105 patients were enrolled in this multicentre, randomized, double-blind study. Individual dose titration was used to assess the minimum effective, maximum tolerated or maximum allowed dose of either OROS-O or IR-O. Blood samples were collected during maintenance therapy with frequent sampling to analyse for R-oxybutynin and R-desethyloxybutynin concentrations. Pre-dose plasma levels before dosing were obtained as the minimum concentrations achieved at steady state during the dosing regimen. In parallel, UUI episodes were assessed at baseline and during maintenance therapy at the final dose level. RESULTS: For both IR-O and OROS-O, initial R-oxybutynin plasma concentrations increased in a dose-dependent fashion. For comparable dosages pre-dose plasma levels were higher for OROS-O than IR-O. After one dose of IR-O plasma concentrations peaked at approximately 27-fold after 1 h and decreased to baseline levels within 4-8 h. In contrast, plasma concentrations of R-oxybutynin remained constant for up to 24 h after taking OROS-O at all doses. The overall percentage reduction in weekly UUI episodes was 84% (to 4.8 episodes) and 88% (to 3.1 episodes) for OROS-O and IR-O, respectively (P < 0.05). Patients who titrated to final dose levels of 10, 15 and 20 mg OROS-O differed in their weekly UUI episodes at baseline (14.5, 30.3 and 42.0). Because of individual dose titration, UUI episodes/week were profoundly reduced at all applied doses (1.9-2.0, respectively). Fewer patients reported moderate to severe dry mouth with OROS-O than with IR-O (25% vs 46%, P < 0.05). CONCLUSION: The pharmacokinetics of OROS-O are proportional to dose, with minimal fluctuations between peak and trough concentrations, as associated with IR-O. In clinical practice OROS-O may thus facilitate the highly effective severity-dependent treatment of UUI with flexible dose adaptations based on the patients' needs.

Regional heterogeneity of cerebral blood flow response to graded pressure-controlled hemorrhage.

BACKGROUND: Little is known about the regional distribution of cerebral blood flow (CBF) in nonanesthetized animals during periods of lowered blood pressure. The present investigation addresses the specific reaction patterns of local cerebral blood flow (LCBF) in comparison with mean CBF during graded pressure-controlled hemorrhagic shock in conscious rats. METHODS: Conscious rats were subjected to graded pressure-controlled hemorrhage (to 85, 70, 55, or 40 mm Hg) by arterial blood withdrawal. After a period of 30 minutes, blood pressure was stabilized by withdrawal or reinfusion of blood. LCBF was determined autoradiographically by the iodo(14C)antipyrine method in 34 brain structures, and mean CBF was calculated and compared with the values of nonhemorrhaged control animals. RESULTS: Mean CBF remained unchanged except for the group with the lowest blood pressure of 40 mm Hg (decrease in CBF of 28%). Otherwise, LCBF was increased in some brain structures at an unchanged mean CBF. Congruently, at 40 mm Hg, the decrease in mean CBF did not show up in all brain structures, the local pattern of CBF varying between an unchanged and a profoundly decreased CBF. The mean coefficient of variation of CBF was increased with the severity of hemorrhagic shock, which indicates an enhanced heterogeneity of CBF. CONCLUSION: Because of the substantial heterogeneity in the responses of LCBF to pressure-controlled hemorrhage, autoregulation of CBF during pressure-controlled hemorrhagic shock has to be reconsidered on a regional basis.

Treatment patterns and associated symptom improvement during six months of care for overactive bladder: a prospective, observational study.

BACKGROUND: Several pharmacologic and nonpharmacologic interventions are available for the treatment of symptoms of overactive bladder (OAB). The relationship between type of initial intervention and subsequent symptom improvement and resource utilization has not been explored in detail. OBJECTIVE: The purpose of this study was to assess (1) the proportion of patients continuing with their initially prescribed treatment for OAB 3 and 6 months after the initial evaluation and (2) the relationship between actual treatment patterns, symptom improvement. and number of physician office visits. METHODS: A total of 31 physicians enrolled patients with OAB for this 6-month prospective, observational study. Baseline data on OAB symptom severity and OAB management strategies were obtained and initial treatment(s) were prescribed by physicians during a routine office visit. Follow-up data on symptom changes, treatment changes, number of physician office visits, and the frequency of absorbent pad use were collected via telephone interviews with patients 3 and 6 months after the initial visit. Stepwise logistic regression was used to assess the relationship between patient characteristics, prescription of medication, and symptom improvement. RESULTS: A total of 213 patients were enrolled; 122 (57.3%) and 100 (46.9%) patients provided follow-up data at the 3-month and 6-month assessments, respectively. The mean age was 61.2 years; 85.2% of patients were female, and 77.7% were white. OAB symptom improvement was significantly related to being prescribed medication (odds ratio [OR], 4.3; 95% CI, 1.8-9.9) and the mean number of daily leakage incidents at baseline (OR, 3.2; 95% CI, 1.2-8.4). Although patients who were prescribed drugs at baseline tended to have fewer physician office visits and were less likely to be prescribed nondrug interventions than patients who were not treated initially with drugs, these differences were not statistically significant. CONCLUSIONS: Pharmacologic treatment for symptoms of OAB appears to be associated with greater symptom improvement than nonpharmacologic treatment. Larger studies of experimental design are needed to determine whether patients treated with medication use fewer nondrug interventions and require fewer physician office visits than patients treated without medication.

Effect of pentosan polysulfate therapy on intravesical potassium sensitivity.

OBJECTIVES: To evaluate further the intravesical potassium sensitivity test (PST) as an indicator of the epithelial leak of interstitial cystitis (IC) and determine whether successful pentosan polysulfate (PPS; Elmiron) treatment is associated with a change in PST results. Most individuals with IC appear to have an abnormally permeable epithelium that allows urinary solutes such as potassium to penetrate to the bladder interstitium, provoking symptoms. METHODS: Data were from an optimal dose trial of PPS in IC. Patients underwent a PST before and after a 32-week trial of 300, 600, or 900 mg PPS/day. The response to PPS treatment was measured using the Patient Overall Rating of Improvement in Symptoms scale. The before and after treatment PSTs and Patient Overall Rating of Improvement of Symptoms scores were compared. RESULTS: Of 377 patients with IC at 28 centers, 302 (80%) had a positive PST at entry. Of the 198 patients who completed the study, 153 were PST positive at entry and 92 (60%) showed clinical improvement at exit. Clinically improved patients had significant improvement on the PST analog pain and urgency scales (3.2 to 1.3 and 3.6 to 1.9, respectively; P <0.0001). In contrast, patients with no clinical improvement had no significant change in pain (3.1 to 2.7) or urgency (3.6 to 3.2). CONCLUSIONS: PST shows abnormal epithelial permeability in most patients with IC and a significant reduction in this permeability after successful PPS therapy. PST appears to be a valid indicator of epithelial abnormality and a reliable test in the diagnosis of IC.

Long-term safety of extended-release oxybutynin chloride in a community-dwelling population of participants with overactive bladder: a one-year study.

In this multicenter, open-label study of extended- and immediate-release oxybutynin chloride, community-dwelling participants were studied for up to 12 months to evaluate the long-term safety profile of extended-release oxybutynin. Quality-of-life assessments designed to measure the impact of incontinence and evaluate treatment outcome were used to study subjective improvement. A total of 904 women and 163 men (mean age 64 years, range 29-91 years) were enrolled. The majority of discontinuations were in the first 3 months (25.5%); of those who continued after 3 months, 62% remained on extended-release oxybutynin chloride for one year. The majority of discontinuations were for adverse events; dry mouth was the most frequently cited event leading to discontinuation (8.4%). Significant improvements were seen in QOL measures. Long-term therapy with extended-release oxybutynin chloride was generally well tolerated and effective, improving quality of life significantly in participants with overactive bladder over 3-12 months of therapy.