Effect of a 5-HT2c receptor agonist on urethral closure mechanism in healthy women.

AIMS: To evaluate the effect of ASP2205, a selective serotonin 5-HT2c receptor agonist, and Duloxetine on the urethral pressure in healthy female subjects. METHODS: Healthy females aged 18 to 55 years were recruited for this phase 1, single site, placebo-controlled, randomized, four-period, cross-over study. The interventions were single oral doses of 10 and 60 mg ASP2205, 80 mg duloxetine, and placebo. As a pharmacodynamics endpoint, opening urethral pressure (OUP), corrected for placebo, was measured using urethral pressure reflectometry under both resting and squeezing condition of the pelvic floor at predose and 3, 6, 12, and 24 hours after dosing. Safety and tolerability of ASP2205 were also compared with duloxetine and placebo. RESULTS: Eighteen healthy women signed informed consent, however, one dropped out before dosing and one dropped out after the first period, therefore, 16 subjects completed the study. Duloxetine significantly increased the OUP during both resting and squeezing condition (maximal increase 18.1 and 16.8 cmH2 O, respectively). Both doses of ASP2205 did not increase OUP at any time point. During squeezing OUP decreased significantly in the ASP2205 60 mg group from 6 to 24 hours after dosing. All subjects experienced predominantly central nervous system-related side effects (eg, dizziness and nausea) during ASP2205 treatment, which was most pronounced at 60 mg. CONCLUSIONS: ASP2205, a serotonin 5-HT2c receptor agonist, does not increase the urethral pressure and it is therefore unlikely that 5-HT 2c receptor agonists can be used as a treatment for stress urinary incontinence. ASP2205 was less well tolerated than the high dose of duloxetine.

Long-Term Safety and Efficacy of Solifenacin in Children and Adolescents with Overactive Bladder.

PURPOSE: We evaluated the long-term safety and efficacy of once daily oral solifenacin suspension in children (5 to less than 12 years old) and adolescents (12 to less than 18 years old) with overactive bladder. MATERIALS AND METHODS: We conducted a 40-week, open label extension of a 12-week double-blind, placebo controlled trial. Outcome measures included incidence and severity of adverse events (primary end point), laboratory variables, vital signs, 12-lead electrocardiogram, post-void residual volume, and change from baseline to end of treatment in mean number of micturitions and incontinence episodes per 24 hours, number of incontinence-free days per 7 days and number of grade 3 or 4 urgency episodes per 24 hours (adolescents only). RESULTS: A total of 119 children and 29 adolescents were enrolled in the study. The incidence of drug related treatment emergent adverse events was 34.7% (children) and 37.9% (adolescents), the most common of which were constipation (11.9%), electrocardiogram QT prolonged (8.5%) and dry mouth (4.2%) in children, and electrocardiogram QT prolonged (13.8%) and nausea (6.9%) in adolescents. Adverse events resulted in 10.2% (children) and 13.8% (adolescents) of participants discontinuing treatment. There were no cases of urinary retention or increases in post-void residual volume and no clinically relevant changes in laboratory variables or vital signs. Two cases of dizziness but no other central nervous system drug related treatment emergent adverse events were reported. Improvements in all efficacy parameters and grade 3 or 4 urgency episodes observed by 3 weeks were further improved and/or maintained during the study. CONCLUSIONS: Once daily solifenacin oral suspension was well tolerated for up to 52 weeks in children 5 to less than 12 years old and adolescents 12 to less than 18 years old diagnosed with overactive bladder, with constipation and electrocardiogram QT prolonged as the most common adverse reactions, respectively. Improvements in efficacy at 3 weeks were sustained during the study.

Solifenacin in Children and Adolescents with Overactive Bladder: Results of a Phase 3 Randomised Clinical Trial.

BACKGROUND: Solifenacin, an effective, well-tolerated treatment for adult overactive bladder (OAB) symptoms, has not been evaluated in placebo-controlled paediatric clinical trials. OBJECTIVES: To evaluate the efficacy and safety of once-daily oral solifenacin suspension in OAB patients aged 5-<12 yr (children) and 12-<18 yr (adolescents). DESIGN, SETTING, AND PARTICIPANTS: The study involved a 4-wk urotherapy run-in followed by 1:1 randomisation to 12-wk double-blind solifenacin or placebo treatment alongside urotherapy. INTERVENTION: Solifenacin paediatric equivalent doses (PEDs) of adult doses: 2.5mg, 5mg, 7.5mg, and 10mg. The starting dose was PED 5mg; all patients were titrated to an optimum dose at 3-wk intervals over 9 wk, resulting in ≥3 wk at the optimum dose before end of treatment (EoT). OUTCOME MEASUREMENTS AND STATISTICS: Superiority of solifenacin versus placebo in change from baseline to EoT for mean volume voided/micturition (MVV, primary endpoint); daytime maximum volume voided/micturition (DMaxVV); incontinence episodes (mean/24h); mean number of incontinence-free days or nights/7 d; micturition frequency; and Micturition frequency adjusted for baseline total voided volume (VTB) as an exploratory parameter). Efficacy parameters were analysed using analysis of covariance. Safety parameters (treatment-emergent adverse events, serious adverse events, laboratory variables, vital signs, electrocardiogram, postvoid residual volume) are summarised using descriptive statistics. RESULTS AND LIMITATIONS: In children, solifenacin was superior to placebo in terms of the change from baseline to EoT for MVV (solifenacin-placebo difference 12.1ml, 95% confidence interval [CI] 0.2-24.0; p=0.046), DMaxVV (difference in adjusted mean change from baseline for solifenacin-placebo 31.9ml, 95% CI 4.3-59.5; p=0.024), VTB-adjusted micturition frequency (p=0.028). Other endpoints were not significantly different. Solifenacin was well tolerated. For adolescents, it was not possible to draw firm efficacy conclusions because of the low numbers recruited. CONCLUSIONS: Once-daily solifenacin oral suspension in children with OAB was superior to placebo for MVV (primary efficacy endpoint) and was well tolerated. PATIENT SUMMARY: In this 12-wk study, a once-daily oral suspension of solifenacin in children aged 5-<12 yr with overactive bladder was superior to placebo in increasing mean volume voided/micturition, the primary efficacy variable in the study. Solifenacin was well tolerated, with a low incidence of dry mouth and constipation. This study is registered at ClinicalTrials.gov as NCT01565707.

Hand hygiene and face touching in family medicine offices: a Cincinnati Area Research and Improvement Group (CARInG) network study.

BACKGROUND: Family medicine offices may play an important role in the transmission of common illnesses such as upper respiratory tract infections (URTIs). There has, however, been little study of whether physicians teach patients about URTI transmission and what their own actions are to prevent infection. The purpose of this study was to assess the quality of hand hygiene and the frequency with which family physicians and staff touch their eyes, nose, and mouth (the T-zone) as well as physician and staff self-reported behaviors and recommendations given to patients regarding URTI prevention. METHODS: We observed family physicians and staff at 7 offices of the Cincinnati Area Research and Improvement Group (CARInG) practice-based research network for the quality of hand hygiene and number of T-zone touches. After observations, participants completed surveys about personal habits and recommendations given to patients to prevent URTIs. RESULTS: A total of 31 clinicians and 48 staff participated. They touched their T-zones a mean of 19 times in 2 hours (range, 0-105 times); clinicians did so significantly less often than staff (P < .001). We observed 123 episodes of hand washing and 288 uses of alcohol-based cleanser. Only 11 hand washings (9%) met Centers for Disease Control and Prevention criteria for effective hand washing. Alcohol cleansers were used more appropriately, with 243 (84%) meeting ideal use. Participants who were observed using better hand hygiene and who touched their T-zone less report the same personal habits and recommendations to patients as those with poorer URTI prevention hygiene. CONCLUSIONS: Clinicians and staff in family medicine offices frequently touch their T-zone and demonstrate mixed quality of hand cleansing. Participants' self-rated URTI prevention behaviors were not associated with how well they actually perform hand hygiene and how often they touch their T-zone. The relationship between self-reported and observed behaviors and URTIs in family medicine office settings needs further study.

How much ritonavir is needed to boost protease inhibitors? Systematic review of 17 dose-ranging pharmacokinetic trials.

BACKGROUND: Ritonavir has been evaluated at boosting doses of 50­800 mg daily with seven protease inhibitors: amprenavir, atazanavir, darunavir, indinavir, lopinavir,saquinavir and tipranavir. Minimizing the boosting dose of ritonavir could improve tolerability and lower costs. METHODS: A MEDLINE search identified 17 phamacokinetic trials using different ritonavir doses with protease inhibitors. The dose of ritonavir used was correlated with plasma levels of each boosted protease inhibitor. For the five pharmacokinetic trials of lopinavir/ritonavir, a meta-analysis was used to estimate the effects of lopinavir dose versus ritonavir dose on lopinavir pharmacokinetics. RESULTS: Saquinavir, fosamprenavir and darunavir were boosted equally well by lower(50­100 mg) versus higher doses of ritonavir. Indinavir, tipranavir and lopinavir were boosted more by higher ritonavir doses. Data on atazanavir were inconclusive. The ritonavir dose-dependence of boosting effects did not correlate with their bioavailability or their effects on ritonavir plasma levels. Atazanavir and indinavir raised plasma ritonavir levels by 69­72%, whereas saquinavir had no effects on ritonavir. Darunavir,lopinavir, tipranavir and fosamprenavir all lowered ritonavir plasma levels. For the meta-analysis of lopinavir/ritonavir trials, the 200/150 mg twice daily (b.i.d.) dose of lopinavir/ritonavir (one Meltrex 200/50mg tablet and one ritonavir 100mg b.i.d.)showed lopinavir area under the curve and minimum concentration similar to the standard 400/100mg b.i.d. dose. CONCLUSION: It may be possible to use three protease inhibitors (saquinavir, amprenavir and darunavir) with lower doses of ritonavir. A 200/150 mg b.i.d. dose of lopinavir/ritonavir could lower costs while maintaining very similar lopinavir plasma levels to the standard dose. New pharmaco enhancer drugs may need to be used at different doses to boost different antiretrovirals.

Effects of first-line use of nucleoside analogues, efavirenz, and ritonavir-boosted protease inhibitors on lipid levels.

INTRODUCTION: Treatment with ritonavir-boosted protease inhibitors or efavirenz and nucleoside analogues leads to rises in lipids, which might contribute to cardiovascular risk. METHOD: A MEDLINE search for clinical trials of first-line HAART with standardized 48-week lipids data available for combinations of two nucleoside analogues identified 13 with additional boosted protease inhibitor (PI/r) regimens (n = 5,281) and two with efavirenz (n = 1,087). Inverse-variance weighting was used to provide estimates of combined 48-week elevations in each lipid parameter. RESULTS: The trials were well balanced for mean baseline total cholesterol (155 mg/dL), triglycerides (125 mg/dL), LDL (95 mg/dL), and HDL (37 mg/dL). The PIs showed two different types of lipid elevations: Group 1: saquinavir/r, atazanavir/r, and darunavir/r; and Group 2: lopinavir/ritonavir and fosamprenavir/r. There were greater elevations in total cholesterol and triglycerides for Group 2 compared to Group 1 but no differences in LDL or HDL between Group 1 and Group 2. Patients treated with efavirenz showed similar rises in total cholesterol and LDL compared with the PIs in Group 2 but showed smaller rises than in Group 1. In addition, patients treated with abacavir/lamivudine, zidovudine/lamiuvudine, or stavudine/lamivudine showed significantly higher elevations in all four lipid parameters, compared with patients given tenofovir/emtricitabine. CONCLUSION: There is a wide range of lipid elevations during 48 weeks of first-line HAART, which depends on the choice of antiretrovirals used.

Changes in hematologic parameters and efficacy of thymidine analogue-based, highly active antiretroviral therapy: a meta-analysis of six prospective, randomized, comparative studies.

BACKGROUND: Hematologic changes that occur with HIV infection and antiretroviral therapy may impact the quality of life of patients and have been associated with morbidity and mortality. The management of anemia and neutropenia has improved survival in persons with HIV. OBJECTIVES: This meta-analysis was performed to assess the changes in hemoglobin (Hb) levels and neutrophil counts that occur during thymidine analogue-based triple therapy and to establish whether different regimens of triple therapy are similar in efficacy based on CD4(+) T-cell count and viral load changes. METHODS: This was a meta-analysis of the impact of zidovudine (AZT) compared with stavudine (d4T) in triple therapy regimens in HIV patients with regard to hematologic parameters and efficacy markers. The peer-reviewed literature was searched with use of MEDLINE, PubMed, EMBASE, and the Cochrane database of systematic reviews (key terms: HIV, antiretroviral therapy, CD4, viral load, three, triple, and highly active antiretroviral therapy [HAART]). Searches were initially not limited by publication type, study design, date, or language but subsequently were sorted to include only studies performed in treatment-naive adult patients; randomized; and comparative of a regimen that included d4T with a regimen that included AZT; to involve regimens that included a minimum of 3 drugs each; and to include hematologic outcomes data. Outcomes were CD4(+), viral load, and hematologic parameters. RESULTS: This meta-analysis included 6 studies. Treatment efficacy as measured by changes in CD4(+) T-cell counts and viral load did not differ significantly between regimens. Hb levels decreased with AZT treatment by a mean (SE) 0.4 (0.05) g/dL and 0.2 (0.06) g/dL at weeks 24 and 48, respectively, but increased with d4T treatment by 0.45 (0.03) g/dL and 0.58 (0.04) g/dL, respectively. All grades of anemia and neutropenia events were consistently more common with AZT-based regimens relative to d4T-based therapy. CONCLUSIONS: AZT-based HAART has a greater negative impact on hematologic parameters relative to d4T-based regimens. AZT recipients are more likely than d4T recipients to experience anemia and neutropenia events of any grade, and AZT is associated with a net decrease in Hb level relative to a net increase with d4T. These factors may influence the choice of drug used in the treatment of certain patient populations.

Economic evaluation of highly purified menotropin compared with recombinant follicle-stimulating hormone in assisted reproduction.

OBJECTIVE: To determine the cost of achieving pregnancy with different gonadotropin preparations. DESIGN: Cost-minimization analysis of a prospective randomized clinical trial. SETTING: Twenty-two centers in six countries. PATIENT(S): Women 18 to 36 years of age with infertility for more than 1 year who were undergoing IVF or ICSI. INTERVENTION(S): Highly purified hMG or recombinant FSH. RESULT(S): Mean cost of achieving an ongoing pregnancy. The mean cost per patient treatment cycle was estimated to be pound 2423 with highly purified hMG (95% CI, pound 2356 to pound 2495) and pound 2745 with recombinant FSH (95% CI, pound 2658 to pound 2830). The ongoing pregnancy rate was 22% with highly purified hMG and 19% with recombinant FSH. The cost per ongoing pregnancy was pound 10781 with highly purified hMG (95% CI, pound 9056 to pound 12919) and pound 14284 with recombinant FSH (95% CI, pound 11883 to pound 17891). CONCLUSION(S): Highly purified hMG and recombinant FSH are equally effective, but highly purified hMG is less expensive per cycle. Using highly purified hMG instead of recombinant FSH would translate into a 13% increase in the number of cycles that could be offered.