A comparison of hyaluronic acid and estradiol treatment in vulvovaginal atrophy.

OBJECTIVE: This study aims to compare the effects of vaginal estrogen and hyaluronic acid on vulvovaginal atrophy. PATIENTS AND METHODS: This randomized controlled study included a total of 300 patients, with 150 patients in each group (Group E and Group H). The VHI score was determined based on a pre-treatment evaluation conducted by a gynecologist. After one month of receiving vaginal estrogen in Group E and vaginal hyaluronic acid in Group H, the patients were re-evaluated by their physicians. RESULTS: A statistically significant difference was found between the pre- and post-treatment VHI scores in Group E and Group H (p = 0.000; p = 0.000). No statistical difference was found between Group E and Group H in terms of treatment efficacy (p = 0.712). The pre- and post-treatment complaints of dryness, itching, dyspareunia, burning, and dysuria were found to be statistically significant in Group E and Group H (p = 0.000; p = 0.000; p = 0.000; p = 0.000; p = 0.000 in Group E, respectively) (p = 0.000; p = 0.000; p = 0.000; p = 0.000; p = 0.000 in Group H, respectively). No statistical difference was observed regarding dyspareunia, dysuria, and burning complaints (p = 0.632; p = 0.106; p = 0.128, respectively). However, hyaluronic acid was found to be significantly more effective for itching complaints (p = 0.002), while estrogen was found to be significantly more effective for dryness complaints (p = 0.012). CONCLUSIONS: Hyaluronic acid and estrogen were equally effective in vaginal treatment. Hyaluronic acid may be preferred for patients in whom hormonal therapy is contraindicated or for those who prefer non-hormonal therapy.

Effect of Pharmacotherapy for Overactive Bladder on the Incidence of and Factors Related to Urinary Tract Infection: A Systematic Review and Meta-analysis.

PURPOSE: The aim of this meta-analysis was to investigate the effect of pharmacotherapy for overactive bladder on the pathogenesis of urinary tract infection. MATERIALS AND METHODS: A comprehensive search was performed in MEDLINE and the Cochrane Library using terms for overactive bladder, antimuscarinic agents, and beta 3-adrenoceptor agonists. The primary end point was the emergence of urinary tract infection after pharmacotherapy for overactive bladder. The secondary end point was the emergence of urinary retention, dysuria, and/or increased residual urine volume after overactive bladder treatment. Meta-analyses were conducted using random-effects models. RESULTS: A total of 35,939 patients in 33 trials (29 trials of antimuscarinic agents vs placebo, and 9 trials of beta 3-adrenoceptor agonists vs placebo) that included patients with overactive bladder were identified. At 1-3 months after treatment, the incidence of urinary tract infections was statistically significantly higher in the patients treated with antimuscarinic agents (RR: 1.23, 95% CI: 1.04, 1.45; P = .013) than in the placebo control group. The incidence of urinary tract infections was not increased in the patients treated with beta 3-adrenoceptor agonists (RR: 1.04, 95% CI: 0.76, 1.42; P = .796). Antimuscarinic agents also statistically significantly increased the risks of urinary retention, dysuria, and/or increased residual urine volume (RR: 2.88, 95% CI: 1.79, 4.63; P < .001), whereas beta 3-adrenoceptor agonists did not (RR: 1.26, 95% CI: 0.38, 4.14; P = .708). CONCLUSIONS: This meta-analysis showed that antimuscarinic agents statistically significantly increased the incidences of urinary tract infection and lower urinary tract symptoms and dysfunction, but beta 3-adrenoceptor agonists did not. To prevent urinary tract infection emergence, beta 3-adrenoceptor agonists might be safer than antimuscarinic agents.

Impact of darolutamide on local symptoms: pre-planned and post hoc analyses of the ARAMIS trial.

OBJECTIVE: To assess, the effect of darolutamide (a structurally distinct androgen receptor inhibitor) on urinary and bowel symptoms, using data from the phase III ARAMIS trial (NCT02200614) that showed darolutamide significantly reduced the risk of metastasis and death versus placebo. PATIENTS AND METHODS: Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) were randomised 2:1 to darolutamide (n = 955) or placebo (n = 554). Local symptom control was assessed by first prostate cancer-related invasive procedures and post hoc analyses of time to deterioration in quality of life (QoL) using total urinary and bowel symptoms, and individual questions for these symptoms from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer Module subscales and Functional Assessment of Cancer Therapy-Prostate prostate cancer subscale. Prostate-specific antigen (PSA) responses were correlated with urinary and bowel adverse events (AEs). RESULTS: Fewer patients receiving darolutamide (4.7%) versus placebo (9.6%) underwent invasive procedures, and time to first procedure was prolonged with darolutamide (hazard ratio 0.42, 95% confidence interval 0.28-0.62). Darolutamide significantly (P < 0.01) delayed worsening of QoL for total urinary and bowel symptoms versus placebo, mostly attributed by individual symptoms of urinary frequency, associated pain, and interference with daily activities. AEs of urinary retention and dysuria were less frequent with darolutamide, and greater PSA response (≥90%, ≥50% and <90%, <50%) among darolutamide-treated patients was associated with lower incidences of urinary retention (2.2%, 4.2%, 5.1%) and dysuria (0.5%, 3.2%, 5.1%), respectively. CONCLUSIONS: Darolutamide demonstrated a positive impact on local disease recurrence and symptom control in patients with nmCRPC, delayed time to deterioration in QoL related to urinary and bowel symptoms, and a favourable safety profile showing similar incidence of urinary- and bowel-related AEs compared with placebo.

Opioid Analgesics Adverse Effects: The Other Side of the Coin.

BACKGROUND: Opioids are the cornerstone of the management of cancer pain. However, the development of adverse effects may compromise the opioid response. They include nausea and vomiting, constipation, drowsiness, sleep disorders, cognitive dysfunction, myoclonus, pruritus, dysuria, dependence and the development of aberrant behaviors, respiratory depression, and some endocrine responses. METHODS: The goal of this paper is to identify the most common opioid-related adverse effects, their pathophysiology, and proposing the possible treatments. This narrative review will describe how these adverse effects may develop and how to prevent or to treat. CONCLUSION: Intensity of adverse effects tend to decrease with continuous use. However, they may be persistent and may require symptomatic treatment or more complex treatment including alternative strategies for pain management.

Auto-Generated Physiological Chain Data for an Ontological Framework for Pharmacology and Mechanism of Action to Determine Suspected Drugs in Cases of Dysuria.

INTRODUCTION: Patients often take several different medications for multiple conditions concurrently. Therefore, when adverse drug events (ADEs) occur, it is necessary to consider the mechanisms responsible. Few approaches consider the mechanisms of ADEs, such as changes in physiological states. We proposed that the ontological framework for pharmacology and mechanism of action (pharmacodynamics) we developed could be used for this approach. However, the existing knowledge base contains little data on physiological chains (PCs). OBJECTIVE: We aimed to investigate a method for automatically generating missing PC from the viewpoint of anatomical structures. This study was conducted to determine dysuria-related adverse events more likely to occur during multidrug administration. METHODS: We adopted a systematic approach to determine drugs suspected to cause adverse events and incorporated existing data and data generated in our newly developed method into our ontological framework. The performance of automated data generation was evaluated using this newly developed system. Suspected drugs determined by the system were compared with those derived from adverse events databases. RESULTS: Of the 242 drugs involving suspected drug-induced urinary retention or dysuria, 26 suspected drugs were determined. Of these, five were drugs with side effects not listed in drug package inserts. The system derived potential mechanisms of action, PCs, and suspected drugs. CONCLUSION: Our method is novel in that it generates PC data from anatomical structural properties and could serve as a knowledge base for determining suspected drugs by potential mechanisms of action.

Intermediate-Term Efficacy and Tolerance of Statins in Children.

OBJECTIVES: To evaluate the intermediate-term efficacy and tolerance of statins in children and adolescents with familial hypercholesterolemia. STUDY DESIGN: A total of 131 children or adolescents treated with statins for familial hypercholesterolemia were prospectively included. The efficacy of treatment was established by the percentage of children who achieved low density lipoprotein-cholesterol (LDL-C) levels <160 mg/dL during treatment. Treatment tolerance was evaluated by the occurrence of clinical or laboratory side effects, regularity of increases in height and weight, and pubertal development. RESULTS: The median duration of treatment with statins was 4 years. A median decrease of 32% in LDL-C levels was observed (P < .0001). The therapeutic target (LDL-C <160 mg/dL) was achieved in 67% of cases. Increases in height and weight and sexual maturation were not affected by the treatment. Minor side effects were reported for 24 (18.4%) patients including 3 cases of a clinically asymptomatic increase in creatine phosphokinase (CPK) levels, 2 cases of an increase in CPK levels with muscular symptoms, 14 cases of myalgia without an increase in CPK levels, 3 cases of abdominal pain, 1 case of dysuria, and 1 case of diffuse pain. None of these side effects led to the discontinuation of statin therapy, although a change of statin was required in 7 cases. This new statin was tolerated in all cases. No patients had abnormal liver function during treatment. CONCLUSIONS: The results of this large cohort confirm the intermediate-term safety and efficacy of statin therapy in children with familial hypercholesterolemia.

Evaluation of Antidepressant Effects on Recovery of Electrical Field Stimulation-Induced Contractions that have been Suppressed by Clonidine in Isolated Rat Vas Deferens.

BACKGROUND: A report examining whether clinically available antidepressants increase urethral smooth muscle contraction via antagonistic effects on the α2-adrenoceptor (α2-AR) is lacking. OBJECTIVES: The present study was performed to evaluate the potential of clinically available antidepressants to reverse α2-AR-mediated contractile inhibition in rat vas deferens, in order to predict whether they can induce voiding impairment. METHOD: The effects of 18 antidepressants of different classes on electrical field stimulation (EFS)-induced contractions suppressed by 10-8 mol/L clonidine (a selective α2-AR agonist) in isolated rat vas deferens were investigated and related to their respective clinical blood concentrations. RESULTS: The EFS-induced contractions suppressed by clonidine were recovered by amitriptyline (a tricyclic antidepressant), mirtazapine (a noradrenergic and specific serotonergic antidepressant), and trazodone (a serotonin 5-HT2A receptor antagonist) at concentrations close to the clinical blood levels. EFS-induced contractions were also recovered by trimipramine, clomipramine (tricyclic antidepressants), mianserin (a tetracyclic antidepressant), sertraline (a selective serotonin reuptake inhibitor [SSRI]), and sulpiride (a dopamine D2-receptor antagonist), albeit at concentrations that substantially exceeded their clinically-achievable blood levels. EFS-induced contractions were not significantly affected by imipramine, nortriptyline, amoxapine (tricyclic antidepressants), maprotiline (a tetracyclic antidepressant), fluvoxamine, paroxetine, escitalopram (SSRIs), milnacipran, duloxetine (serotonin and noradrenaline reuptake inhibitors), and aripiprazole (a dopamine partial agonist). CONCLUSIONS: These findings suggest that amitriptyline, mirtazapine, and trazodone induce voiding impairment caused by increased urethral resistance by enhancing sympathetic nerve activities attributed to α2-AR antagonism.

Quadruple immunotherapy of Bacillus Calmette-Guérin, interferon, interleukin-2, and granulocyte-macrophage colony-stimulating factor as salvage therapy for non-muscle-invasive bladder cancer.

BACKGROUND: Bacillus Calmette-Guérin (BCG) is the most effective initial intravesical therapy for high-grade non-muscle invasive bladder cancer, but many patients still fail. Combination intravesical BCG and interferon (IFN) will salvage some patients but results remain suboptimal. OBJECTIVE: We hypothesized that further immunostimulation with intravesical interleukin-2 and subcutaneous granulocyte-macrophage colony-stimulating factor may improve response to intravesical BCG and IFN in patient with prior BCG failure(s). METHODS: A retrospective review was performed. Patients received 6 treatments of quadruple immunotherapy (intravesical solution with one-third dose BCG, 50 million units IFN, and 22 million units interleukin-2, along with a 250-mcg subcutaneous sargramostim injection). Surveillance began 4 to 6 weeks after treatment completion. Patients received maintenance if recurrence-free. Success was defined as no recurrence (bladder or extravesical) and bladder preservation. Analysis was performed by Kaplan-Meier method (P<0.05). RESULTS: Fifty-two patients received treatment with a median recurrence follow-up of 16.3 months and overall follow-up of 41.8 months. All patients had at least 1 prior BCG failure and 13% had 2 or more prior failures. Only 3 patients (6%) were unable to tolerate full induction. Treatment success was 55% at 1 year, and 53% at 2 years. Thirteen patients (25%) underwent cystectomy at a median time of 17.3 months with disease progression to T2 in 1 patient and T3 in 2 patients. No patients had positive surgical margins or positive lymph nodes. CONCLUSIONS: In patients with non-muscle-invasive bladder cancer with prior BCG failure, quadruple immunotherapy demonstrated good treatment success in some patients and warrants further evaluation.

Complications associated with single-dose, perioperative mitomycin-C for patients undergoing bladder tumor resection.

OBJECTIVES: To better understand the risk of short-term complications associated with perioperative intravesical mitomycin-C (MMC) therapy for patients undergoing endoscopic management of non-muscle invasive bladder cancer. METHODS AND MATERIALS: Using an institutional database of patients with bladder cancer, we performed a retrospective case-control study of patients receiving perioperative MMC after tumor resection (2008-2012). MMC cases were matched by clinical stage to controls receiving endoscopic resection alone. Demographic information, clinicopathologic details, and outcomes were compared between groups. Outcomes of interest included overall, genitourinary, and major complications. Chi-square tests and multivariable logistic regression were used to evaluate associations among patient characteristics, clinical factors, exposure to MMC, and outcomes of interest. RESULTS: One-hundred sixteen patients treated with MMC were matched to 116 controls. Patients receiving MMC were younger (P = 0.04) and more likely to have invasive disease (i.e. T1 or greater) (23% vs. 15%, P = 0.02). Complications were more frequent among patients who were treated with MMC (34.5% vs. 19.8%, Odds Ratio 2.89, 95% Confidence Interval 1.43-5.81). The most common complication among MMC patients that required medical management was dysuria (17%). Major complications were more common among MMC patients (5.2% vs. 0.9%), but this difference did not reach statistical significance (P = 0.11). CONCLUSIONS: Use of MMC is associated with a greater odds of complications compared with controls. Patients should be counseled regarding both the benefits and potential risks of perioperative intravesical MMC. Continued research is required to understand the safety implications associated with the use of perioperative, intravesical MMC.

[A case of Ifosfamide-induced dysuria which could be avoided by changing the regimen of mesna].

A 39-year-old woman with advanced and recurrent cervical carcinoma received chemotherapy with IFM+CDDP(IFM 5, 000mg/m2 by intravenous infusion for 24 hours and CDDP 50 mg/m2 by intravenous infusion for one hour)in September of 2011. Mesna(3, 200mg/body)was administered intravenously for 30min three times a day to prevent IFM-induced hemorrhagic cystitis. She complained of residual urine from the evening of day 2 and felt pain during urination from day 3 (urinary tract pain: Grade 1 CTCAE v4.0 ). Both symptoms continued until day 6. When the infusion rate of mesna was changed to 24 hours of continuous administration, as with IFM on the second course, no symptoms which occurred during the first course were observed. The chemotherapy could be continued without compromising her QOL. The present finding suggests that IFM-induced dysuria could be avoided by changing the regimen to mesna, due to the increase in its binding potency and the metabolite of IFM, acrolein.

Ketamine is associated with lower urinary tract signs and symptoms.

BACKGROUND: Case reports and series indicate that ketamine, an anesthetic agent, causes lower urinary tract symptoms (LUTS). This study explored whether ketamine users were more likely to report LUTS compared to other substance users. METHODS: Participants were recruited through an online survey on erowid.org, a drug information website. A notice posted on the website invited substance users to participate in a web-based survey on "drug use and health". The notice did not mention ketamine, or other aspects of the research questions, to avoid participation bias. The anonymous survey collected demographics, drug use history, and history of LUTS (urinary frequency, urgency, incontinence, hematuria, and dysuria). RESULTS: Of 18,802 participants, 18.7% and 5.8% reported ever (lifetime) and recent (past-6-month) use of ketamine, respectively. Prevalence of LUTS among ever, recent, and never users of ketamine were 28%, 30%, and 24% respectively. Multivariate analysis showed significant associations between recent ketamine use and urinary symptoms. For each additional day of ketamine use in the last 180 days, the odds of developing urinary frequency, urgency, dysuria, and hematuria increased by 1.6%, 1.4%, 1.7%, and 1.9% respectively. One excess case of urinary frequency was reported per 17 recent users of ketamine. CONCLUSION: Compared to non-users, recent ketamine users had increased odds of LUTS. This is the first large-scale community-based study assessing the association of non-medical ketamine use with LUTS. Associations between ketamine and urological symptoms should be confirmed through longitudinal studies.

[Systemic adverse effects of topical ocular instillation of atropine in two children]. / Effets systémiques des collyres mydriatiques atropiniques chez deux enfants.

A medication-related cause must be sought when unusual symptoms occur. Topical treatments, including eye drops, whose side effects are more common in exposed children, need to be verified. We report here the cases of two children who developed systemic symptoms after the administration of atropine-based mydriatic eye drops. A 6-month-old boy was admitted to the emergency department with acute urine retention lasting 36h. Investigations identified only eye drop treatment 3h before the onset of symptoms, with 2 drops of homatropine 1 %, as a cause. No other urinary retention was observed during the 1-year follow-up. A 2-year-old boy was admitted to the emergency department for drowsiness, thirst, and dry mouth 30min after the administration of three eye drops of atropine 1 % instead of atropine 0.3 % (error made by the pharmacy). Symptoms disappeared after 6h. Both observations highlight the possible side effects related to mydriatic eye drops. Indeed, because of small penetration of such medications in the eye, a high concentration of the active part of the medication is contained in each drop. In young children, at least 20 to 40 % of the volume of a drop drains into the nasolacrimal duct and thereby into the systemic circulation, without passage through the liver. A close national pharmacologic vigilance follow-up has been set up for atropine-based mydriatic eye drops in young children, who are the most exposed to systemic and potentially severe complications of these medications. We emphasize the appropriate procedure for the use of eye drops in young children to limit systemic passage, with only a 0.3 % maximum atropine concentration in infants, compression of the internal angle of the eye for at least 1min, and at least a 15-mins interval between two eye drop administrations.

Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guérin.

OBJECTIVES: Evaluate the efficacy and safety of valrubicin for bacillus Calmette-Guérin (BCG)-refractory carcinoma in situ (CIS) of the bladder based on updated phase III pivotal trial efficacy data together with efficacy and safety data from a supportive phase II/III study. MATERIALS AND METHODS: In a phase II/III open-label study (A9303), BCG refractory/intolerant adults with CIS (≥ 1 previous course of BCG or could not complete a BCG course owing to toxicity or contraindication) were randomized to receive 6 or 9 weekly intravesical valrubicin (800 mg) instillations. In the pivotal phase III open-label study, BCG-refractory/recurrent adults with CIS (≥ 2 previous courses of intravesical therapy, including ≥ 1 BCG course) received 6 weekly intravesical valrubicin (800 mg) instillations. Patients with muscle-invasive disease were excluded. Patients underwent a primary disease evaluation (PDE) at 3 months (≈ 6 weeks after last dose) that included cytoscopy, biopsy, and cytology. Disease recurrence was monitored at 3-month intervals. Complete response (CR) was defined as no evidence of disease at the PDE (month 3) and follow-up (month 6). Efficacy data from the pivotal trial reflect updated information based on US Food and Drug Administration review. Safety assessments in A9303 included local bladder adverse events (LBAEs) and other adverse events (AEs). RESULTS: Eighty patients enrolled and 78 completed treatment and underwent the PDE in study A9303; in the pivotal trial, the respective numbers were 90 and 87 patients. In study A9303, 39% of patients had received ≥ 2 previous courses of BCG and 11% had received ≥ 3 courses vs. 70% and 28%, respectively, in the pivotal trial. In both studies, the CR rate was 18%. In A9303, LBAEs were the most common AEs, reported by 86% of patients during treatment and 45% during follow-up; most treatment-related LBAEs were mild to moderate. 2 serious AEs in 1 patient (azotemia/reflux nephropathy) were judged as definitely or possibly treatment related; none of the patient deaths were judged to be related to valrubicin. CONCLUSIONS: Two trials of valrubicin in patients with CIS demonstrate a consistent degree of efficacy in highly pretreated patients (pivotal trial; BCG-refractory patients) and those with fewer previous therapies (A9303; BCG-refractory/intolerant patients).

Histological changes due to intravesical instillation of mitomycin C.

OBJECTIVE: Transurethral resection (TUR) is highly effective in the local control of superficial bladder cancer. However, the recurrence rate can reach 80% of the cases. Adjuvant intravesical chemotherapy may decrease significantly tumor recurrence. We describe a bladder adverse reaction to mitomycin C as adjuvant therapy for non-invasive bladder cancer METHODS: Three patients with diagnosis of pTa G1 urothelial carcinoma were treated by TUR plus an instillation of 40 mg. of mitomicin C. A month later, the patients were attended for dysuria and hematuria. Cystoscopy and bladder biopsy were performed in all cases. RESULTS: Multiple sessile lesions suspicious of tumor recurrence were found on cystoscopy. The histopathological diagnosis disclosed the existence of severe atypia of the urothelium and stromal changes similar to those observed after radiotherapy CONCLUSIONS: Adjuvant intravesical chemotherapy with mitomycin C may cause local reactions with macroscopic patterns similar to tumoral recurrences.

Prevalence of opioid-related dysuria in patients with advanced cancer having pain.

The aim of this study was to assess the prevalence of opioid-induced dysuria in patients with advanced cancer having pain and to evaluate the possible factors associated. A consecutive sample of cancer patients admitted to an acute pain relief and palliative care unit during 8 months was surveyed. Most patients (147, 86.5%) were receiving opioids at admission. The mean age was 65.1 (SD 12.2) and 106 patients were males. Twenty-five patients presented with dysuria at admission (of which 22 were taking opioids, 14.9%). Eleven patients were inserted a bladder catheter at admission for urine monitoring and 18 patients had urinary incontinence. During admission, 31 patients presented dysuria (19% of population was taking opioids). The prevalence of dysuria was more frequent in males, in patients presenting pelvic masses or who had pelvic surgery, and patients with neurological deficits. Opioid switching during admission was correlated to the occurrence of dysuria. Patients with chronic cancer pain receiving opioid therapy present a prevalence of bladder dysfunction of about 15%, which is influenced by several concomitant factors. Given the complex clinical picture of advanced cancer patients, further studies should be performed to explore the presence of dysuria in patients with no pain and not receiving opioids to know the real weight of opioid therapy with respect to other variables.

Efficacy evaluation for depression with somatic symptoms treated by electroacupuncture combined with Fluoxetine.

OBJECTIVE: This study is to investigate the clinical therapeutic effects and safety of treating mild or moderate depression with somatic symptoms with electroacupuncture combined with Fluoxetine. METHODS: 95 cases of mild or moderate depression with somatic symptoms were randomly divided into a Fluoxetine group, and an electroacupuncture plus Fluoxetine group. Hamilton Depression Scale (HAMD) was used for the assessment of clinical therapeutic effects and Treatment Emergent Symptom Scale (TESS) was used for assessment of adverse reactions. RESULTS: The total effective rate was 77.27% in the Fluoxetine group and 78.26% in the electroacupuncture plus Fluoxetine group, showing no statistically significant difference between these two groups (P > 0.05). However, the treatment took effect after two weeks in the electroacupuncture plus Fluoxetine group but after four weeks in Fluoxetine group. During this time, a better therapeutic effect on depression with mild or moderate somatic symptoms was found in the electroacupuncture plus Fluoxetine group, which also had fewer adverse reactions than the Fluoxetine group. CONCLUSION: Electroacupuncture combined with Fluoxetine takes effect faster for relieving the somatic symptoms with fewer adverse reactions. It is worth popularizing clinically.