RESUMEN
Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia.
Asunto(s)
Antipsicóticos , Esquizofrenia , Humanos , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/uso terapéutico , Antipsicóticos/efectos adversos , Antagonistas Muscarínicos/uso terapéutico , Antagonistas Muscarínicos/efectos adversos , Piridinas/uso terapéutico , Piridinas/efectos adversos , Piridinas/farmacología , Bencilatos/uso terapéutico , Bencilatos/efectos adversos , Combinación de Medicamentos , Animales , Agonistas Muscarínicos/uso terapéutico , Agonistas Muscarínicos/efectos adversos , Tiadiazoles/uso terapéutico , Tiadiazoles/efectos adversos , Tiadiazoles/farmacologíaRESUMEN
Importance: A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia. Objective: To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia. Design, Setting, and Participants: EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023. Interventions: Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks. Main Outcomes and Measures: The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated. Results: A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups. Conclusions and Relevance: Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity. Trial Registration: ClinicalTrials.gov Identifier: NCT04738123.
Asunto(s)
Antipsicóticos , Bencilatos , Nortropanos , Esquizofrenia , Humanos , Esquizofrenia/tratamiento farmacológico , Masculino , Adulto , Femenino , Método Doble Ciego , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Antipsicóticos/farmacología , Persona de Mediana Edad , Nortropanos/efectos adversos , Nortropanos/uso terapéutico , Nortropanos/farmacología , Bencilatos/efectos adversos , Bencilatos/farmacología , Bencilatos/uso terapéutico , Combinación de Medicamentos , Resultado del Tratamiento , Piridinas , TiadiazolesRESUMEN
AIMS: Depression is one of the common neurological comorbidities in patients with inflammatory bowel disease (IBD). The current study aimed to investigate the potential impact of niacin on colitis-induced depressive-like behavior in rats. MATERIALS AND METHODS: Animals were given 5 % dextran sulfate sodium (DSS) in drinking water for one week to induce colitis. Niacin (80 mg/kg), with or without mepenzolate bromide (GPR109A blocker), was administered once per day throughout the experimental period. Rats were tested for behavioral changes using open field and forced swimming tests. KEY FINDINGS: Niacin significantly ameliorated DSS-induced behavioral deficits and alleviated macroscopic and microscopic colonic inflammatory changes. It also augmented the hippocampal levels of ZO-1, occludin, and claudin-5 proteins, indicating the ability of niacin to restore the blood-brain barrier (BBB) integrity. Moreover, niacin decreased hippocampal IL-1êµ and NF-ĸB contents but increased GSH, Sirt-1, Nrf-2, HO-1 concentrations. All these beneficial effects were partially abolished by the co-administration of mepenzolate bromide. SIGNIFICANCE: The neuroprotective effect of niacin against DSS-induced depressive-like behavior was partially mediated through GPR109A-mediated mechanisms. Such mechanisms are also involved in modulating neuronal oxidative stress and inflammation via Sirt-1/Nrf-2/HO-1 signaling pathways.
Asunto(s)
Colitis , Niacina , Animales , Ratas , Bencilatos/efectos adversos , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colon/metabolismo , Citocinas/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Niacina/farmacologíaRESUMEN
INTRODUCTION: To clarify the efficacy and safety of propiverine hydrochloride for incontinence after robot-assisted laparoscopic prostatectomy (RALP)/laparoscopic radical prostatectomy (LRP), along with changes in the urethral pressure profile (UPP) and quality of life in patients treated with propiverine hydrochloride. MATERIALS AND METHODS: In this randomized, comparative study, 104 patients who were aware of urinary incontinence after RALP or LRP were assigned to receive propiverine hydrochloride (treatment group) or not (controls). Pad test results, International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) scores, and UPP results [including maximum urethral closure pressure (MUCP) and functional urethral length (FUL)], were recorded immediately and at 6 months postoperatively. RESULTS: No serious intraoperative complications or adverse events were caused by propiverine hydrochloride. The pad-test negative rate was significantly greater in the treatment group than in controls (89.1% vs. 73.2%, p = 0.044). Changes in ICIQ-SF scores and MUCP were significantly greater in the treatment group than in controls [-6.5 vs. -4.5 points (p = 0.021), and +49.5 vs. +28.7 mmHg (p = 0.038), respectively]. FUL change did not significantly differ between groups [+4.5 vs. +3.8 mm (p = 0.091)]. In univariate logistic regression analyses, body mass index (BMI), MUCP, and treatment with propiverine hydrochloride were significantly associated with continence status. In multivariate analyses, BMI and MUCP were independently associated with continence status [odds ratio (OR), 1.266; 95% confidence interval (CI), 1.047-1.530 (p = 0.015), and OR, 0.986; 95% CI, 0.973-0.999 (p = 0.042), respectively]. CONCLUSIONS: Treatment with propiverine hydrochloride alleviated urinary incontinence while improving patient symptoms and quality of life after RALP or LRP.
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Bencilatos , Prostatectomía , Incontinencia Urinaria , Bencilatos/efectos adversos , Humanos , Laparoscopía , Masculino , Prostatectomía/efectos adversos , Prostatectomía/métodos , Neoplasias de la Próstata/cirugía , Calidad de Vida , Robótica , Incontinencia Urinaria/tratamiento farmacológico , Incontinencia Urinaria/etiologíaRESUMEN
BACKGROUND: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown. METHODS: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2. RESULTS: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups. CONCLUSIONS: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).
Asunto(s)
Antipsicóticos/uso terapéutico , Bencilatos/uso terapéutico , Antagonistas Colinérgicos/uso terapéutico , Agonistas Muscarínicos/uso terapéutico , Nortropanos/uso terapéutico , Piridinas/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Tiadiazoles/uso terapéutico , Administración Oral , Adulto , Antipsicóticos/efectos adversos , Bencilatos/efectos adversos , Antagonistas Colinérgicos/efectos adversos , Método Doble Ciego , Combinación de Medicamentos , Femenino , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Agonistas Muscarínicos/efectos adversos , Nortropanos/efectos adversos , Piridinas/efectos adversos , Tiadiazoles/efectos adversosRESUMEN
Overactive bladder syndrome (OAB) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence, in the absence of urinary tract infection or other obvious pathology. The mainstay of treatment of OAB is anticholinergic/antimuscarinic medication. These drugs block muscarinic receptors throughout the body, not only the bladder, including in the brain, which may lead to cognitive side effects. Anticholinergic load or burden is the cumulative effect of taking drugs that are capable of producing anticholinergic adverse effects. The elderly are more susceptible to these effects, especially as there is increased permeability of the blood brain barrier. The anticholinergic drugs for OAB are able to enter the central nervous system and lead to central side effects. There is increasing evidence that a high anticholinergic load is linked to the development of cognitive impairment and even dementia. Some studies have found an increased risk of mortality. In view of this, care is needed when treating OAB in the elderly. Trospium chloride is a quaternary amine anticholinergic, which has a molecular structure, which theoretically means it is less likely to cross the blood brain barrier and exert central side effects. Alternatively, mirabegron can be used, which is a beta-3 adrenoceptor agonist, which does not add to the anticholinergic load or exert central nervous system side effects. Conservative therapy can be used as an alternative to pharmacological treatment in the form of behavioral modification, fluid management and bladder retraining. Neuromodulation or the use of botox can also be alternatives, but success may be less in the older adult and will require increased hospital attendances.
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Antagonistas Colinérgicos/efectos adversos , Disfunción Cognitiva/inducido químicamente , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Acetanilidas/efectos adversos , Anciano , Terapia Conductista , Bencilatos/efectos adversos , Barrera Hematoencefálica/efectos de los fármacos , Disfunción Cognitiva/prevención & control , Femenino , Humanos , Antagonistas Muscarínicos/uso terapéutico , Nortropanos/efectos adversos , Tiazoles/efectos adversos , Vejiga Urinaria Hiperactiva/psicologíaRESUMEN
ABSTRACT Objective To evaluate the effects of solifenacin, darifenacin, and propiverine on nasal-, subfoveal-, temporal choroidal thicknesses (NCT, SFCT, TCT), intraocular pressure (IOP) and pupil diameter (PD). Materials and Methods Patients with overactive bladder (OAB) diagnosed according to The International Continence Society were administered with solifenacin, darifenacin or propiverine on a daily basis between November 2017 and May 2018. NCT, SFCT, TCT, IOP, and PD of these patients were measured and compared as initial, fourth and twelfth weeks. Results A total of 165 patients (330 eyes) with OAB were evaluated. Solifenacin (n=140) significantly reduced IOP from 17.30±2.72 mmHg to 16.67±2.56 mmHg (p=0.006) and 16.57±2.41 mmHg (p=0.002), at the fourth and twelfth weeks, respectively. Darifenacin (n=110) significantly reduced NCT from 258.70±23.96 μm to 257.51±22.66 μm (p=0.002) and 255.36±19.69 μm (p=0.038), at the fourth and twelfth weeks, respectively. Propiverine (n=80) significantly increased PD from 4.04±0.48 mm to 4.08±0.44 mm (p=0.009) and 4.09±0.45 mm (p=0.001), at the fourth and twelfth weeks, respectively. Conclusion These findings can help to decide appropriate anticholinergic drug choice in OAB patients. We finally suggest further well-designed randomized prospective studies with a larger population to evaluate the anticholinergic-related complications in eyes.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Anciano , Anciano de 80 o más Años , Adulto Joven , Pirrolidinas/efectos adversos , Bencilatos/efectos adversos , Benzofuranos/efectos adversos , Pupila/efectos de los fármacos , Coroides/efectos de los fármacos , Antagonistas Muscarínicos/efectos adversos , Succinato de Solifenacina/efectos adversos , Presión Intraocular/efectos de los fármacos , Pirrolidinas/administración & dosificación , Bencilatos/administración & dosificación , Benzofuranos/administración & dosificación , Estudios Prospectivos , Estudios de Seguimiento , Antagonistas Muscarínicos/administración & dosificación , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Succinato de Solifenacina/administración & dosificación , Persona de Mediana EdadRESUMEN
OBJECTIVE: To evaluate the effects of solifenacin, darifenacin, and propiverine on nasal-, subfoveal-, temporal choroidal thicknesses (NCT, SFCT, TCT), intraocular pressure (IOP) and pupil diameter (PD). MATERIALS AND METHODS: Patients with overactive bladder (OAB) diagnosed according to The International Continence Society were administered with solifenacin, darifenacin or propiverine on a daily basis between November 2017 and May 2018. NCT, SFCT, TCT, IOP, and PD of these patients were measured and compared as initial, fourth and twelfth weeks. RESULTS: A total of 165 patients (330 eyes) with OAB were evaluated. Solifenacin (n=140) signifi cantly reduced IOP from 17.30±2.72 mmHg to 16.67±2.56 mmHg (p=0.006) and 16.57±2.41 mmHg (p=0.002), at the fourth and twelfth weeks, respectively. Darifenacin (n=110) signifi cantly reduced NCT from 258.70±23.96 µm to 257.51±22.66 µm (p=0.002) and 255.36±19.69 µm (p=0.038), at the fourth and twelfth weeks, respectively. Propiverine (n=80) signifi cantly increased PD from 4.04±0.48 mm to 4.08±0.44 mm (p=0.009) and 4.09±0.45 mm (p=0.001), at the fourth and twelfth weeks, respectively. CONCLUSION: These findings can help to decide appropriate anticholinergic drug choice in OAB patients. We finally suggest further well-designed randomized prospective studies with a larger population to evaluate the anticholinergic-related complications in eyes.
Asunto(s)
Bencilatos/efectos adversos , Benzofuranos/efectos adversos , Coroides/efectos de los fármacos , Presión Intraocular/efectos de los fármacos , Antagonistas Muscarínicos/efectos adversos , Pupila/efectos de los fármacos , Pirrolidinas/efectos adversos , Succinato de Solifenacina/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Bencilatos/administración & dosificación , Benzofuranos/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/administración & dosificación , Estudios Prospectivos , Pirrolidinas/administración & dosificación , Succinato de Solifenacina/administración & dosificación , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Adulto JovenRESUMEN
Trospium chloride, a muscarinic receptor blocker, is poorly absorbed with different rates from areas in the jejunum and the cecum/ascending colon. To evaluate whether organic cation transporter (OCT) 1, OCT2 and multidrug and toxin extrusion (MATE) 1 and MATE2-K are involved in pharmacokinetics, competitions with ranitidine, a probe inhibitor of the cation transporters, were evaluated in transfected HEK293 cells. Furthermore, a drug interaction study with trospium chloride after intravenous (2 mg) and oral dosing (30 mg) plus ranitidine (300 mg) was performed in 12 healthy subjects and evaluated by noncompartmental analysis and population pharmacokinetic modeling. Ranitidine inhibited OCT1, OCT2, MATE1, and MATE2-K with half maximal inhibitory concentration values of 186 ± 25 µM, 482 ± 105 µM, 134 ± 37 µM, and 35 ± 11 µM, respectively. In contrast to our hypothesis, coadministration of ranitidine did not significantly decrease oral absorption of trospium. Instead, renal clearance was lowered by â¼15% (530 ± 99 vs 460 ± 120 mL/min; P < .05). It is possible that ranitidine was not available in competitive concentrations at the major colonic absorption site, as the inhibitor is absorbed in the small intestine and undergoes degradation by microbiota. The renal effects apparently result from inhibition of MATE1 and/or MATE2-K by ranitidine as predicted by in vitro to in vivo extrapolation. However, all pharmacokinetic changes were not of clinical relevance for the drug with highly variable pharmacokinetics. Intravenous trospium significantly lowered mean absorption time and relative bioavailability of ranitidine, which was most likely caused by muscarinic receptor blocking effects on intestinal motility and water turnover.
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Bencilatos/efectos adversos , Bencilatos/farmacocinética , Antagonistas Muscarínicos/efectos adversos , Antagonistas Muscarínicos/farmacocinética , Nortropanos/efectos adversos , Nortropanos/farmacocinética , Proteínas de Transporte de Catión Orgánico/metabolismo , Ranitidina/farmacología , Ranitidina/farmacocinética , Administración Intravenosa , Administración Oral , Adulto , Bencilatos/administración & dosificación , Bencilatos/sangre , Disponibilidad Biológica , Células Cultivadas , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Masculino , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/sangre , Nortropanos/administración & dosificación , Nortropanos/sangre , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Ranitidina/administración & dosificación , Ranitidina/sangreRESUMEN
OBJECTIVE: This analysis was conducted to investigate the cardiovascular (CV) safety outcomes from the MILAI II study. MILAI II was conducted to evaluate the long-term safety and efficacy of antimuscarinic add-on therapy to mirabegron over 52 weeks in patients with overactive bladder (OAB) symptoms. METHODS: MILAI II consisted of a 2-week screening period (patients received mirabegron 50 mg once daily) plus a 52-week treatment period (patients were randomized to receive a combination of mirabegron 50 mg/d plus solifenacin 5 mg/d, propiverine 20 mg/d, imidafenacin 0.2 mg/d, or tolterodine 4 mg/d). CV safety was assessed using treatment-emergent adverse events (TEAEs), vital signs, and 12-lead electrocardiograms (ECGs). Vital signs and ECG data were evaluated for each patient using worst post-baseline values reported. RESULTS: Of 647 patients, 570 (88.1%) were female with a mean age of 65 years. CV history at baseline and CV-related concomitant medication use throughout the study were balanced between groups. The incidences of overall and drug-related CV TEAEs were ≤8.1% and ≤6.2%, respectively, for all groups. The most common TEAEs were ECG T wave amplitude decreased, ECG QT prolonged, and ventricular extrasystoles. Overall, 36 TEAEs of interest related to the CV system that were possibly/probably related to treatment were reported with similar incidences for each group. For the worst post-baseline vital signs and ECGs, no relationships were noted in terms of either timing or treatment group. CONCLUSION: A favorable CV safety profile was observed following long-term combination treatment with mirabegron and an antimuscarinic in patients with OAB symptoms.
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Acetanilidas/uso terapéutico , Enfermedades Cardiovasculares/epidemiología , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/efectos adversos , Tiazoles/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Agentes Urológicos/uso terapéutico , Anciano , Anciano de 80 o más Años , Bencilatos/administración & dosificación , Bencilatos/efectos adversos , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Japón , Masculino , Persona de Mediana Edad , Succinato de Solifenacina/administración & dosificación , Succinato de Solifenacina/efectos adversos , Tartrato de Tolterodina/administración & dosificación , Tartrato de Tolterodina/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVES: To evaluate the long-term safety (primary objective) and efficacy (secondary objective) of antimuscarinic add-on therapy in patients receiving mirabegron. METHODS: During a 2-week screening period, patients (aged ≥20 years, mirabegron treatment for ≥6 weeks, residual overactive bladder symptoms) received mirabegron 50 mg once daily. These patients were subsequently randomized to 52 weeks' treatment with mirabegron 50 mg/day plus an antimuscarinic (solifenacin 5 mg, propiverine 20 mg, imidafenacin 0.2 mg, or tolterodine 4 mg) with the potential to double the antimuscarinic dose (except for tolterodine) at week 8. Safety assessments included treatment-emergent adverse events, vital signs, 12-lead electrocardiograms, post-void residual volume, and laboratory evaluations. Efficacy was assessed using changes from baseline in overactive bladder symptom score total score; overactive bladder questionnaire short form score; micturitions, urgency episodes, urinary incontinence episodes, and urgency urinary incontinence episodes/24 h; mean volume voided per micturition; and number of night-time micturitions. RESULTS: Overall, 80.2% of patients (88.1% women, mean age 65 years) experienced at least one treatment-emergent adverse event, with similar rates for all treatments. The adverse events most commonly reported were dry mouth, nasopharyngitis, and constipation. No marked change was observed in systolic or diastolic blood pressure for any treatment, although pulse rate increased slightly in the mirabegron and propiverine, and mirabegron and tolterodine groups. For all treatments, significant improvements were observed in all efficacy parameters, including overactive bladder symptom score total and questionnaire short form scores. CONCLUSIONS: Antimuscarinic add-on therapy is well tolerated and effective after initial treatment with mirabegron in patients with overactive bladder symptoms.
Asunto(s)
Acetanilidas/efectos adversos , Agonistas de Receptores Adrenérgicos beta 3/efectos adversos , Antagonistas Muscarínicos/efectos adversos , Tiazoles/efectos adversos , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Incontinencia Urinaria/tratamiento farmacológico , Acetanilidas/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 3/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Bencilatos/administración & dosificación , Bencilatos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Estreñimiento/inducido químicamente , Estreñimiento/epidemiología , Método Doble Ciego , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Japón , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/administración & dosificación , Nasofaringitis/inducido químicamente , Nasofaringitis/epidemiología , Índice de Severidad de la Enfermedad , Succinato de Solifenacina/administración & dosificación , Succinato de Solifenacina/efectos adversos , Tiazoles/administración & dosificación , Factores de Tiempo , Tartrato de Tolterodina/administración & dosificación , Tartrato de Tolterodina/efectos adversos , Resultado del Tratamiento , Vejiga Urinaria Hiperactiva/complicaciones , Vejiga Urinaria Hiperactiva/diagnóstico , Incontinencia Urinaria/diagnóstico , Incontinencia Urinaria/etiología , Xerostomía/inducido químicamente , Xerostomía/epidemiologíaRESUMEN
BACKGROUND: Benign prostatic hyperplasia (BPH) is a common condition in ageing men that may cause lower urinary tract symptoms (LUTS). Treatment aims are to relieve symptoms and prevent disease-related complications. Naftopidil is an alpha-blocker (AB) that has a high affinity for the A1d receptor that may have advantages in treating LUTS in this setting. This is an update of a Cochrane Review first published in 2009. Since that time, several large randomised controlled trials (RCTs) have been reported, making this update relevant. OBJECTIVES: To evaluate the effects of naftopidil for the treatment of LUTS associated with BPH. SEARCH METHODS: We performed a comprehensive search using multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, LILAC, and Web of Science), trials registries, other sources of grey literature, and conference proceedings with no restrictions on the language of publication or publication status up to 31 May 2018 SELECTION CRITERIA: We included all parallel RCTs. We also included cross-over design trials. DATA COLLECTION AND ANALYSIS: Two review authors independently classified and abstracted data from the included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. Primary outcomes were urological symptom scores, quality of life (QoL) and treatment withdrawals for any reason; secondary outcomes were treatment withdrawals due to adverse events, acute urinary retention, surgical intervention for BPH, and cardiovascular and sexual adverse events. We considered outcomes measured up to 12 months after randomisation as short term, and later than 12 months as long term. We rated the certainty of the evidence according to the GRADE approach. MAIN RESULTS: We included 22 RCTs with 2223 randomised participants across four comparisons for short-term follow-up. This abstract focuses on only two of four comparisons for which we found data since two comparators (i.e. propiverine and Eviprostat (phytotherapy)) are rarely used. One study comparing naftopidil to placebo did not report any relevant outcomes and was therefore excluded. There were no trials that compared to combination therapy with naftopidil or any 5-alpha reductase inhibitors (5-ARIs) to combination therapy with other ABs and any 5-ARIs.All included studies were conducted in Asian countries. Study duration ranged from four to 12 weeks. Mean age was 67.8 years, prostate volume was 35.4 mL, and International Prostate Symptom Score was 18.3. We were unable to perform any of the preplanned subgroup analyses based on age and baseline symptom score.Naftopidil versus tamsulosinBased on 12 studies with 965 randomised participants, naftopidil may have resulted in little or no difference in urological symptom score (mean difference (MD) 0.47, 95% confidence interval (CI) -0.09 to 1.04 measured on a scale from 0 to 35 with higher score representing increased symptoms), QoL (MD 0.11, 95% CI -0.09 to 0.30; measured on a scale from 0 to 6 with higher scores representing worse QoL), and treatment withdrawals for any reason (risk ratio (RR) 0.92, 95% CI 0.64 to 1.34; corresponding to 7 fewer per 1000 participants, 95% CI 32 fewer to 31 more). Naftopidil may have resulted in little to no difference in sexual adverse events (RR 0.54, 95% CI 0.24 to 1.22); this would result in 26 fewer sexual adverse events per 1000 participants (95% CI 43 fewer to 13 more). We rated the certainty of evidence as moderate for urological symptom score and low for the other outcomes.Naftopidil versus silodosinBased on five studies with 652 randomised participants, naftopidil may have resulted in little or no difference in the urological symptom scores (MD 1.04, 95% CI -0.78 to 2.85), QoL (MD 0.21, 95% CI -0.23 to 0.66), and treatment withdrawals for any reason (RR 0.80, 95% CI 0.52 to 1.23; corresponding to 26 fewer per 1000 participants, 95% CI 62 fewer to 32 more). We rated the certainty of evidence as low for all these outcomes. Naftopidil likely reduced sexual adverse events (RR 0.15, 95% CI 0.06 to 0.42; corresponding to 126 fewer sexual adverse events per 1000 participants, 95% CI 139 fewer to 86 fewer). We rated the certainty of evidence as moderate for sexual adverse events. AUTHORS' CONCLUSIONS: Naftopidil appears to have similar effects in the urological symptom scores and QoL compared to tamsulosin and silodosin. Naftopidil has similar sexual adverse events compared to tamsulosin but has fewer compared to silodosin.
Asunto(s)
Antagonistas Adrenérgicos alfa/uso terapéutico , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Naftalenos/uso terapéutico , Piperazinas/uso terapéutico , Hiperplasia Prostática/complicaciones , Prostatismo/tratamiento farmacológico , Agentes Urológicos/uso terapéutico , Antagonistas Adrenérgicos alfa/efectos adversos , Bencilatos/efectos adversos , Bencilatos/uso terapéutico , Combinación de Medicamentos , Etamsilato/efectos adversos , Etamsilato/uso terapéutico , Humanos , Indoles/efectos adversos , Indoles/uso terapéutico , Síntomas del Sistema Urinario Inferior/etiología , Masculino , Naftalenos/efectos adversos , Piperazinas/efectos adversos , Extractos Vegetales/efectos adversos , Extractos Vegetales/uso terapéutico , Prostatismo/etiología , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Tamsulosina/efectos adversos , Tamsulosina/uso terapéutico , Agentes Urológicos/efectos adversosRESUMEN
OBJECTIVES: To show the efficacy of propiverine hydrochloride in the management of symptoms of stress urinary incontinence in female patients with mixed-type urinary incontinence. METHODS: The study was carried out as a multicenter single-arm clinical trial at 64 institutions in Japan. The participants were female patients aged ≥20 years with mixed-type urinary incontinence. The frequency of stress urinary incontinence and urgency urinary incontinence was evaluated at baseline and 4, 8 and 12 weeks after treatment with propiverine hydrochloride. Subjective symptoms were evaluated using the Overactive Bladder Symptom Score and the International Consultation on Incontinence Questionnaire-Short Form. Functional urethral length and maximum urethral closing pressure were also measured at baseline and 12 weeks after treatment at the institutions where the urethral pressure profile was taken. RESULTS: In total, 49 mixed-type urinary incontinence patients were enrolled in the present study. The number of cases of urgency urinary incontinence was reduced time-dependently, which showed statistically significant differences between baseline and 4, 8 and 12 weeks after treatment. A similar statistically different reduction was also observed for stress urinary incontinence. The mean reduction rates of urgency urinary incontinence and stress urinary incontinence at 12 weeks after treatment were 63.9% and 44.3%, respectively. The total scores of International Consultation on Incontinence Questionnaire-Short Form and Overactive Bladder Symptom Score were gradually reduced, and the differences were statistically significant. Functional urethral length and maximum urethral closing pressure at 12 weeks after treatment did not show any statistical differences compared with those at baseline. CONCLUSIONS: Propiverine hydrochloride can be an effective therapeutic option for stress urinary incontinence in patients with mixed-type urinary incontinence.
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Bencilatos/uso terapéutico , Antagonistas Muscarínicos/uso terapéutico , Incontinencia Urinaria/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Bencilatos/efectos adversos , Femenino , Humanos , Japón , Persona de Mediana Edad , Antagonistas Muscarínicos/efectos adversos , Estudios Prospectivos , Calidad de Vida , Análisis de Regresión , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Resultado del Tratamiento , Incontinencia Urinaria/clasificaciónRESUMEN
OBJECTIVES: In recent years, some patients have been unresponsive to anticholinergics used in the treatment of pollakisuria/urinary incontinence. It has been suggested that propiverine hydrochloride, which has not only anticholinergic activity, but also calcium antagonistic activity, may be useful in poor responders to other anticholinergics. In this study, a specific drug use-results survey was conducted in poor responders to other anticholinergics to evaluate the usefulness of propiverine hydrochloride. METHODS: In this survey, propiverine hydrochloride was administered for 12 weeks to poor responders to previous anticholinergics, and its usefulness was evaluated by the overactive bladder symptom score (OABSS). RESULTS: A total of 3851 subjects at 680 institutions were enrolled in the survey. Of the 3624 subjects included in the safety evaluation (male 1899, female 1725, mean age 73.4 years), 2932 were included in the efficacy evaluation (male 1610, female 1322, mean age 73.8 years). Propiverine hydrochloride significantly improved the OABSS without any safety concerns in poor responders to previous anticholinergics (OABSS, 8.22 at baseline, 6.50 at Week 4, 5.87 at Week 8, and 5.57 at Week 12, P < 0.001). CONCLUSIONS: The present findings indicate that propiverine hydrochloride may be a useful therapeutic option for poor responders to previous anticholinergics.
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Bencilatos/administración & dosificación , Antagonistas Muscarínicos/administración & dosificación , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Agentes Urológicos/administración & dosificación , Anciano , Bencilatos/efectos adversos , Esquema de Medicación , Sustitución de Medicamentos , Femenino , Humanos , Masculino , Cumplimiento de la Medicación , Antagonistas Muscarínicos/efectos adversos , Resultado del Tratamiento , Vejiga Urinaria Neurogénica/tratamiento farmacológico , Incontinencia Urinaria/tratamiento farmacológico , Agentes Urológicos/efectos adversosRESUMEN
AIMS: To compare efficacy and tolerability of solifenacin 5 mg/day versus other oral antimuscarinic agents for the treatment of overactive bladder (OAB). METHODS: Literature searches of MEDLINE, Embase, and the Cochrane Library were undertaken to identify randomized controlled trials in OAB (2000-2015) for antimuscarinic agents. A network meta-analysis (NMA) was performed to estimate efficacy and tolerability outcomes for solifenacin 5 mg/day relative to other antimuscarinics. RESULTS: The NMA included 53 eligible trials (published, n = 48; unpublished on search date, n = 5). Solifenacin 5 mg/day was significantly more effective than tolterodine 4 mg/day for reducing incontinence and urgency urinary incontinence (UUI) episodes, but significantly less effective than solifenacin 10 mg/day for micturition; no other statistically significant differences were noted for efficacy. Solifenacin 5 mg/day had a statistically significant lower risk of dry mouth compared with darifenacin 15 mg/day, fesoterodine 8 mg/day, oxybutynin extended-release 10 mg/day, oxybutynin immediate-release (IR) 9-15 mg/day, tolterodine IR 4 mg/day, propiverine 20 mg/day, and solifenacin 10 mg/day. There were no significant differences between solifenacin 5 mg/day and other antimuscarinics for risk of blurred vision, or for 11 of 17 active comparators for risk of constipation. CONCLUSIONS: This NMA suggests that the efficacy of solifenacin 5 mg/day is at least similar to other common antimuscarinics across the spectrum of OAB symptoms analyzed, and is more effective than tolterodine 4 mg/day in reducing incontinence and UUI episodes. Solifenacin 5 mg/day has a lower risk of dry mouth compared with several agents.
Asunto(s)
Antagonistas Muscarínicos/uso terapéutico , Succinato de Solifenacina/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/uso terapéutico , Bencilatos/efectos adversos , Bencilatos/uso terapéutico , Humanos , Ácidos Mandélicos/efectos adversos , Ácidos Mandélicos/uso terapéutico , Antagonistas Muscarínicos/efectos adversos , Metaanálisis en Red , Succinato de Solifenacina/efectos adversos , Tartrato de Tolterodina/efectos adversos , Tartrato de Tolterodina/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: To investigate the effect of trospium chloride, which has an anticholinergic effect, used in overactive bladder (OAB) treatment on the intraocular pressure (IOP) and tear secretion after 12 weeks of treatment. MATERIALS AND METHODS: This prospective study was performed at a single center between October 2014 and January 2016. A detailed history was obtained from the female OAB patients at the eye outpatient department. After checking the exclusion criteria, oral trospium chloride 30 mg bd was started. The patients were followed-up in terms of drug effectiveness and ophthalmic and other side effects at the 4th and 12th weeks. All procedures were repeated at both of these time-points. RESULTS: The mean age of the patients was 48.98 ± 11.98 years (range 19-75). The data of 80 OAB patients were evaluated in the study. Trospium chloride did not cause any significant change in the OAB patients regarding their 4th week and 12th week IOP measurements (p = 0.251, p = 0.340, respectively). It was found to decrease tear secretion significantly at both time-points (p = 0.020, p = 0.001, respectively). Trospium chloride treatment of one patient (1.25%) was discontinued due to dry eye. CONCLUSIONS: Trospium chloride decreases the symptoms in female OAB patients. Trospium chloride can be safely used in female OAB patients with normal IOP and no comorbidity as regards IOP changes as it did not cause a significant change in IOP in these patients. Pre-treatment and post-treatment dry eye symptoms of OAB patients about to start using trospium chloride should be queried beforehand as it can cause a statistically significant decrease in tear secretion. We concluded that it would be appropriate to refer the patients to an ophthalmologist before starting the drug if relevant symptoms are present.
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Bencilatos/uso terapéutico , Nortropanos/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Agentes Urológicos/uso terapéutico , Adulto , Anciano , Bencilatos/efectos adversos , Femenino , Humanos , Presión Intraocular/efectos de los fármacos , Persona de Mediana Edad , Nortropanos/efectos adversos , Lágrimas/metabolismo , Vejiga Urinaria Hiperactiva/metabolismo , Agentes Urológicos/efectos adversos , Adulto JovenRESUMEN
Proper subcellular trafficking is essential to prevent protein mislocalization and aggregation. Transport of the peroxisomal enzyme D-amino acid oxidase (DAAO) appears dysregulated by specific pharmaceuticals, e.g., the anti-overactive bladder drug propiverine or a norepinephrine/serotonin reuptake inhibitor (NSRI), resulting in massive cytosolic and nuclear accumulations in rat kidney. To assess the underlying molecular mechanism of the latter, we aimed to characterize the nature of peroxisomal and cyto-nuclear shuttling of human and rat DAAO overexpressed in three cell lines using confocal microscopy. Indeed, interference with peroxisomal transport via deletion of the PTS1 signal or PEX5 knockdown resulted in induced nuclear DAAO localization. Having demonstrated the absence of active nuclear import and employing variably sized mCherry- and/or EYFP-fusion proteins of DAAO and catalase, we showed that peroxisomal proteins ≤134 kDa can passively diffuse into mammalian cell nuclei-thereby contradicting the often-cited 40 kDa diffusion limit. Moreover, their inherent nuclear presence and nuclear accumulation subsequent to proteasome inhibition or abrogated peroxisomal transport suggests that nuclear localization is a characteristic in the lifecycle of peroxisomal proteins. Based on this molecular trafficking analysis, we suggest that pharmaceuticals like propiverine or an NSRI may interfere with peroxisomal protein targeting and import, consequently resulting in massive nuclear protein accumulation in vivo.
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Bencilatos/efectos adversos , Núcleo Celular/metabolismo , D-Aminoácido Oxidasa/metabolismo , Transporte de Proteínas/efectos de los fármacos , Animales , Núcleo Celular/efectos de los fármacos , Dicroismo Circular , D-Aminoácido Oxidasa/genética , Células HEK293 , Humanos , Peso Molecular , Mutagénesis Sitio-Dirigida , Receptor de la Señal 1 de Direccionamiento al Peroxisoma/genética , Receptor de la Señal 1 de Direccionamiento al Peroxisoma/metabolismo , Peroxisomas/efectos de los fármacos , Peroxisomas/metabolismo , Ratas , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismoRESUMEN
Chronic exposure to propiverine, a frequently prescribed pharmaceutical for treatment of overactive bladder and incontinence, provokes massive protein accumulation in the cytosol and nucleus of renal proximal tubule epithelial cells in rats. Previously, the accumulating protein was identified as D-amino acid oxidase (DAAO), a peroxisomal flavoenzyme expressed in kidney, liver and brain. The cellular mechanism of propiverine-induced DAAO accumulation, however, remains unexplained and poorly characterized. Therefore, to further increase the understanding of DAAO accumulation in rat kidney, this study aimed to characterize DAAO accumulations using differential immunofluorescent staining of rat kidney sections as well as in vitro binding analyses and proteasomal activity studies. We demonstrated that propiverine is neither a ligand of DAAO nor an inhibitor of the proteasome in vitro. However, propiverine treatment resulted in a significant decrease of peroxisomal size in rat proximal tubule epithelial cells. Moreover, peroxisomal catalase also accumulated in the cytosol and nuclei of propiverine-treated rats concurrently with DAAO. Taken together, our study indicates that propiverine treatment affects the trafficking and/or degradation of peroxisomal proteins such as DAAO and catalase by a so far unique and unknown mechanism.
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Bencilatos/efectos adversos , Antagonistas Colinérgicos/efectos adversos , D-Aminoácido Oxidasa/metabolismo , Túbulos Renales Proximales/efectos de los fármacos , Peroxisomas/efectos de los fármacos , Agentes Urológicos/efectos adversos , Animales , Bencilatos/administración & dosificación , Catalasa/metabolismo , Núcleo Celular/efectos de los fármacos , Núcleo Celular/enzimología , Núcleo Celular/metabolismo , Antagonistas Colinérgicos/administración & dosificación , Citosol/efectos de los fármacos , Citosol/enzimología , Citosol/metabolismo , D-Aminoácido Oxidasa/química , D-Aminoácido Oxidasa/genética , Relación Dosis-Respuesta a Droga , Estabilidad de Enzimas/efectos de los fármacos , Femenino , Humanos , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/enzimología , Masculino , Ratones , Tamaño de los Orgánulos/efectos de los fármacos , Peroxisomas/metabolismo , Transporte de Proteínas/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Pruebas de Toxicidad Crónica , Agentes Urológicos/administración & dosificaciónRESUMEN
BACKGROUND: Propiverine hydrochloride (P4) is an antimuscarinic drug used in overactive bladder syndrome. METHODS: Two studies were performed: one in 24 patients with open-angle glaucoma (OAG) treated with topical ß-blockers, one in 24 patients with narrow-angle glaucoma (NAG) treated with pilocarpine ± topical ß-blockers. Patients were treated in randomized, placebo-controlled, double-blind parallel-group fashion (15 : 9 attribution to P4 vs. placebo (PL)). TREATMENTS: Single-blind PL dose in the morning of day 1 for baseline; double-blind 15 mg P4 or matched placebo t.i.d. from the afternoon of day 1 until the morning of day 7. RESULTS: In the morning of day 7, trough mean serum P4 concentrations were 169.4 ng/mL (CV (coefficient of variation): 0.55) and 140.7 ng/mL (CV: 0.56) in OAG and NAG; at 3:15 hours after dosing: 237.4 ng/mL (CV: 0.47) and 212.4 ng/mL P4 (CV: 0.38), respectively. P4-treatment led to a prompt (OAG) or more gradient (NAG) increase in pupil diameter (PUD), with a maximum difference from PL of 0.97 mm (95% confidence interval (CI): 0.67 - 1.27) and 0.87 mm (95% CI: 0.36 - 1.39) in OAG and NAG, respectively. However, there was no average increase in intraocular pressure (IOP) or increase in noteworthy safety-relevant individual IOP values (or changes thereof). There was no effect on visual acuity or accommodation. CONCLUSIONS: 1-week treatment with P4 appeared to be safe 1) in OAG patients treated with topical ß-blockers and 2) in NAG patients treated with topical pilocarpine ± ß-blockers, irrespective of whether the eyes had previously been treated with glaucoma surgery or laser therapy.â©.
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Bencilatos/efectos adversos , Glaucoma de Ángulo Cerrado/tratamiento farmacológico , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Antagonistas Muscarínicos/efectos adversos , Antagonistas Adrenérgicos beta/uso terapéutico , Anciano , Bencilatos/sangre , Método Doble Ciego , Femenino , Humanos , Presión Intraocular/efectos de los fármacos , Masculino , Persona de Mediana Edad , Método Simple CiegoRESUMEN
PURPOSE: Evaluation of the efficacy and safety of different doses of trospium chloride in patients with idiopathic overactive bladder. MATERIALS AND METHODS: Large-scale observational program "Resource" included 669 patients with idiopathic OAB - 359 women and 310 men. At the first visit, all patients were assigned to use of trospium chloride at a standard dose of 45 mg per day. The results of treatment were evaluated during follow-up visits at 3, 6, 9 and 12 weeks. Depending on the results of examination, the dose was reduced in the presence of adverse events and increased in case of insufficient treatment effects. RESULTS: After 12 weeks, 102 patients have been receiving the drug at a dose of 30 mg/day, 241 - at a dose of 45 mg/day, 257 - at a dose of 60 mg/day, and 22 - at a dose of 75 mg/day. CONCLUSIONS: Individual approach to the selection of doses of trospium chloride in patients with idiopathic OAB can be quite effective and safe measure to achieve optimal clinical outcome with a good safety profile.