Metabolomics approach: Interpretation of changes in rat plasma metabolites after solifenacin treatment

Abstract Changes in metabolite levels of patients using the long-term drug can be comprehensively demonstrated by pharmacometabolomic studies. In this study, biological alterations induced by the administration of solifenacin succinate were investigated with a pharmacometabolomics approach on rat metabolism. Plasma samples obtained from rats were analyzed by LC-Q- TOF/MS/MS. METLIN and HMDB databases were used to identify metabolites. Data were processed and classified with MATLAB 2017b. 53 m/z values were found to be significantly different between the drug and control groups (p ≤ 0.01 and fold analysis > 1.5) and identified by comparing METLIN and HMDB databases. According to multivariate data analysis, changes in arachidonic acid, thromboxane A2, palmitic acid, choline, calcitriol, histamine phosphate, retinyl ester, l-cysteine, l-leucine, beta-alanine, l-histidine levels were found to be statistically significant compare to the control group. Differences in the biosynthesis of phenylalanine, aminoacyl-tRNA, tyrosine, tryptophan, metabolism of glycerophospholipid, cysteine, methionine, histidine, arachidonic metabolism have been successfully demonstrated by the metabolomics approach. Our study provides important information to explain the efficacy and toxicity of chronic administration of solifenacin succinate

Costoefectividad del régimen combinado de mirabegron/solifenacina en el tratamiento del síndrome de vejiga hiperactiva en Colombia / Cost-effectiveness of the Combined Regimen of Mirabegron/Solifenacin in the Treatment of Overactive Bladder Syndrome in Colombia

Objetivo Evaluar la costoefectividad incremental del régimen combinado de mirabegron/solifenacina en comparación con el uso temprano de toxina botulínica, desde la perspectiva del sistema de salud colombiano, para el tratamiento de adultos con vejiga hiperactiva. Métodos Se empleó un modelo de Markov en que se comparan dos secuencias de tratamiento, una con y otra sin mirabegron/solifenacina, para evaluar la costoefectividad en un horizonte temporal de cinco años. Debido a la perspectiva de análisis, sólo se tuvieron en cuenta los costos médicos directos. La eficacia del tratamiento evaluado y su comparador fue medida en términos de la reducción de episodios diarios de incontinencia y de la frecuencia de micciones. Los costos fueron expresados en pesos colombianos de 2019, y se aplicó una tasa de descuento de 5% tanto para desenlaces como para costos. Resultados Para el caso base, el costo del tratamiento en la secuencia que incluye mirabegron/solifenacina fue mayor, pero generó un mayor número de años de vida ajustados por calidad, y así e obtuvo una razón de costoefectividad incremental de $13.637,184 si se considera el desenlace de reducción de episodios diarios de incontinencia de 50%, y de $29.313,848 si se considera el del 100%. Conclusiones De acuerdo con los resultados de esta evaluación, para un horizonte de análisis de cinco años, la secuencia de tratamiento con mirabegron/solifenacina es una alternativa costoefectiva, si se considera un umbral de disposición a pagar de tres veces el producto interno bruto (PIB) per cápita.

Aim To evaluate the incremental cost-effectiveness of the combined regimen of mirabegron/solifenacin compared with the early use of botulinum toxin, from the perspective of the Colombian health system, for the treatment of adults with overactive bladder. Methods A Markov model comparing two treatment sequences, one with and one without mirabegron/solifenacin, was used to assess cost-effectiveness over a five-year period. Due to the perspective of the analysis, only direct medical costs were considered. The efficacy of the evaluated treatment and its comparator was measured in terms of the reduction in the daily incontinence episodes and the frequency of micturition. The costs were expressed in Colombian pesos of 2019, and a discount rate of 5% was applied for both outcomes and costs. Results For the base case, the cost of the treatment in the sequence that includes mirabegron/solifenacin was higher, but it generated a greater number of quality-adjusted years of life, thus obtaining an incremental cost-effectiveness ratio of $13,637,184 when considering the outcome of 50% of reduction in the daily incontinence episodes, and $29,313,848 when considering 100%. Conclusions According to the results of the present assessment, for a five-year period of analysi, the mirabegron/solifenacin treatment sequence is a cost-effective alternative when considering a threshold of willingness to pay three times the per capita gross domestic product (GDP).

The effects of pregabalin, solifenacin and their combination therapy on ureteral double-J stent-related symptoms: A randomized controlled clinical trial

ABSTRACT Background: Many medical therapies have been tested to deal with urinary stent-related symptoms (USRS). Several preventive and pharmaceutical methods have been already used for better compatibility of stents. However, the existing evidence for pharmacological treatment is still controversial. This study aims to evaluate the effects of pregabalin, solifenacin, and combination therapy on ureteral double-J stent-related symptoms following ureteroscopy and transureteral lithotripsy (TUL). Materials and methods: In a randomized controlled clinical trial, from November 2017 to March 2019, 256 patients who underwent ureteroscopy were enrolled. Patients were randomly divided into four groups including: group A received pregabalin 75mg BID (twice daily), group B received solifenacin 5mg orally once daily, group C received combination of pregabalin and solifenacin and the group D (control) given no drugs. Results: One hundred and fifty-one (58.9%) males and 101 (41.1%) females were enrolled in this study with a mean age of 43.47±7 (p=0.32, p=0.67). USSQ domains score such as urinary symptoms, pain, general condition, work performance, sexual matters and additional problems were significantly differenced during second and fourth week of follow-up among study groups (p <0.0001). In Tukey's multiple comparison test, urinary symptoms (p=0.735), pain (p=0.954) and sexual matters (p=0.080) in second week and work performance in forth week in group B was not significantly better than group D. Only group C in all indexes of USSQ showed significantly beneficial effects over group D (p <0.0001). Conclusion: Combination therapy of pregabalin and solifenacin has a significant effect on stent-related symptoms and is preferred over monotherapy of the respected medications.

A comparison of the efficacy and tolerability of treating primary nocturnal enuresis with Solifenacin Plus Desmopressin, Tolterodine Plus Desmopressin, and Desmopressin alone: a randomized controlled clinical trial

ABSTRACT Introduction: Nocturnal enuresis (enuresis) is one of the most common developmental problems of childhood, which has often a familial basis, causes mental and psychological damage to the child and disrupts family solace. Objectives: In this study, we compared therapeutic efficacy and tolerability of treating primary nocturnal enuresis (PNE) with solifenacin plus desmopressin, tolterodine plus desmopressin, and desmopressin alone. Because we don't have enough information about this comparison especially about solifenacin plus desmopressin. Patients and Methods: This clinical trial study was performed on 62 patients with enuresis aged 5-15 years who referred to the urology clinic of Imam Khomeini Hospital in Ahwaz in 2017-2018. Patients were randomly assigned to one of the three different therapeutic protocols and any participants were given a specific code. After that, we compared the therapeutic response and the level of satisfaction of each therapeutic group in different months. Data were analyzed using SPSS 22 software and descriptive and analytical statistics. Results: The mean age of patients was 8.70±66 years. In the therapeutic group with desmopressin and solifenacin, 19 of 20 patients (95%) achieved complete remission (1) after a 3-month treatment in comparison with monotherapy group in which 14 of 22 patients (63.63%) achieved complete remission; and in the combination therapy group of desmopressin and tolterodine, in the study and the evaluation of the consequences of 3-month treatment of this group, it was found that 17 of 20 patients (85%) had complete remission. Overall, the therapeutic response in combination therapy groups of desmopressin plus anticholinergic was higher than the monotherapy group of desmopressin alone. Conclusion: Our results demonstrate that the combination of desmopressin and an anticholinergic agent is highly effective in treatment of children with PMNE. Although desmopressin has long been a first - line treatment for PMNE, desmopressin monotherapy often fails to achieve a successful response in patients with PMNE.

Comparision effects of solifenacin, darifenacin, propiverine on ocular parameters in eyes: A prospective study

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.

The relation between the storage symptoms before and after transurethral resection of the prostate, analysis of the risk factors and the prevention of the symptoms with solifenacin

ABSTRACT Objective and Hypothesis We aimed to investigate the reasons of storage symptoms ( SS) after transurethral resection of the prostate (TURP). The hypothesis was that a positive correlation would be identified between preoperative and postoperative SS in patients with undergoing TURP and starting early solifenacin treatment in patients with high preoperative SS would be reasonable. In addition, we aimed to analyze multiple other risk factors for post-TURP SS. Materials and Methods A total of 160 patients undergoing TURP were prospectively evaluated and divided into two groups according to their OABS. Those with a score of ≥10 points were Group 1 (G1), and those with <10 points Group 2 (G2). In addition, patients in each group were randomly further divided into two subgroups: those who were started on 5 mg solifenacin succinate in the early postoperative period (G1/G2 A) and those who were not (G1/G2 B). In additions to SS Preop, perop and at the 3rd-month of postoperatively 14 variable were evaluated. The effects of these factors, surgery and the efficacy of an early medical treatment on the postoperative SS were investigated. LUTS were assessed by International Prostate Symptom Score (IPSS) and SS were assessed by sum of IPSS 2, 4 and 7 questionnaires (Storage, S- IPSS). Results Preoperative IPSS and S-IPSS were significantly higher in G1 (p<0.001); there was a significant improvement at IPSS, S-IPSS, QoL score, Qmax, and PVR for all groups after surgery. Only preoperative S-IPSS was found to have significant effect on postoperative SS (p<0.001). There was a significant difference between G1A and G1B but no significant difference between G2A and G2B in terms of SS at postoperatively. In addition to this, prostatic volume was found smaller than non-symptomatic patients in de novo SS patients. Conclusion TURP provides significant improvement in both storage and voiding symptoms. The predictive value of the preoperative S-IPSS on postop SS is significant. These results suggest that 5 mg solifenacin succinate treatment in the early postoperative period may be beneficial for patients with high preoperative SS and may not be beneficial in others. Small prostatic volume may bode ill for postoperative SS in the patients with de novo SS.

Efficacy and tolerability of mirabegron in female patients with overactive bladder symptoms after surgical treatment for stress urinary incontinence

ABSTRACT Purpose To evaluate the efficacy and tolerability of mirabegron in females with overactive bladder (OAB) symptoms after surgical treatment for stress urinary incontinence (SUI). Materials and Methods The study was conducted with a prospective, randomized and double-blinded design. 62 patients over the age of 40 who met the inclusion-exclusion criterias of the study were enrolled and randomly divided into two groups as Group A (mirabegron 50mg) and B (solifenacin 5mg). Patients were compared based on efficacy of treatment [Patient Perception of Bladder Condition (PPBC) scale and micturition diaries], safety of treatment (heart rate, systolic and diastolic blood pressure, adverse events), number of micturitions per day, patient's satisfaction status after treatment [Visual Analog Scale(VAS)] and quality of life. Results The mean age of the population was 48.2±3.8 years and the duration of OAB symptoms was 5.9±2.9 months. Baseline values for the mean number of micturitions, volume voided in each micturition, nocturia episodes, urgency and urgency incontinence episodes were 15.3±0.34, 128±3.88mL, 3.96±1.67, 5.72±1.35 and 4.22±0.69, respectively. After treatment, values for these parameters were 11.7±0.29, 164.7±2.9mL, 2.25±0.6, 3.38±0.71, 2.31±0.49 respectively. Quality of life score, symptom bother score, VAS for treatment satisfaction score, PPBC score after treatment were 66.1±0.85, 43.7±0.77, 4.78±0.14, 4.78±0.14, respectively. There were no significant differences between two groups on any parameter. However, mirabegron showed better tolerability than solifenacin, particularly after 6 months. Conclusion Mirabegron is safe, effective and tolerable in the long-term treatment of females with OAB symptoms after surgery for stress urinary incontinence.

Overactive bladder - pharmacological treatment

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

Effectiveness and durability of solifenacin versus percutaneous tibial nerve stimulation versus their combination for the treatment of women with overactive bladder syndrome: a randomized controlled study with a follow-up of ten months

ABSTRACT Purpose To assess effectiveness and durability of Solifenacin (SS) versus tibial nerve stimulation (PTNS) versus combination therapy (PTNS + SS) in women with overactive bladder syndrome (OAB). Materials and Methods 105 women with OAB were divided randomly into three groups of 35 patients each. In group A women received SS, in group B women underwent PTNS, in group C women underwent combination of PTNS + SS. Improvements in OAB symptoms were assessed with OABSS questionnaire; patients' quality of life was assessed with OAB-q SF questionnaire. Evaluation of effectiveness of treatments was performed with PGI-I questionnaire. OABSS and PGI-I were also assessed monthly for ten months. Results All treatments were effective on symptoms. PTNS showed a greater effectiveness than SS, but PTNS + SS was more effective than SS and PTNS. Furthermore, PTNS + SS showed a greater duration of effectiveness than PTNS and SS. Conclusions Combination of PTNS with SS showed more effectiveness and more durability than PTNS and SS alone.

Eficacia y seguridad del uso de solifenacina en pacientes con hiperactividad vesical refractarios a oxibutinina / Efficacy and safety of the use of solifenacin in patients with bladder hyperactivity refractory to oxybutynin

INTRODUCCIÓN: Antecedentes: El presente dictamen presenta la evaluación de la eficacia y seguridad del uso de solifenacina para el tratamiento de hiperactividad vesical. Aspectos Generales: La hiperactividad vesical es un síndrome definido por la presencia de urgencia urinaria, usualmente acompañada de alta frecuencia urinaria durante el día y/o la noche, y/o incontinencia urinaria de urgencia. Una alta frecuencia urinaria se refiere a frecuencia miccional de ocho o más veces durante el día, o 2 o más veces durante la noche. La incontinencia urinaria, como signo, es la fuga involuntaria de orina. La urgencia urinaria es la sensación aguda y repentina de necesidad de miccionar inmediatamente, la cual se da por la contracción del músculo detrusor en la vejiga.Tecnología Sanitaria de Interés: El succinato de solifenacina es un antagonista competitivo de los receptores muscarínicos. Su naturaleza es química, siendo un ácido butanodioico, con fórmula empírica C23H26N202 • C4H604 y peso molecular de 480.55. La solifenacina ejerce su acción bloqueando los receptores muscarínicos en el músculo vesical (músculo detrusor), los cuales son mediadores de las funciones colinérgicas como la contracción de dichos músculos. Al unirse a los receptores muscarínicos en el tejido muscular de la vejiga, la solifenacina impide la unión de la acetilcolina (neurotransmisor colinérgico) e interrumpe la señal que estimula la contracción. De esta manera, la solifenacina evita las contracciones repentinas que originan la urgencia urinaria en el síndrome de hiperactividad vesical. MÉTODOLOGÍA: Estrategia de Búsqueda: Se llevó a cabo una búsqueda de la literatura con respecto a la eficacia y seguridad de solifenacina en el tratamiento de hiperactividad vesical en las bases de datos de PubMed, TRIPDATABASE y www.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como The National Institute for Health and Care Excellence (NICE), the American Urological Association (AUA), the International Continence Society (ICS), the International Consultation on Incontinence (ICI), the International Urogynecological Association (IUGA), the European Association of Urology (EAU), the Urinary Incontinence Treatment Network (UITN), the Society of Obstetricians and Gynecologists of Canada (SOGC), y the American Congress of Obstetricians and Gynecologists (ACOG). RESULTADOS: Sinopsis de la Evidencia: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de solifenacina en el tratamiento de pacientes con hiperactividad vesical. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: Las GPC encontradas no emiten recomendaciones acerca del uso de solifenacina en pacientes refractarios al tratamiento con oxibutinina. Sin embargo, la GPC de AUA menciona que en los casos de refractariedad al tratamiento con algún agente farmacológico (anti-muscarínicos), por principio clínico, es posible cambiar la dosis o el agente. Aunque esta afirmación se basa en opinión de expertos y estudios observacionales. No se ha encontrado un ECA que evalúe la eficacia del uso de solifenacina en pacientes refractarios a oxibutinina. Se identificó únicamente un estudio observacional que sugiere un efecto positivo del uso de solifenacina en pacientes refractarios o intolerantes a oxibutinina. A pesar de que dicho estudio presenta una serie de limitaciones serias, se rescata la fuerza de las asociaciones encontradas. Adicionalmente, estudios sobre eventos adversos relacionados al uso de solifenacina reportan que este fármaco es seguro en el tratamiento de hiperactividad vesical. El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) aprueba el uso de solifenacina como alternativa de tratamiento en pacientes con hiperactividad vesical refractaria a oxibutinina. El periodo de vigencia de este dictamen es de un año y la continuación de dicha aprobación estará sujeta a los resultados obtenidos de los pacientes que se beneficien con dicho tratamiento y a nueva evidencia que pueda surgir en el tiempo.

Efectividad y seguridad de la oxibutinina o tolterodina comparado con darifenacina, solifenacina, fesoterodina y placebo para el tratamiento de la incontinencia / Effectiveness and safety of oxybutynin or tolterodine compared to darifenacin, solifenacin, fesoterodine and placebo for the treatment of incontinence

Introducción: Alrededor del 16% al 45% de los adultos tiene síntomas de vejiga hiperactiva, que se manifiestan con urgencia para orinar, aumento en la frecuencia de micciones o incontinencia urinaria de urgencia, o ambos, denominado síndrome de vejiga hiperactiva. Los fármacos anticolinérgicos son los tratamientos más comunes para el tratamiento farmacológico y entre ellos la oxibutinina y la tolterodina. Esta evaluación tecnológica se desarrolló en el marco de la actualización integral del Plan Obligatorio de Salud para el año 2015. Objetivo: evaluar la efectividad y seguridad de la oxibutinina o la tolterodina para la incontinencia urinaria, comparadas con otros medicamentos antimuscarínicos como: solifenacina, darifenacina, fesoterodina para informar la toma de decisiones. Metodología: la evaluación fue realizada de acuerdo al protocolo definido previamente por el grupo desarrollador. Se realizó una búsqueda sistemática en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects y LILACS, sin restricciones de idioma y limitada a revisiones sistemáticas publicadas en los últimos cinco años. Las búsquedas electrónicas fueron hechas entre octubre y noviembre de 2014 y se complementaron mediante búsqueda manual en bola de nieve y una consulta con expertos temáticos. La tamización de referencias se realizó por dos revisores de forma independiente y los desacuerdos fueron resueltos por consenso. La selección de estudios fue realizada mediante la revisión en texto completo de las referencias preseleccionadas, verificando los criterios de elegibilidad. La calidad de los estudios fue valorada con la herramienta AMSTAR. Las características de los estudios fueron extraídas a partir de las publicaciones originales. Se realizó una síntesis narrativa de las estimaciones del efecto para las comparaciones y desenlaces de interés a partir de los estudios de mejor calidad con AMSTAR. Resultados: se seleccionó una revisión sistemática que incluyó un total de 86 ensayos clínicos (31,249 pacientes) con medicamentos muscarínicos incluyendo a la Oxibutinina y la Tolterodina. Se realizaron comparaciones directas entre medicamentos y comparaciones intratecnología (dosis y presentaciones). Cuando se comparó la Tolterodina versus la Oxibutinina, no se encontró diferencia estadisticamente significativa en los desenlaces de calidad de vida, la percepción de cura o mejora y cuantificación de los síntomas. Cuando se comparó solifenacina versus tolterodina, se encontró diferencia estadisticamente significativa en los mismos desenlaces a favor de la solifenacina, e igual se reportó en la comparación fesoterodina versus tolterodina, a favor de la fesoterodina. Respecto a seguridad se comparó tolterodina versus oxibutinina y el retiro por eventos adversos fue más frecuente en el grupo de la oxibutinina RR 0.52 IC95% 0.40 a 0.66. En la comparación de soliferacina versus oxibutinina el retiro por eventos adversos fue más frecuente en el grupo de oxibutinina RR 0.45 IC95% 0.22 a 0.91 y al comparar la fesoterodina versus la tolterodina el retiro por eventos adversos fue más frecuente en el grupo de la fesoterodina RR 1.45 IC95% 1.07 a 1.98. Conclusiones: Efectividad: No se evidenció diferencia en efectividad entre la Oxibutinina y Tolterodina en los desenlaces de calidad de vida y la percepción de cura o mejora. Para la comparación de efectividad entre Oxibutinina versus Darifenacina y Solifenacina, no se reportaron resultados. La Solfenacina y Fesoterodina son más efectivas que la Tolterodina, en los desenlaces de calidad de vida y la percepción de cura o mejora. Seguridad: Tolterodina fue más seguro que la Oxibutinina, respecto al abandono por eventos adversos. La comparación entre Darifenacina versus oxibutinina no reportó resultados. Solifenacina fue más seguro que la oxibutinina, respecto al abandono por eventos adversos. Tolterodina fue más seguro que Fesoterodina, respecto al abandono por eventos adversos y boca seca.(AU)