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1.
Cell Prolif ; 52(6): e12675, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31553127

RESUMO

OBJECTIVES: To evaluate the regenerative potential of human dental pulp stem cells (hDPSCs) in an animal model of stress urinary incontinence (SUI). SUI, an involuntary leakage of urine, is due to physical stress involving an increase in bladder pressure and a damage of external urethral sphincter affecting muscles and nerves. Conventional therapies can only relieve the symptoms. Human DPSCs are characterized by peculiar stemness and immunomodulatory properties and might provide an alternative tool for SUI therapy. MATERIALS AND METHODS: In vitro phase: hDPSCs were induced towards the myogenic commitment following a 24 hours pre-conditioning with 5-aza-2'-deoxycytidine (5-Aza), then differentiation was evaluated. In vivo phase: pudendal nerve was transected in female rats to induce stress urinary incontinence; then, pre-differentiated hDPSCs were injected in the striated urethral sphincter. Four weeks later, urethral sphincter regeneration was assayed through histological, functional and immunohistochemical analyses. RESULTS: Human DPSCs were able to commit towards myogenic lineage in vitro and, four weeks after cell injection, hDPSCs engrafted in the external urethral sphincter whose thickness was almost recovered, committed towards myogenic lineage in vivo, promoted vascularization and an appreciable recovery of the continence. Moreover, hDPSCs were detected within the nerve, suggesting their participation in repair of transected nerve. CONCLUSIONS: These promising data and further investigations on immunomodulatory abilities of hDPSCs would allow to make them a potential tool for alternative therapies of SUI.


Assuntos
Polpa Dentária/efeitos dos fármacos , Células-Tronco/citologia , Uretra/efeitos dos fármacos , Incontinência Urinária por Estresse/tratamento farmacológico , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Polpa Dentária/citologia , Modelos Animais de Doenças , Feminino , Humanos , Ratos , Uretra/citologia
2.
Mol Med Rep ; 19(6): 4727-4734, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059065

RESUMO

The aim of the present study was to investigate the protective effect of integrin ß1 in the treatment of stress urinary incontinence (SUI) by electrical stimulation, and the underlying mechanisms by which electrical stimulation regulates the collagen metabolism of female vaginal wall fibroblasts (FVWFs). FVWFs obtained from the vaginal wall tissue of patients with (Ingelman­Sundberg scale; grade II, n=8; grade III, n=10) or without (n=8) SUI during gynecological operations were isolated by enzymatic digestion and subsequently identified by immunocytochemistry. Following this, cultured FVWFs were treated with an inhibitor of integrin ß1, recombinant human integrin ß1 and electrical stimulation (100 mv/mm, 2 h, 20 Hz), followed by total mRNA and protein extraction. mRNA and protein expression levels of integrin ß1, transforming growth factor (TGF)­ß1 and collagen (COL) I and III in FVWFs were quantified by reverse transcription­quantitative PCR (RT­qPCR) and western blot analysis respectively. Integrin ß1, TGF­ß1 and COL I and III expression levels were decreased in patients with SUI compared with healthy controls, and the grade III group had lower levels than the grade II group. Following electrical stimulation treatment, the expression levels of TGF­ß1, COL I and III were enhanced in the grade II group, but not in the grade III group. Nevertheless, the inhibitor of integrin ß1 reduced the protective effect of electrical stimulation in the grade II group. In addition, electrical stimulation combined with recombinant human integrin ß1 could also protect cells from SUI in the grade III group. The present study provides evidence for the increased degradation of the extracellular matrix and integrin ß1 in the vaginal wall tissues of patients with SUI, and the protective effect of electrical stimulation against SUI via integrin ß1. These results provide a novel mechanism for the treatment of SUI using electrical stimulation.


Assuntos
Estimulação Elétrica/métodos , Integrina beta1/farmacologia , Integrina beta1/uso terapêutico , Incontinência Urinária por Estresse/tratamento farmacológico , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Matriz Extracelular/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Fator de Crescimento Transformador beta1 , Incontinência Urinária , Vagina/metabolismo , Vagina/patologia
3.
Oxid Med Cell Longev ; 2019: 2039856, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30962861

RESUMO

Apoptosis and oxidative damage are involved in the pathogenesis and progression of stress urinary incontinence (SUI). Our previous results indicate that cell apoptosis and oxidative damage increase in a mouse model of mechanical injury-induced SUI and in fibroblasts treated with excessive mechanical strain. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a well-characterized global antioxidant gene inducer that can reduce oxidative damage and apoptosis. Therefore, we predicted that Nrf2 may have a protective role in mechanical trauma-induced SUI. To test this hypothesis, a mouse model of vaginal distension- (VD-) induced SUI was established. Leak point pressure (LPP); levels of apoptosis, apoptosis-related proteins, and peroxidation products; and the activities of antioxidative proteins in the anterior vaginal wall were measured in wild-type (Nfe2l2+/+) C57BL/6 mice and Nrf2-knockout mice (Nfe2l2-/-). The results showed that Nrf2 knockout aggravated VD-induced reduction in LPP, increase in cell apoptosis and peroxidation product levels, decrease in antioxidative protein activities, and alterations in apoptosis-related protein levels in the vaginal walls of mice. To further confirm the role of Nrf2 in mechanical trauma-induced apoptosis and SUI, VD was performed on mice overexpressing Nrf2 via in vivo transfection of LV-Nfe2l2. The results showed that Nrf2 overexpression significantly alleviated VD-induced abnormalities in the anterior vaginal wall. Taken together, our data suggested that Nrf2 is a potential protective factor in mechanical trauma-induced apoptosis in a mouse model of SUI. Antioxidative therapy may be a promising treatment for mechanical trauma-related SUI.


Assuntos
Fator 2 Relacionado a NF-E2/uso terapêutico , Incontinência Urinária por Estresse/tratamento farmacológico , Incontinência Urinária por Estresse/etiologia , Vagina/lesões , Animais , Apoptose , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/farmacologia , Estresse Oxidativo , Transfecção , Incontinência Urinária por Estresse/patologia
4.
Neurourol Urodyn ; 38(4): 1076-1080, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30843263

RESUMO

AIMS: In two open-label trials, imipramine alleviated symptoms in patients with stress urinary incontinence and is therefore used off-label for this indication. However, it has never been confirmed that imipramine increases urethral pressure in a placebo-controlled setting. The purpose of this study was to investigate whether imipramine increases the opening urethral pressure compared to placebo in healthy women using urethral pressure reflectometry. METHODS: A randomized, double-blind, placebo-controlled, crossover study in 16 healthy women. Opening urethral pressure was measured predose and 1 hour after a single dose of 50 mg imipramine or placebo. The washout period was minimum of 1 week. The study was approved by the local ethics committee, conducted according to the Good Clinical Practice guidelines, and registered on ClinicalTrials.gov and EudraCT before recruitment of subjects. Funding was provided by the clinical department. RESULTS: There were no dropouts and no serious adverse events. There were 13 adverse drug reactions related to imipramine in seven subjects, one adverse event related to placebo, and two adverse events related to the measurements with urethral pressure reflectometry. Imipramine compared to placebo increased opening urethral pressure in the resting condition with 6.5 cmH2 O (95% confidence interval [CI]: -0.5, 13.5), P = 0.07, and in the squeeze condition with 7.9 cmH 2 O (95% CI: -0.3, 16.1), P = 0.06. CONCLUSIONS: In conclusion, the increase in opening urethral pressure after imipramine treatment compared to placebo was neither statistically significant nor clinically relevant, and we do therefore not recommend the off-label use of imipramine for the treatment of stress urinary incontinence.


Assuntos
Imipramina/farmacologia , Uretra/efeitos dos fármacos , Agentes Urológicos/farmacologia , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Imipramina/uso terapêutico , Pessoa de Meia-Idade , Uso Off-Label , Pressão , Resultado do Tratamento , Incontinência Urinária por Estresse/tratamento farmacológico , Agentes Urológicos/uso terapêutico , Saúde da Mulher , Adulto Jovem
5.
Urol Clin North Am ; 46(1): 1-15, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30466694

RESUMO

Urethral injection is a safe and minimally invasive method of treating female stress urinary incontinence with multiple bulking agents currently commercially available. Although there are numerous studies that demonstrate efficacy, long-term success is not yet proven. This article aims to describe the mechanism of action and properties of various agents, patient selection factors, available techniques for injection, outcomes of urethral injections, and complications associated with the procedure.


Assuntos
Materiais Biocompatíveis/administração & dosagem , Incontinência Urinária por Estresse/tratamento farmacológico , Resinas Acrílicas , Animais , Colágeno , Dimetil Sulfóxido , Dimetilpolisiloxanos , Durapatita , Feminino , Géis , Glucanos , Glutaral , Humanos , Ácido Hialurônico , Injeções , Polivinil , Povidona , Zircônio
6.
Neurourol Urodyn ; 37(S4): S69-S74, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-30133793

RESUMO

AIMS: The management of recurrent stress urinary incontinence following failed previous continence surgery remains challenging. Whilst the role of urodynamic investigations has been questioned in the management of primary stress incontinence there is a widely held view that women with recurrent symptoms require further investigation although there is no agreement regarding which tests are required. We sought to understand what testing is recommended prior to managing this difficult cohort of patients. METHOD: This research proposal was presented at the International Consultation on Incontinence Research Society (ICI-RS) in order to clarify our current knowledge regarding the assessment of urethral function and to set research priorities for the future. RESULTS: Whilst the majority of clinicians would advocate urodynamic evaluation of women with recurrent stress incontinence following previous surgery there is no consensus of opinion as to which tests should be performed, on whom or where. The available evidence to date suggests that urethral function tests do have a role with regard to prognosis following surgery and also in planning the most appropriate surgical intervention. CONCLUSION: The ICI-RS developed a list of research questions which may be able to assist in improving the investigation and management of women with recurrent SUI. Questions included whether patients felt the information gained via urethral function tests had an important role in their counseling regarding outcome of repeat SUI surgery.


Assuntos
Incontinência Urinária por Estresse/diagnóstico , Urodinâmica/fisiologia , Técnicas de Diagnóstico Urológico , Humanos , Recidiva , Incontinência Urinária por Estresse/tratamento farmacológico , Incontinência Urinária por Estresse/fisiopatologia , Procedimentos Cirúrgicos Urológicos
7.
Georgian Med News ; (279): 143-150, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30035737

RESUMO

The objective of the study was immunohistochemical evaluation of distribution of various NO synthase fractions in the structural elements of the bladder wall under stress urinary incontinence and its overactivity prior and post Mirabegron, Spasmex, Quercetin therapies and their combinations with Testosterone and Estradiol. Using the immunohistochemical method, we studied the expression of the main fractions of NO synthase in experimental models of hyperactive bladder (OAB) and stress urinary incontinence (SUI). We found that OAB and SUI were characterized by emergence of expression of the inducible fraction (iNOS) predominantly in the interstitial cells of the muscular layer of the bladder and reduced expression of endothelial (eNOS) and neuronal (nNOs) NO synthase fractions. In contrast to Spasmex, Mirabegron and Quercetin in combination with Testosterone and Estradiol contributed to stabilization of eNOS and nNOs expression already at early observation phases, and reduced the level of iNOS expression with its further disappearance in the later observation period.


Assuntos
Óxido Nítrico Sintase/metabolismo , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/enzimologia , Incontinência Urinária por Estresse/tratamento farmacológico , Incontinência Urinária por Estresse/enzimologia , Acetanilidas/uso terapêutico , Animais , Benzilatos/uso terapêutico , Quimioterapia Combinada , Estradiol/uso terapêutico , Feminino , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Nortropanos/uso terapêutico , Quercetina/uso terapêutico , Ratos , Testosterona/uso terapêutico , Tiazóis/uso terapêutico , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo
8.
J Pharmacol Exp Ther ; 366(2): 322-331, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29875227

RESUMO

Stress urinary incontinence (SUI) is characterized by involuntary leakage associated with exertion, effort, sneezing, coughing, or lifting. Duloxetine, a serotonin norepinephrine reuptake inhibitor, is approved for the treatment of patients with SUI in some European countries, but not in the United States. There is currently no globally approved pharmacological drug for the treatment of patients with SUI. Therefore, a new pharmacological treatment option is required. TAS-303 [4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-day7 )acetate hydrochloride] is a novel small-molecule selective norepinephrine reuptake inhibitor that displays significant norepinephrine transporter (NET) inhibitory activity toward the serotonin or dopamine transporters. In this report, we describe the pharmacological properties of TAS-303 and its effects on urethral function, using preclinical in vitro and in vivo studies. Radioligand-binding studies showed that TAS-303 selectively and potently inhibited [3H]norepinephrine binding to the human NET. Oral administration of TAS-303 (3 mg/kg) significantly increased norepinephrine levels in the plasma, whereas it did not significantly affect epinephrine, dopamine, and serotonin levels. TAS-303 (0.3, 1, and 3 mg/kg) dose-dependently increased basal urethral pressure in normal rats and leak point pressure in vaginal distention rats, exhibiting a maximal effect comparable to duloxetine. In the forced swimming test, TAS-303 (100 mg/kg) showed no significant effects on immobility time in rats, raising the possibility that this agent would have minimal central nervous system side effects at an effective dose for urethral function. These results demonstrate that TAS-303 has therapeutic potential for the treatment of patients with SUI.


Assuntos
Norepinefrina/metabolismo , Piperidinas/farmacologia , Pressão , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Uretra/efeitos dos fármacos , Uretra/fisiologia , Incontinência Urinária por Estresse/tratamento farmacológico , Animais , Monoaminas Biogênicas/sangue , Transporte Biológico/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacocinética , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Distribuição Tecidual , Uretra/fisiopatologia , Incontinência Urinária por Estresse/fisiopatologia
9.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 43(3): 260-267, 2018 Mar 28.
Artigo em Chinês | MEDLINE | ID: mdl-29701187

RESUMO

OBJECTIVE: To investigate the effects of 7-difluoromethy-5, 4'-dimethoxygenistein (DFMG) on stress urinary incontinence (SUI) model in Sprague Dawley (SD) rats and its possible mechanisms.
 Methods: SD rat model of SUI was established through simulating pregnancy, birth trauma and ovarian castration. The rats were divided into a normal control group, a SUI group, and a DFMG group at 10 or 20 mg/kg. They were treated with 10 mg/kg normal saline (NS), 10 mg/kg NS, 10 mg/kg DFMG and 20 mg/kg DFMG, respectively, via gastric gavage every other day. Maximal bladder capacity (MBC), leak point pressure (LPP), abdominal leak point pressure (ALPP), hematoxylin-eosin (HE) staining, and Masson staining were performed to detect the index for the model. MiR-26b and its down-stream gene phosphatase and tensin homolog deleted on chromosome 10 (PENT) mRNA in urethral sphincter muscles cells (USMCs) were analyzed by RT-PCR. The protein levels of PENT, phosphatidylinositol 3-kinase (PI3K), protein kinaseB (AKT), B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), cytochrome C(Cyt-c) and caspase-3 were examined by Western blot. The apoptotic rate of USMCs was determined by flow cytometry (FCM), and the proliferative rate of USMCs was examined by MTT assay.
 Results: The SD rat model of SUI was successfully established. HE staining and Masson staining showed that the pathological features of urethral sphincter were improved in the DFMG-treated groups compared with the SUI group. The urine dynamics indexes of model rats, such as MBC, LPP and ALPP, were improved (all P﹤0.05). The results of RT-PCR showed that the miR-26b mRNA was up-regulated (P﹤0.05) and PENT mRNA was down-regulated (P﹤0.05) in the DFMG-treated groups compared with the SUI group. Simultaneously, compared with the SUI group, the protein levels of PENT, Bax, Cyt-c and caspase-3 were down-regulated (all P﹤0.05) and the protein levels of PI3K, AKT and Bcl-2 protein were up-regulated (all P﹤0.05), accompanied by the decreased apoptotic rate of USMCs (P﹤0.05) and the increased proliferative rate of USMCs (P﹤0.05) in the DFMG-treated groups.
 Conclusion: The DFMG can significantly improve the symptoms of urinary dynamics, which might be related to the up-regulation of miR-26b expression and the regulation of PI3/AKT-Bcl-2/ Bax signaling pathways.


Assuntos
Genisteína/análogos & derivados , MicroRNAs/metabolismo , Uretra/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Incontinência Urinária por Estresse/tratamento farmacológico , Animais , Apoptose , Caspase 3/metabolismo , Proliferação de Células , Citocromos c/metabolismo , Modelos Animais de Doenças , Genisteína/farmacologia , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para Cima , Uretra/metabolismo , Incontinência Urinária por Estresse/metabolismo , Incontinência Urinária por Estresse/fisiopatologia , Proteína X Associada a bcl-2/metabolismo
10.
Neurourol Urodyn ; 37(8): 2382-2388, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29624732

RESUMO

AIMS: The serotonin (5-HT2c) receptor is known to be involved in the mechanism of urethral closure in a model of stress incontinence. Lorcaserin (Belviq®) has received Food and Drug Administration approval for the treatment of obesity. However, it is unclear whether this selective 5-HT2c receptor agonist enhances urethral closure in stress urinary incontinence (SUI) models. Therefore, we investigated whether lorcaserin could enhance urethral closure in female rats with vaginal distention (VD). METHODS: Normal female rats and rats with stress incontinence induced by VD were tested. We evaluated the effect of a single dose of lorcaserin (0.03, 0.3, or 0.9 mg/kg with cumulative administration) on the urethral pressure amplitude during electrical stimulation (A-URE) and on the urethral baseline pressure (UBP). The manual compression-induced leak point pressure (LPP) was also measured. RESULTS: In VD rats, a single intravenous injection of lorcaserin (0.3 and 0.9 mg/kg) significantly increased both A-URE and LPP compared to saline (P < 0.05). In normal rats, intravenous lorcaserin (0.3 and 0.9 mg/kg) also significantly increased A-URE and LPP compared to saline (P < 0.05). The changes of A-URE and LPP, which are parameters of active urethral closure, were significantly larger in normal rats than in VD rats. CONCLUSIONS: We showed that lorcaserin can activate the external urethral sphincter and pelvic floor muscles, suggesting an influence on active closure mechanisms. 5-HT2c receptors agonists may have dual effects in patients with SUI, not only by reducing obesity but also by enhancing active urethral closure.


Assuntos
Benzazepinas/administração & dosagem , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Uretra/efeitos dos fármacos , Incontinência Urinária por Estresse/tratamento farmacológico , Animais , Dilatação , Modelos Animais de Doenças , Estimulação Elétrica , Feminino , Injeções Intravenosas , Diafragma da Pelve/fisiologia , Diafragma da Pelve/fisiopatologia , Pressão , Ratos , Ratos Sprague-Dawley , Uretra/fisiologia , Uretra/fisiopatologia , Incontinência Urinária por Estresse/etiologia , Vagina/patologia , Vagina/fisiopatologia
11.
Neurourol Urodyn ; 37(1): 339-345, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28452427

RESUMO

AIMS: To assess the efficacy and safety of peri-urethral bulking injections (PBI) with an innovative bulking material (PDMS-U) in women with stress-urinary incontinence (SUI) who are not optimal candidates for mid-urethral sling surgery. METHODS: A prospective study was performed in women with SUI who, for several reasons, have a relative contraindication for a mid-urethral sling procedure. These reasons include: (i) recurrent SUI after a prior SUI surgical procedure; (ii) a history of oncologic gynaecological surgery; (iii) a history of neurologic disease resulting in voiding problems; (iv) a maximal flow rate of less than 15 mL per second or; (v) women with a contraindication for surgery with general or regional anaesthesia. All women were treated with PBI consisting of PDMS-U, a bulking agent that polymerizes in situ. The primary outcome was subjective improvement, defined as "a little better" to "very much better" on the PGI-I. Secondary outcomes included objective cure, disease specific quality of life and adverse events. RESULTS: Subjective improvement was reported by 18 (90%) of the 20 included patients. The subjective cure rate was 56% and the objective cure rate was 65%. There was a statistically significant improvement of all domain scores of the UDI-6, IIQ-7, and PISQ-12 at 6 months follow up. Abnormal post voiding residual volume (>150 mL) was the most common adverse event (40%), but persisted in only one patient, based on the patient's preference for a catheter. CONCLUSIONS: PBI with PDMS-U is a viable treatment option in women with a relative contra-indication for mid-urethral sling surgery.


Assuntos
Dimetilpolisiloxanos/uso terapêutico , Polivinil/uso terapêutico , Incontinência Urinária por Estresse/tratamento farmacológico , Idoso , Feminino , Humanos , Injeções , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Resultado do Tratamento
12.
BJU Int ; 121(2): 301-312, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28805303

RESUMO

OBJECTIVES: To determine the effects of controlled release of insulin-like growth factor 1 (IGF-1) from alginate-poly-L-ornithine-gelatine (A-PLO-G) microbeads on external urethral sphincter (EUS) tissue regeneration in a rat model of stress urinary incontinence (SUI), as SUI diminishes the quality of life of millions, particularly women who have delivered vaginally, which can injure the urethral sphincter. Despite several well-established treatments for SUI, growth factor therapy might provide an alternative to promote urethral sphincter repair. MATERIALS AND METHODS: In all, 44 female Sprague-Dawley rats were randomised into four groups: vaginal distension (VD) followed by periurethral injection of IGF-1-A-PLO-G microbeads (VD + IGF-1 microbeads; 1 × 104 microbeads/1 mL normal saline); VD + empty microbeads; VD + saline; or sham-VD + saline (sham). RESULTS: Urethral function (leak-point pressure, LPP) was significantly lesser 1 week after VD + saline [mean (sem) 23.9 (1.3) cmH2 O] or VD + empty microbeads [mean (sem) 21.7 (0.8) cmH2 O) compared to the sham group [mean (sem) 44.4 (3.4) cmH2 O; P < 0.05), indicating that the microbeads themselves do not create a bulking or obstructive effect in the urethra. The LPP was significantly higher 1 week after VD + IGF-1 microbeads [mean (sem) 28.4 (1.2) cmH2 O] compared to VD + empty microbeads (P < 0.05), and was not significantly different from the LPP in sham rats, demonstrating an initiation of a reparative effect even at 1 week after VD. Histological analysis showed well-organised skeletal muscle fibres and vascular development in the EUS at 1 week after VD + IGF-1 microbeads, compared to substantial muscle fibre attenuation and disorganisation, and less vascular formation at 1 week after VD + saline or VD + empty microbeads. CONCLUSION: Periurethral administration of IGF-1-A-PLO-G microbeads facilitates recovery from SUI by promoting skeletal myogenesis and revascularisation. This therapy is promising, but detailed and longer term studies in animal models and humans are needed.


Assuntos
Fator de Crescimento Insulin-Like I/farmacologia , Desenvolvimento Muscular/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Uretra/efeitos dos fármacos , Incontinência Urinária por Estresse/fisiopatologia , Animais , Preparações de Ação Retardada/farmacologia , Modelos Animais de Doenças , Feminino , Músculo Esquelético/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Uretra/patologia , Uretra/fisiopatologia , Incontinência Urinária por Estresse/tratamento farmacológico , Incontinência Urinária por Estresse/patologia
13.
Biomed Res Int ; 2018: 2796967, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30627546

RESUMO

Objectives: To evaluate the safety and effectiveness of the injectable bulking agent Opsys® (Promedon, Cordoba, Argentina) for treating minimal postprostatectomy stress urinary incontinence (SUI). Patients and Methods: Single-centre, pilot study on ten male patients with SUI, < 30 g urine loss/ 24 h, more than 1 year after radical prostatectomy. Patients were treated by endoscopic transurethral injections of bulking agent in the presphincteric zone of the urethral submucosa. The results were evaluated using a pad weight test to quantify the differences in urine loss at 1, 3, and 6 months after intervention. Subsequently, the results of treatment were also evaluated by International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF), Incontinence Impact Questionnaire (IIQ-7), Urogenital Distress Inventory Short Form (UDI-6-SF), and the Patient Global Impression of Improvement (PGI-I) at 1, 3, and 6 months after intervention. Results: The primary outcome was the absolute result of the 24-hour pad weight test after treatment. Treatment success was defined as <3 g urine loss/24 h, improvement as ≥50% decrease in urine loss/ 24h, failure as <50% decrease in urine loss/24 h, or worsening of urine loss. Success was demonstrated in one, improvement in one, and failure in eight patients one month after treatment. One patient improved and 9 failed 3 and 6 months after treatment. The median 24-hour pad weight test was higher at all three moments of follow-up (1, 3, and 6 months after treatment). The median 24-hour pad weight test was before treatment 17.3g (6.4-20.9) and 1, 3, and 6 months after treatment, respectively, 40.3g (5.9-130.6) p= 0.038, 38.3g (18.3-202.1) p= 0.014, 55.0g (16.5-314.6) p= 0.028. The ICIQ-SF was significantly higher at 3 and 6 months, respectively 15.0 (12.0-18.5) p= 0.007 and 16.0 (12.5-17.5) p=0.012 versus 10.0 (9.0-12.0) before injection. No significant differences were found between IIQ-7, UDI-6-SF, and PGI-I before and after injection. Complications occurred in four patients: two patients reported spontaneously resolved haematuria and two patients reported urinary frequency. All complications were classified as Clavien-Dindo 1. Conclusion: Injection therapy with Opsys® bulking agent is not an effective treatment option for male SUI after radical prostatectomy. It is not a safe treatment option, due to worsening urine loss after treatment.


Assuntos
Incontinência Urinária por Estresse/tratamento farmacológico , Idoso , Argentina , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prostatectomia/métodos , Inquéritos e Questionários , Resultado do Tratamento , Uretra/efeitos dos fármacos
14.
Cell Physiol Biochem ; 44(5): 1912-1922, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29224018

RESUMO

BACKGROUND/AIMS: To explore the effect of sulforaphane (SFN) treatment in rats through the induction of Stress Urinary Incontinence (SUI) via the Nrf2-ARE pathway. METHODS: A total of 18 female rats (Sprague-Dawley) were assigned to three groups: a control group, an SUI group, and an SUI+SFN group (six rats per group). Rats in the treatment groups were induced via postpartum vaginal balloon dilation and bilateral ovariectomy. Rats in the SUI+SFN group were treated via intraperitoneal injection once per day for a total of one month. Urethral sphincter muscle histological was observed by HE and Masson staining. Peak voiding pressure and interval of micturition were measured by cystometry. Oxidative stress markers and protein expression in the Nrf2-ARE pathway were examined by immunohistochemical staining and western blotting. RESULTS: Prolonged micturition interval and higher peak voiding pressure were observed in the SUI+SFN group. Disturbance of muscle morphology was ameliorated, muscle content was elevated, and collagen content was restrained in response to SFN treatment. The SOD, GSH-Px, and CAT activities were elevated in the SUI+SFN group compared to those in the control group. The level of cell apoptosis was decreased in SUI rats after SFN treatment; however, apoptosis was mainly located in the urethral mucosa instead of the muscle layer. SFN reduced the Bax/Bcl-2 expression ratio. Nrf2 and Nrf2 target antioxidant proteins were elevated in the SFN group. CONCLUSIONS: SFN was effective for SUI treatment via decreasing oxidative stress and activating the Nrf2-ARE pathway.


Assuntos
Anticarcinógenos/uso terapêutico , Isotiocianatos/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Incontinência Urinária por Estresse/tratamento farmacológico , Animais , Anticarcinógenos/toxicidade , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Isotiocianatos/toxicidade , Malondialdeído/sangue , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Uretra/patologia , Incontinência Urinária por Estresse/patologia , Incontinência Urinária por Estresse/veterinária , Proteína X Associada a bcl-2/metabolismo
15.
Actas urol. esp ; 41(7): 458-464, sept. 2017. tab
Artigo em Espanhol | IBECS | ID: ibc-166145

RESUMO

Objetivo: Evaluar la eficacia y seguridad de una inyección intravesical única de Onabotulinumtoxin A (OnaBTA) en el tratamiento de la incontinencia urinaria de urgencia en mujeres. Método: Se realizó un estudio prospectivo de serie de casos en pacientes consecutivas con incontinencia urinaria de esfuerzo refractaria tratadas con una inyección intravesical de OnaBTA. Las pacientes recibieron 100 unidades de OnaBTA inyectada en la pared vesical después de 4 semanas de lavado de anticolinérgicos o agonistas beta 3. Las variables urodinámicas y clínicas fueron evaluadas antes y 6 meses después de la inyección de OnaBTA. La variable principal del estudio fue el número de episodios de escapes urinarios. Resultados: Un total de 204 de las 210 pacientes seleccionadas realizaron una visita válida al sexto mes de la aplicación terapéutica. A los 6 meses del tratamiento con OnaBTA 110 (53,9%) pacientes permanecieron continentes y fueron consideradas como éxito. Por otro lado, 57 (27,9%) presentaron un episodio de escape urinario por día y 37 (18,2%) tuvieron 2 o más. En relación con los parámetros urodinámicos se observaron los siguientes cambios: aumento de la capacidad vesical máxima (p<0,0001) y disminución de la presión del detrusor máxima (p<0,0001). En cuanto al perfil de seguridad, 8 (3,9%) pacientes tuvieron hematuria autolimitada durante el procedimiento, que se resolvió espontáneamente; 9 (4,4%) pacientes tuvieron una retención urinaria aguda que precisó cateterización intermitente. Conclusiones: Este estudio apoya el uso de onabotulinumtoxin A en pacientes con incontinencia urinaria de urgencia que no responden al tratamiento médico


Objective: To assess the safety and efficacy of a single intravesical injection of onabotulinumtoxinA (OnaBTA) for treating urge urinary incontinence (UUI) in women. Method: We performed a prospective case-series study of consecutive patients with refractory UUI treated with an intravesical injection of OnaBTA. The patients were administered 100 units of OnaBTA injected into the bladder wall following 4 weeks of flushing with anticholinergic agents or beta 3 agonists. The urodynamic and clinical endpoints were evaluated before and 6 months after the injection of OnaBTA. The primary study endpoint was the number of episodes of urinary leakage. Results: A total of 204 of the 210 selected patients conducted a valid visit 6 months after the therapeutic application. At 6 months of treatment with OnaBTA, 110 (53.9%) patients remained continent and were considered a success. However, 57 (27.9%) patients experienced one episode of urinary leakage per day, and 37 (18.2%) had 2 or more. In terms of the urodynamic parameters, we observed the following changes: increase in maximum bladder capacity (P<.0001) and reduced maximum pressure of the detrusor (P<.0001). In terms of the safety profile, 8 (3.9%) patients had self-limiting haematuria during the procedure, which resolved spontaneously, and 9 (4.4%) patients had acute urinary retention that required intermittent catheterisation. Conclusions: This study supports the use of OnabotulinumtoxinA in patients with urge urinary incontinence that does not respond to medical treatment


Assuntos
Humanos , Toxinas Botulínicas Tipo A/uso terapêutico , Incontinência Urinária por Estresse/tratamento farmacológico , Estudos Prospectivos , Falha de Tratamento , Resultado do Tratamento , Índice de Gravidade de Doença , Antagonistas Colinérgicos/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico
16.
Cochrane Database Syst Rev ; 7: CD001754, 2017 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-28743177

RESUMO

BACKGROUND: Stress urinary incontinence constitutes a significant health and economic burden to society. Traditional suburethral slings are one of the surgical operations used to treat women with symptoms of stress urinary incontinence. OBJECTIVES: To determine the effects of traditional suburethral slings on stress or mixed incontinence in comparison with other management options. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register (searched 3 June 2010) and the reference lists of relevant articles. SELECTION CRITERIA: Randomised or quasi-randomised trials that included traditional suburethral slings for the treatment of stress or mixed urinary incontinence. DATA COLLECTION AND ANALYSIS: At least three reviewers independently extracted data from included trials onto a standard form and assessed trial methodological quality. The data abstracted were relevant to predetermined outcome measures. Where appropriate, we calculated a summary statistic: a relative risk for dichotomous data and a weighted mean difference for continuous data. MAIN RESULTS: We included 26 trials involving 2284 women. The quality of evidence was moderate for most trials and there was generally short follow-up ranging from 6 to 24 months.One medium-sized trial compared traditional suburethral sling operations with oxybutynin in the treatment of women with mixed urinary incontinence. Surgery appeared to be more effective than drugs in treating participant-reported incontinence (n = 75, risk ratio (RR) 0.18, 95% confidence interval (CI) 0.08 to 0.43).One trial found that traditional slings were more effective than transurethral injectable treatment (RR for clinician-assessed incontinence within a year 0.21, 95% CI 0.09 to 0.21)Seven trials compared slings with open abdominal retropubic colposuspension. Participant-reported incontinence was lower with the slings after one year (RR 0.75, 95% CI 0.62 to 0.90), but not when assessed by clinicians. Colposuspension, however, was associated with fewer peri-operative complications, shorter duration of use of indwelling catheter and less long-term voiding dysfunction. One study showed there was a 20% lower risk of bladder perforation with the sling procedure but a 50% increase in urinary tract infection with the sling procedure compared with colposuspension. Fewer women developed prolapse after slings (compared with after colposuspension) in two small trials but this did not reach statistical significance.Twelve trials addressed the comparison between traditional sling operations and minimally invasive sling operations. These seemed to be equally effective in the short term (RR for incontinence within first year 0.97, 95% CI 0.78 to 1.20) but minimally invasive slings had a shorter operating time, fewer peri-operative complications (other than bladder perforation) and some evidence of less post-operative voiding dysfunction and detrusor symptoms.Six trials compared one type of traditional sling with another. Materials included porcine dermis, lyophilised dura mater, fascia lata, vaginal wall, autologous dermis and rectus fascia. Participant-reported improvement rates within the first year favoured the traditional autologous material rectus fascia over other biological materials (RR 0.45, 95% CI 0.21 to 0.98). There were more complications with the use of non-absorbable Gore-Tex in one trial.Data for comparison of bladder neck needle suspension with suburethral slings were inconclusive because they came from a single trial with a small specialised population.No trials compared traditional suburethral slings with anterior repair, laparoscopic retropubic colposuspension or artificial sphincters. Most trials did not distinguish between women having surgery for primary or recurrent incontinence when reporting participant characteristics.For most of the comparisons, clinically important differences could not be ruled out. AUTHORS' CONCLUSIONS: Traditional slings seem to be as effective as minimally invasive slings, but had higher rates of adverse effects. This should be interpreted with some caution however, as the quality of evidence for the studies was variable, follow-up short and populations small, particularly for identifying complication rates. Tradional sling procedures appeared to confer a similar cure rate in comparison to open retropubic colposuspension, but the long-term adverse event profile is still unclear. A brief economic commentary (BEC) identified two studies suggesting that traditional slings may be more cost-effective compared with collagen injection but not cost-effective when compared with minimally invasive sling operations. Reliable evidence to clarify whether or not traditional suburethral slings may be better or worse than other surgical or conservative management options is lacking.


Assuntos
Slings Suburetrais , Incontinência Urinária por Estresse/cirurgia , Adulto , Feminino , Humanos , Politetrafluoretileno/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Slings Suburetrais/efeitos adversos , Slings Suburetrais/economia , Resultado do Tratamento , Incontinência Urinária/tratamento farmacológico , Incontinência Urinária/cirurgia , Incontinência Urinária por Estresse/tratamento farmacológico
17.
CMAJ ; 189(5): E194-E203, 2017 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-28246265

RESUMO

BACKGROUND: The European Medicines Agency makes clinical study reports publicly available and publishes reasons for not approving applications for marketing authorization. Duloxetine has been approved in Europe for the treatment of stress urinary incontinence in women. The reported adverse effects of duloxetine include mental health problems and suicidality. We obtained clinical study reports from the European Medicines Agency concerning use of this drug for stress urinary incontinence. METHODS: We performed a meta-analysis of 4 randomized placebo-controlled trials of duloxetine (involving a total of 1913 patients) submitted to the European Medicines Agency for marketing approval for the indication of stress urinary incontinence in women. We used data from the clinical study reports (totalling 6870 pages and including individual patient data) to assess benefits (including frequency of incontinence and changes in quality-of-life scores, such as Patient Global Impression of Improvement rating) and harms (both general harms, including discontinuation because of adverse events, and harms related to suicidality, violent behaviour and their potential precursors, such as akathisia and activation [stimulating effects such as insomnia, anxiety and agitation]). RESULTS: Duloxetine was significantly better than placebo in terms of percentage change in weekly incontinence episodes (mean difference -13.56%, 95% confidence interval [CI] -21.59% to -5.53%) and change in Incontinence Quality of Life total score (mean difference 3.24, 95% CI 2.00 to 4.48). However, the effect sizes were small, and a sensitivity analysis (with removal of one trial) showed that the number needed to treat for a Patient Global Impression of Improvement rating of "much better or very much better" was 8 (95% CI 6 to 13). The numbers needed to harm were 7 (95% CI 6 to 8) for discontinuing because of an adverse event and 7 (95% CI 6 to 9) for experiencing an activation event. No suicidality, violence or akathisia events were noted. INTERPRETATION: Although duloxetine is effective for stress urinary incontinence in women, the rates of associated harm were high when individual patient data were analyzed, and the harms outweighed the benefits.


Assuntos
Antidepressivos/uso terapêutico , Cloridrato de Duloxetina/uso terapêutico , Incontinência Urinária por Estresse/tratamento farmacológico , Sintomas Afetivos/induzido quimicamente , Acatisia Induzida por Medicamentos/etiologia , Ansiedade/induzido quimicamente , Feminino , Humanos , Transtornos Mentais/induzido quimicamente , Psicoses Induzidas por Substâncias/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Ideação Suicida , Resultado do Tratamento , Violência
18.
Int J Urol ; 24(6): 461-467, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28332237

RESUMO

OBJECTIVES: To examine the inhibitory effects of tumor necrosis factor-α on myogenic differentiation of human urethral rhabdosphincter cells. METHODS: A rhabdosphincter sample was obtained from a patient who underwent total cystectomy. To expand the lifespan of the primary cultured cells, rhabdosphincter myogenic cells were immortalized with mutated cyclin-dependent kinase 4, cyclin D1 and telomerase. The differential potential of the cells was investigated. The transfected human rhabdosphincter cells were induced for myogenic differentiation with recombinant human tumor necrosis factor-α and/or the tumor necrosis factor-α antagonist etanercept at different concentrations, and activation of signaling pathways was monitored. RESULTS: Human rhabdosphincter cells were selectively cultured for at least 40 passages. Molecular analysis confirmed the expression of myosin heavy chain, which is a specific marker of differentiated muscle cells, significantly increased after differentiation induction. Although tumor necrosis factor-α treatment reduced the myosin heavy chain expression in a concentration-dependent manner, etanercept inhibited this suppression. Tumor necrosis factor-α suppressed phosphorylation of protein kinase B and p38, whereas etanercept pretreatment promoted phosphorylation and myosin heavy chain expression in a concentration-dependent manner. CONCLUSIONS: Tumor necrosis factor-α inhibits differentiation of urethral rhabdosphincter cells in part through the p38 mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. Inhibition of tumor necrosis factor-α might be a useful strategy to treat stress urinary incontinence.


Assuntos
Diferenciação Celular/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Mioblastos Esqueléticos/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Cistectomia , Etanercepte/farmacologia , Etanercepte/uso terapêutico , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Desenvolvimento Muscular/efeitos dos fármacos , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/citologia , Mioblastos Esqueléticos/efeitos dos fármacos , Cadeias Pesadas de Miosina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/isolamento & purificação , Uretra/citologia , Uretra/efeitos dos fármacos , Uretra/fisiologia , Neoplasias da Bexiga Urinária/cirurgia , Incontinência Urinária por Estresse/tratamento farmacológico , Incontinência Urinária por Estresse/fisiopatologia
19.
Int Urogynecol J ; 28(9): 1309-1317, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28210793

RESUMO

INTRODUCTION AND HYPOTHESIS: Urethral injection therapy (UIT) has been performed since the early 20th century and a variety of agents have been launched. In 2006, polyacrylamide hydrogel (PAGH) was introduced and is now widely used as an agent. The objective was to evaluate the efficacy of PAGH based on a national population over a 5-year period (2007-2011) and the influence of patient-related factors, surgeon experience, and department volume. METHODS: A retrospective cohort study was carried out based on data from the Danish Urogynaecological Database (DugaBase). RESULTS: A total of 731 women were registered in the DugaBase. Cure was achieved in 75 out of 252 women (29.8%) and no leakage at all in 23 out of 252 (9.1%) at the 3-month follow-up. The mean total International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) score decreased from 16 (SD 3.8) to 10.6 (SD 6.2; p < 0.001). UIT was performed at 16 departments, of which four high-volume departments performed 547 out of 814 UITs (67.2%). Women with severe UI had a decreased chance of cure (all ICIQ-SF scores), as did women on antimuscarinic drugs (adjusted OR 0.14; 95%, CI 0.04-0.41 "frequency") and (adjusted OR 0.33; 95%, CI 0.13-0.82, "amount"). Women treated by a high-volume surgeon had a higher chance of cure (OR 4.51; 95% CI, 1.21-16.82, "frequency") and a lower risk of 30-day hospital contacts (OR 0.27; 95% CI 0.09-0.76). CONCLUSION: The study represented a cure for UIT among women in an everyday life setting. A surgeon learning curve for UIT was indicated, as was assigning interventions to fewer hands to improve the surgical training value and consequently the cure rate for women with UIT.


Assuntos
Resinas Acrílicas/administração & dosagem , Incontinência Urinária por Estresse/tratamento farmacológico , Incontinência Urinária/tratamento farmacológico , Administração Tópica , Adulto , Bases de Dados Factuais , Dinamarca , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Uretra
20.
Int Urogynecol J ; 28(6): 947-955, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28168411

RESUMO

INTRODUCTION AND HYPOTHESIS: We investigated the effect of punicalagin (PUN; 2,3-hexahydroxydiphenoyl-gallagyl-D-glucose), on mechanical-trauma-induced stress urinary incontinence (SUI) in mouse and the mechanisms underlying any effects. METHODS: Ninety virgin female C57BL/6 mice were randomized into six groups: five groups underwent vaginal distention (VD) for 1 h and leak-point pressure (LPP) was measured on the 1st, 3rd, 7th, 14th, and 28th day following (VD groups 1 d, 3 d, 7 d, 14 d, and 28 d). The sixth group was a noninstrumented control (NC) group. Then, 75 virgin female C57BL/6 mice were randomized into five groups: a VD group (that just underwent VD) and an NC group were orally administered saline every day for 7 days; and three VD + PUN groups that underwent VD and were orally administered PUN respectively at 2.5, 5, and 10 mg/kg every day for 7 days. LPP was tested on the day 7, then all mice were sacrificed and their urethras and anterior vaginal walls harvested for Masson staining, immunohistochemistry study, Western blot analysis, and quantitative polymerase chain reaction (qPCR). RESULTS: LPPs after VD were significantly lower than the NC group, and the LPPs of mice on days 14 and 28 day after VD were significantly higher than on the days 1, 3, and 7. PUN significantly improved VD-induced drops in LPP and alleviated VD-induced decrease of collagen I, collagen III, α-smooth muscle actin (SMA), transforming growth factor (TGF)-ß1, and p-Smad3, nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), and glutathione peroxidase (GPx1) protein levels, and increase of 8-hydroxydeoxyguanosine (OHdG) in urethra and anterior vaginal wall. PUN also up-regulated the expression of manganese superoxide dismutase (MnSOD), whereas protein levels of Smad 2, p-Smad2, and Smad3 were not changed. CONCLUSIONS: PUN exerts certain therapeutic effect on mechanical-trauma-induced SUI in mice, which might be through the activation of TGF-ß1/Smad3 and Nrf2/antioxidant response element (ARE) signaling activation.


Assuntos
Taninos Hidrolisáveis/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos , Incontinência Urinária por Estresse/tratamento farmacológico , Actinas/metabolismo , Animais , Colágeno/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Modelos Animais de Doenças , Feminino , Glutationa Peroxidase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína Smad3/metabolismo , Superóxido Dismutase/metabolismo , Uretra/metabolismo , Incontinência Urinária por Estresse/etiologia , Incontinência Urinária por Estresse/metabolismo , Vagina/metabolismo
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