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1.
Int. j. morphol ; 38(3): 627-633, June 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1098298

RESUMO

Diabetes Mellitus (DM) is a condition marked by hyperglycaemia that causes systemic complications, including urinary vesicle dysfunction due to oxidative stress. Further, antioxidants, as well as alpha lipoic acid (ALA), may be a response to this pathological condition. The present study verified the action of ALA as a supplement in ration on glycemia and urinary vesicle structures of rats induced by streptozotocin. The rats were divided into 4 groups: Control (CG), Alpha Lipoic (ALAG), Diabetic control (DCG), and the Diabetic alpha lipoic (DALAG) group. For induction, the diabetic groups were initially induced with streptozotocin (dose 60 mg/kg). Subsequently, group glycemia was evaluated weekly. After 8 weeks, the rats were euthanized and the bladder was collected. The bladders were histologically processed and the slides were stained with Masson's Trichrome for the histomorphometry of epithelial height, connective and muscular tissue and coloration of PicroSirius Red for further analysis of collagen fibers of the bladder. The data of the glycemia demonstrated an inferior median in DALAG compared to DGC (p<0.01). The epithelial height and percentage of the muscle tissue were greater in DALAG compared to the DGC, but not significant. However, GDAL showed improvement in the organization of collagen fibers. In conclusion, bladder the morphology alterations caused by DM were not alleviated by the administration of ALA in 8 weeks of the experiments.


La diabetes mellitus (DM) es una afección marcada por hiperglucemia que causa complicaciones sistémicas, incluida la disfunción de la vejiga urinaria debido al estrés oxidativo. Además, los antioxidantes, así como el ácido alfa lipoico (ALA), pueden ser una respuesta a esta condición patológica. El presente estudio verificó la acción de ALA como suplemento en la ración sobre la glucemia y las estructuras de la vejiga urinaria de ratas inducidas por estreptozotocina. Las ratas se dividieron en 4 grupos: control (CG), alfa lipoico (ALAG), control diabético (DCG) y el grupo diabético alfa lipoico (DALAG). Para la inducción, los grupos diabéticos se aplicó estreptozotocina (dosis 60 mg/kg). Posteriormente, la glucemia grupal se evaluó semanalmente. Después de 8 semanas, las ratas se sacrificaron y se retiró la vejiga urinaria. Las vejigas se procesaron histológicamente y las muestras se tiñeron con tricromo de Masson para la histomorfometría y así evaluar la altura epitelial, el tejido conectivo y muscular. Además se tiñeron cond PicroSirius Red para un análisis posterior de las fibras colágenas de la vejiga urinaria. Los datos de la glucemia demostraron una mediana inferior en DALAG en comparación con DGC (p <0,01). La altura epitelial y el porcentaje de tejido muscular fueron mayores en DALAG en comparación con el DGC, pero no estadísticamente significativos. Sin embargo, GDAL mostró una mejora en la organización de las fibras de colágeno. En conclusión, la morfología de las alteraciones de la vejiga causada por DM no se alivió con la administración de ALA en 8 semanas de estudio.


Assuntos
Animais , Ratos , Bexiga Urinária/efeitos dos fármacos , Ácido Tióctico/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Antioxidantes/administração & dosagem , Glicemia/análise , Suplementos Nutricionais
2.
PLoS One ; 15(3): e0230355, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226049

RESUMO

OBJECTIVE: To systematically review outcomes in patients with refractory overactive bladder (OAB) patients who underwent sacral neuromodulation therapy (SNM) therapy after unsuccessful onabotulinumtoxinA (BTX) therapy, and to compare outcomes with those who SNM as initial therapy. METHODS: A systematic search of Cochrane Library, Pubmed and Embase databases from July 2002 to November 2019, to analyze randomized controlled trials and retrospective studies of SNM therapy after failed initial BTX therapy. Two reviewers independently screened the studies and extracted data. A quality assessment of the included literature was conducted using Newcastle-Ottawa Scale (NOS), and Stata 12.0 software was used to conduct a meta-analysis of the collected data. RESULTS: A total of seven studies involving 319 patients were finally included. The success rate in refractory OAB patients who used SNM therapy after failed BTX therapy was 58.5%, 95% CI (0.47-0.70). There was no significant difference between refractory OAB patients who chose SNM as replacement therapy after failed BTX therapy and those who used SNM therapy as first choice [RR = 0.96, 95%CI (0.72-1.26), P = 0.735]. CONCLUSION: OAB patients for whom an initial choice of BTX therapy ends in failure or dissatisfaction may consider switching to SNM therapy. There is no difference in outcomes between these patients and those whose first choice was SNM therapy.


Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Terapia por Estimulação Elétrica/métodos , Plexo Lombossacral/fisiopatologia , Bexiga Urinária Hiperativa/terapia , Bexiga Urinária/efeitos dos fármacos , Humanos , Plexo Lombossacral/efeitos dos fármacos , Satisfação do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Falha de Tratamento , Bexiga Urinária/inervação , Bexiga Urinária Hiperativa/fisiopatologia
3.
Anesth Analg ; 130(4): 1077-1084, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31490256

RESUMO

BACKGROUND: Neuromodulation, as a therapeutic modality for pain treatment, is an alternative to opioid therapies and therefore receiving increased interest and use. Neuromodulation at a peripheral nerve target, in the form of bilateral electrical pudendal nerve stimulation (bPNS), has been shown to reduce bladder hypersensitivity in rats and anecdotally reduces pain in humans with pelvic pain of urological origin. Recent studies have identified a role for spinal γ-aminobutyric acid (GABA) receptors in this effect. Concomitant medication use, such as benzodiazepines, could alter responses to neuromodulation, and so before the development of a clinical trial to confirm translation of this potential therapy, the potential interactions between acute and chronic use of benzodiazepines and bPNS were examined in a preclinical model. METHODS: Bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Diazepam (1-5 mg/kg intraperitoneal [i.p.]) or vehicle was administered acutely (with or without bPNS) and chronically (5 mg/kg subcutaneous [s.c.] daily for 2 weeks before the final experiment). bPNS was delivered as bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Visceromotor responses (VMRs; abdominal muscle contractile responses to urinary bladder distension [UBD]) were used as nociceptive end points. Due to the profound effects of diazepam, the effect of midazolam (0.5-1.0 mg/kg i.p.) on VMRs and bPNS effects was also studied. RESULTS: Diazepam and midazolam both produced a dose-dependent, flumazenil-reversible inhibition of VMRs to UBD. bPNS resulted in statistically significant inhibition of VMRs to UBD in hypersensitive rats that had received vehicle injections. Select doses of diazepam and midazolam suppressed the inhibitory effect of bPNS on VMRs. CONCLUSIONS: This study suggests that inhibitory effects of bPNS on bladder pain could be suppressed in subjects receiving benzodiazepine therapy, suggesting that potential clinical testing of pudendal nerve stimulation for the treatment of painful bladder syndromes may be confounded by the use of benzodiazepines. Clinical assessment of other forms of neuromodulation should also be screened for impacts of benzodiazepines.


Assuntos
Benzodiazepinas/farmacologia , Nociceptividade/efeitos dos fármacos , Nervo Pudendo/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Animais , Diazepam/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Feminino , Flumazenil/farmacologia , Moduladores GABAérgicos/farmacologia , Midazolam/farmacologia , Neurônios Motores/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos
4.
Urology ; 135: 38-43, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31600558

RESUMO

OBJECTIVE: To evaluate differences in adverse events (AE) in asymptomatic patients with a positive urine dip (UD) at time of intradetrusor onabotulinumtoxinA (BTX-A) injection vsthose with a defined negative UD. MATERIALS AND METHODS: All intradetrusor BTX-A injections were retrospectively reviewed at a single institution between 2016 and 2018. Exclusion criteria included an indwelling catheter, recent positive urine culture, recent antibiotic course, or absence of UD on the day of injection. A positive UD was defined using 7 different definitions with varying combinations of any level of positive blood, leukocyte esterase, or nitrite. Negative UDs were defined those excluded from the positive UD group. We compared multiple positive UD-defined groups to their respective negative UD cohorts with regards to outcomes and demographics. RESULTS: A total of 212 patients underwent 335 cycles of BTX-A injections over a 2-year period. The average age was 65 years (range: 21-90). The majority received 100 units (73%) of BTX-A for a non-neurogenic diagnosis (73%). The overall rate of AEs, urinary tract infection, and urinary retention was 14.6%, 9%, and 3%, respectively. In all groups, the most common AE was urinary tract infection followed by urinary retention. There were no major Clavien-Dindo-defined complications. There was no statistically significant difference in the total or categorical AE rates between positive and negative UD groups using all 7 definitions of a positive UD (P = .05-1.0). CONCLUSION: These data do not support the practice of obtaining a preprocedure UD in asymptomatic patients undergoing intradetrusor BTX-A injection for any indication; test results are unable to predict outcomes or AEs.


Assuntos
Toxinas Botulínicas Tipo A/efeitos adversos , Fármacos Neuromusculares/efeitos adversos , Bexiga Urinária Hiperativa/tratamento farmacológico , Retenção Urinária/epidemiologia , Infecções Urinárias/epidemiologia , Administração Intravesical , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas/terapia , Toxinas Botulínicas Tipo A/administração & dosagem , Feminino , Humanos , Injeções Intramusculares/efeitos adversos , Injeções Intramusculares/métodos , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/administração & dosagem , Estudos Retrospectivos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/fisiopatologia , Retenção Urinária/etiologia , Infecções Urinárias/etiologia , Infecções Urinárias/urina , Urodinâmica/efeitos dos fármacos , Adulto Jovem
5.
Urology ; 135: 32-37, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626856

RESUMO

OBJECTIVE: To ascertain whether a poor response and adverse events (voiding dysfunction and urinary tract infection) were predictable for first time botulinum toxin-A (BTX-A) injections in a patient cohort of refractory idiopathic overactive bladder with detrusor overactivity. METHODS: Patients who received BTX-A injections for the first time between the dates of March 2004-August 2017 were analyzed in this single center study. Urogenital Distress Inventory short form (UDI-6) questionnaires were collected both preinjection and postinjection prospectively. A poor response was defined as a decrease of less than 16.7 on the UDI-6 questionnaire. Additional information was gathered from patient records in a retrospective fashion. Predictors of poor response, voiding dysfunction, and UTI were analyzed with multivariate logistic regression analysis. RESULTS: Seventy-four patients were analyzed. The only predictor of poor response was male gender (OR, 5.45; 95% CI 1.83-16.47; P = .002). Lower maximum urinary flow rates (OR, 0.91; 95% CI, 0.83-0.99; P = .023), male gender (OR, 5.14; 95% CI 1.41-18.72; P = .013), and hysterectomy in females (OR, 4.55; 95% CI, 1.09-18.87; P = .038) were predictors of clean intermittent self catheterisation (CISC). There was an increased risk of UTIs in patients who performed CISC (OR, 5.26; 95% CI 1.38-20.0; P = .015). CONCLUSION: Male gender was associated with a poor response to BTX-A injections and increased risk of CISC. Lower maximum urinary flow rates and women with hysterectomies were at increased risk of requiring CISC postinjection. Performing CISC was associated with increased risk of UTI. These factors could be helpful when counselling or selecting patients.


Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Fármacos Neuromusculares/administração & dosagem , Bexiga Urinária Hiperativa/terapia , Administração Intravesical , Toxinas Botulínicas Tipo A/efeitos adversos , Feminino , Humanos , Injeções Intramusculares/métodos , Cateterismo Uretral Intermitente/efeitos adversos , Cateterismo Uretral Intermitente/métodos , Cateterismo Uretral Intermitente/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/efeitos adversos , Prognóstico , Estudos Retrospectivos , Autocuidado/métodos , Autocuidado/estatística & dados numéricos , Fatores Sexuais , Inquéritos e Questionários , Resultado do Tratamento , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/diagnóstico , Bexiga Urinária Hiperativa/fisiopatologia , Infecções Urinárias/epidemiologia , Infecções Urinárias/etiologia , Transtornos Urinários/diagnóstico , Transtornos Urinários/epidemiologia , Transtornos Urinários/etiologia
6.
Chemistry ; 26(8): 1789-1799, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31605633

RESUMO

The synthesis of ruthenium(II) phthalocyanines (RuPcs) endowed with one carbohydrate unit-that is, glucose, galactose and mannose-and a dimethylsulfoxide (DMSO) ligand at the two axial coordination sites, respectively, is described. Two series of compounds, one unsubstituted at the periphery, and the other one bearing eight PEG chains at the isoindole meta-positions, have been prepared. The presence of the axial DMSO unit significantly increases the phthalocyanine singlet oxygen quantum yields, related to other comparable RuPcs. The compounds have been evaluated for PDT treatment in bladder cancer cells. In vitro studies have revealed high phototoxicity for RuPcs unsubstituted at their periphery. The phototoxicity of PEG-substituted RuPcs has been considerably improved by repeated light irradiation. The choice of the axial carbohydrate introduced little differences in the cellular uptake for both series of photosensitizers, but the phototoxic effects were considerably higher for compounds bearing mannose units.


Assuntos
Compostos Organometálicos/química , Fármacos Fotossensibilizantes/síntese química , Oxigênio Singlete/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Luz , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Espectrofotometria , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo
7.
Am J Physiol Cell Physiol ; 318(2): C406-C421, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851526

RESUMO

Nonselective cation channels, consistent with transient receptor potential melastatin-4 (TRPM4), regulate detrusor smooth muscle (DSM) function. TRPM4 channels can exist as homomers or assemble with sulfonylurea receptors (SURs) as complexes. We evaluated contributions of TRPM4/SUR-TRPM4 channels to DSM excitability and contractility by examining the effects of TRPM4/SUR-TRPM4 channel modulators 9-phenanthrol, glibenclamide, and diazoxide on freshly-isolated guinea pig DSM cells (amphotericin-B perforated patch-clamp electrophysiology) and mucosa-free DSM strips (isometric tension recordings). In DSM cells, complete removal of extracellular Na+ decreased voltage-step-induced cation (non-K+ selective) currents. At high positive membrane potentials, 9-phenanthrol at 100 µM attenuated voltage step-induced currents more effectively than at 30 µM, revealing concentration-dependent, voltage-sensitive inhibition. In comparison to 9-phenanthrol, glibenclamide (100 µM) displayed lower inhibition of cation currents. In the presence of glibenclamide (100 µM), 9-phenanthrol (100 µM) further decreased the currents. The SUR-TRPM4 complex activator diazoxide (100-300 µM) weakly inhibited the currents. 9-Phenanthrol, but not glibenclamide or diazoxide, increased cell capacitance (a cell surface area indicator). In contractility studies, glibenclamide displayed lower potencies than 9-phenanthrol attenuating spontaneous and 20 mM KCl-induced DSM phasic contractions. While both compounds showed similar maximum inhibitions on DSM spontaneous phasic contractions, glibenclamide was generally less efficacious on 20 mM KCl-induced phasic contractions. In summary, the observed differential effects of 9-phenanthrol and glibenclamide on DSM excitability and contractility support unique mechanisms for the two compounds. The data suggest that SUR-TRPM4 complexes do not contribute to DSM function. This study advances our understanding of pharmacological effects of glibenclamide and 9-phenanthrol on DSM cell cation currents.


Assuntos
Cátions/metabolismo , Glibureto/farmacologia , Músculo Liso/efeitos dos fármacos , Fenantrenos/farmacologia , Canais de Cátion TRPM/antagonistas & inibidores , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cobaias , Masculino , Potenciais da Membrana/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Técnicas de Patch-Clamp/métodos
8.
BMC Urol ; 19(1): 103, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660941

RESUMO

BACKGROUND: Competent detrusor muscles with coordinated contraction and relaxation are crucial for normal urinary bladder storage and emptying functions. Hence, detrusor instability, and subsequently bladder overactivity, may lead to undesirable outcomes including incontinence. Multiple mechanisms may underlie the pathogenesis of detrusor overactivity including inflammation and oxidative stress. Herein, we tested the possibility that CoQ10 may have a potential therapeutic role in detrusor overactivity. METHODS: Forty adult male Wistar albino rats weighing 100-150 g were used in the present study. Rats were divided (10/group) into control (receiving vehicles), monosodium glutamate (MSG)-treated (receiving 5 mg/kg MSG daily for 15 consecutive days), MSG + OO-treated (receiving concomitantly 5 mg/kg MSG and olive oil for 15 consecutive days), MSG + CoQ10-treated (receiving concomitantly 5 mg/kg MSG and 100 mg/kg CoQ10 daily for 15 consecutive days) groups. RESULTS: MSG resulted in significant increase in bladder weight and sensitised the bladder smooth muscles to acetylcholine. MSG has also resulted in significant increase in bladder TNF-α, IL-6, malondialdehyde, nerve growth factor and connexion 43, with significant decrease in the antioxidant enzymes superoxide dismutase and catalase. Olive oil had no effect on MSG induced alterations of different parameters. Treatment with CoQ10 has resulted in a significant restoration of all the altered parameters. CONCLUSION: Taken together, our results suggest that CoQ10 antagonizes the deleterious effects of MSG on detrusor activity. We propose that CoQ10 could be a therapeutic strategy targeting urinary bladder dysfunction.


Assuntos
Músculo Liso/efeitos dos fármacos , Ubiquinona/análogos & derivados , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Animais , Junções Comunicantes/efeitos dos fármacos , Inflamação/tratamento farmacológico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Glutamato de Sódio/administração & dosagem , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico , Bexiga Urinária Hiperativa/induzido quimicamente
9.
Ren Fail ; 41(1): 937-945, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31599184

RESUMO

The aim of this work was to evaluate the efficacy and safety of botulinum toxin A (BTX-A) treatment in patients with neurogenic detrusor overactivity. PUBMED, EMBASE, and Cochrane Library were identified on 13 May 2017 to identify relevant randomized controlled trials. All data obtained were analyzed using Stata 12.0. Five randomized controlled trials were included in this study. Compared to placebo, the BTX-A groups had significantly fewer urinary incontinence (UI) episodes per day and per week (BTX-A with 300 U for frequency of UI per day at week 2, mean difference (MD): -1.13, 95% confidence interval (CI): -1.89 to -0.37; 200 U; BTX-A with 300 U for frequency of UI per week at week 6, MD: -11.42, 95% CI: -13.91 to -8.93; BTX-A with 200 U for frequency of UI per week at week 6, MD: -10.72, 95% CI: -13.40 to -8.04), increased in maximum cystometric capacity at week 6 (BTX-A with 300 U, MD: 154.88, 95% CI: 133.92-175.84; BTX-A with 200 U, MD: 141.30, 95% CI: 121.28-161.33), decreased maximum detrusor pressure at week 6 (BTX-A with 300 U, MD: -31.72, 95% CI: -37.69 to -25.75; BTX-A with 200 U, MD: -33.47, 95% CI: -39.20 to -27.73). For adverse effects, BTX-A was often associated with more complications and urinary tract infections (BTX-A with 300 U: relative risk (RR):1.42, 95% CI: 1.15-1.76; BTX-A with 200 U: RR: 1.42, 95% CI: 1.11-1.82). This meta-analysis suggests that treatment with BTX-A is effective and safe for neurogenic detrusor overactivity, and recommends using BTX-A with 300 U or with 200 U, as suitable dosage.


Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico , Incontinência Urinária/tratamento farmacológico , Infecções Urinárias/epidemiologia , Administração Intravesical , Toxinas Botulínicas Tipo A/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Injeções , Placebos/administração & dosagem , Placebos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Resultado do Tratamento , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Bexiga Urinaria Neurogênica/complicações , Bexiga Urinaria Neurogênica/fisiopatologia , Bexiga Urinária Hiperativa/complicações , Bexiga Urinária Hiperativa/fisiopatologia , Incontinência Urinária/diagnóstico , Incontinência Urinária/etiologia , Infecções Urinárias/induzido quimicamente
10.
Life Sci ; 238: 116922, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634463

RESUMO

AIMS: Nitric oxide (NO) has a critical, but not well understood, influence in the physiology of the lower urinary tract. We evaluated the effect of NO/phosphodiesterase (PDE)5 signaling in voiding dysfunction in the sickle cell disease (SCD) mouse, characterized by low NO bioavailability. MAIN METHODS: Adult SCD (Sickle) and wild-type (WT) male mice were treated daily with sodium nitrate (10 mM) or vehicle. After 18 days, blood was obtained for nitrite measurement, urethra was collected for organ bath study, and bladder and urethra were collected for Western blot analysis of PDE5 phosphorylation (Ser-92) (activated form). Non-anesthetized mice underwent evaluation of urine volume by void spot assay. eNOS phosphorylation (Ser-1177) and nNOS phosphorylation (Ser-1412) (positive regulatory sites) were evaluated in the bladder and urethra of untreated mice. KEY FINDINGS: Sickle mice exhibited decreased eNOS, nNOS, and PDE5 phosphorylation in the bladder and urethra, decreased plasma nitrite levels, increased relaxation of phenylephrine-contracted urethral tissue to an NO donor sodium nitroprusside, and increased total urine volume, compared with WT mice. Nitrate treatment normalized plasma nitrite levels, relaxation of urethra to sodium nitroprusside, PDE5 phosphorylation in the urethra and bladder, and urine volume in Sickle mice. SIGNIFICANCE: Derangement in PDE5 activity associated with basally low NO bioavailability in the bladder and urethra contributes to the molecular basis for voiding abnormalities in Sickle mice. Inorganic nitrate supplementation normalized voiding in Sickle mice through mechanisms likely involving upregulation of PDE5 activity. These findings suggest that interventions targeting dysregulatory NO/PDE5 signaling may ameliorate overactive bladder in SCD.


Assuntos
Anemia Falciforme/fisiopatologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Nitratos/administração & dosagem , Óxido Nítrico/metabolismo , Uretra/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Administração Oral , Animais , Masculino , Camundongos , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Uretra/metabolismo , Uretra/patologia , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia
11.
Eur J Pharmacol ; 864: 172727, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31600494

RESUMO

The combination of a ß3-adrenoceptor agonist and an antimuscarinic agent was revealed to be more effective than monotherapy for patients with overactive bladder and in animal models. However, its influence on voiding functions has not been well documented. Therefore, during intermittent-cystometry, we studied the effects of vibegron (a novel ß3-adrenoceptor agonist) and imidafenacin (an antimuscarinic agent) alone to determine their dose levels for the combination study. Then, the effects of the combination on voiding functions were investigated in urethane-anesthetized rats (1.0 g/kg s.c.). Independently, vibegron (0.3-3 mg/kg, i.v.) and imidafenacin (0.001 and 0.003 mg/kg, i.v.) dose-dependently increased bladder capacity and voided volume, without affecting voiding functions such as residual volume, voiding efficiency, and micturition pressure. However, vibegron also increased bladder compliance. The combination of vibegron (3 mg/kg) and imidafenacin (0.003 mg/kg) significantly increased bladder capacity and voided volume when compared to those with monotherapy using each individually. The combination did not change residual volume, voiding efficiency, and micturition pressure, compared to those in the vehicle group. We identified no responses in resiniferatoxin (RTX)-treated rats, as opposed to those identified after administering vibegron (3 mg/kg), imidafenacin (0.003 mg/kg), or both to non-RTX-treated rats. These outcomes might have resulted from the combination of the increased effect of vibegron on bladder compliance and the inhibitory effect of both vibegron and imidafenacin on the activation of bladder afferent nerves.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Imidazóis/farmacologia , Antagonistas Muscarínicos/farmacologia , Pirimidinonas/farmacologia , Pirrolidinas/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia , Anestesia , Animais , Interações Medicamentosas , Feminino , Ratos , Ratos Sprague-Dawley
13.
In Vivo ; 33(6): 1819-1826, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31662508

RESUMO

BACKGROUND/AIM: A short-period type 2 diabetes model was established in order to identify changes in oxidative stress in the bladder at the initiation of the disease. The effect of antioxidant treatment was examined. MATERIALS AND METHODS: Diabetes was induced in adult male Wistar rats with a single dose of streptozotocin (40 mg/kg; i.p.). Diabetic animals were then randomly separated into three groups: No treatment (DM), resveratrol treatment, and taurine treatment, and fed with a high-fat diet. Age-matched non-diabetic animals were used and fed with normal diet (control). Two weeks later, animals were sacrificed and bladders were processed for histological evaluation, and further analysis for oxidative stress markers. RESULTS: The body weight of all diabetic animals was significantly lower compared to the controls. The DM group demonstrated a significantly higher bladder weight to body weight ratio compared to the control. The bladder in the DM group demonstrated abruption of the mucosa from the muscularis and edema in the transitional epithelium. Bladders from the resveratrol-, and taurine-treated groups did not demonstrate these histological alterations. The level of malondialdehyde (MDA) in the bladder was significantly higher in the DM group compared to all other groups. Immunohistochemistry showed that diabetes induced a moderate to strong expression of oxidative stress markers MDA and 4-hydroxynonenal, and DNA oxidative stress marker 8-deoxyguanosine in the DM group compared to the other groups. CONCLUSION: Prompt diagnosis and treatment of diabetes is crucial in regard to disease progression. Specifically, in the bladder it appears that both mild damage at the structural level, as well as oxidative damage at the molecular level may be prevented by antioxidant treatment.


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Catalase/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Bexiga Urinária/metabolismo
14.
In Vivo ; 33(6): 1949-1957, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31662524

RESUMO

BACKGROUND: The aetiology of urgency urinary incontinence is a matter of debate. Current treatment options are based on the hypothesis of a neurological disorder of bladder innervation. However, it has also been hypothesised that one main cause is the reduced function of the bladder-holding apparatus, that is, insufficient suspension of the vesico-urethral junction. This study compared the effects of surgical apical vaginal elevation with those of solifenacin on urgency urinary incontinence in women. PATIENTS AND METHODS: Women with mixed and urgency urinary incontinence were randomised to either an established pharmacological arm (10 mg/day solifenacin) or the surgical arm (bilateral uterosacral ligament replacement, cervicosacropexy, CESA; or vaginosacropexy, VASA. Clinical and objective outcomes were assessed at 4 months after each type of intervention. RESULTS: The study was terminated early; 55 patients were operated on and 41 patients received pharmacological treatment. After surgical treatment, 23 patients (42%, 95% confidence intervaI=29-55%) became continent compared to four patients (10%, 95% confidence intervaI=1-19%) during solifenacin treatment. CONCLUSION: Compared to pharmacological treatment, the surgical repair of the apical vaginal end restored urinary continence in significantly more patients.


Assuntos
Succinato de Solifenacina/uso terapêutico , Incontinência Urinária/tratamento farmacológico , Incontinência Urinária/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Doenças dos Genitais Femininos/tratamento farmacológico , Doenças dos Genitais Femininos/terapia , Humanos , Pessoa de Meia-Idade , Bexiga Urinária/efeitos dos fármacos , Transtornos Urinários/tratamento farmacológico , Transtornos Urinários/terapia
15.
Am J Physiol Renal Physiol ; 317(6): F1695-F1706, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31630542

RESUMO

Transient receptor potential vanilloid family member 4 (TRPV4) transcript and protein expression increased in the urinary bladder and lumbosacral dorsal root ganglia of transgenic mice with chronic urothelial overexpression of nerve growth factor (NGF-OE). We evaluated the functional role of TRPV4 in bladder function with open-outlet cystometry, void spot assays, and natural voiding (Urovoid) assays with the TRPV4 antagonist HC-067047 (1 µM) or vehicle in NGF-OE and littermate wild-type (WT) mice. Blockade of TRPV4 at the level of the urinary bladder significantly (P ≤ 0.01) increased the intercontraction interval (2.2-fold) and void volume (2.6-fold) and decreased nonvoiding contractions (3.0-fold) in NGF-OE mice, with lesser effects (1.3-fold increase in the intercontraction interval and 1.3-fold increase in the void volume) in WT mice. Similar effects of TRPV4 blockade on bladder function in NGF-OE mice were demonstrated with natural voiding assays. Intravesical administration of HC-067047 (1 µM) significantly (P ≤ 0.01) reduced pelvic sensitivity in NGF-OE mice but was without effect in littermate WT mice. Blockade of urinary bladder TRPV4 or intravesical infusion of brefeldin A significantly (P ≤ 0.01) reduced (2-fold) luminal ATP release from the urinary bladder in NGF-OE and littermate WT mice. The results of the present study suggest that TRPV4 contributes to luminal ATP release from the urinary bladder and increased voiding frequency and pelvic sensitivity in NGF-OE mice.


Assuntos
Trifosfato de Adenosina/urina , Morfolinas/farmacologia , Fator de Crescimento Neural/biossíntese , Pelve , Pirróis/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Micção/efeitos dos fármacos , Urotélio/metabolismo , Animais , Brefeldina A/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator de Crescimento Neural/genética , Estimulação Física , Inibidores da Síntese de Proteínas/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/fisiopatologia , Urotélio/efeitos dos fármacos
16.
Transpl Infect Dis ; 21(6): e13185, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31571390

RESUMO

We present a patient with virus-associated hemorrhagic cystitis who underwent kidney and allogenic hematopoietic stem cell transplantations (allo-HSCT). Six months post-allo-HSCT, adenovirus hemorrhagic cystitis occurred, which has been in remission after a single dose of intravesical cidofovir. This might cause prolonged neutropenia and nephrotoxicity, suggesting cidofovir absorption in the blood.


Assuntos
Cidofovir/efeitos adversos , Cistite/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hematúria/tratamento farmacológico , Transplante de Rim/efeitos adversos , Neutropenia/induzido quimicamente , Administração Intravesical , Aloenxertos/efeitos dos fármacos , Aloenxertos/fisiopatologia , Cidofovir/administração & dosagem , Cidofovir/farmacocinética , Cistite/complicações , Cistite/urina , Cistite/virologia , Hematúria/urina , Hematúria/virologia , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Distribuição Tecidual , Transplante Homólogo/efeitos adversos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/virologia
17.
PLoS One ; 14(8): e0220788, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31461445

RESUMO

INTRODUCTION: Current treatments for overactive bladder (OAB) are often discontinued due to side effects or lack of efficacy. The goal of this study was to determine if combining a phosphodiesterase type 4 inhibitor (PDE4i); with a type 5 inhibitor (PDE5i); would have a beneficial effect on OAB symptoms and if a reduced dose of PDE4i in combination with PDE5i could also provide a beneficial effect in OAB. We hypothesized that PDE5i and PDE4i combination treatment could be utilized to reduce non-voiding contractions and smooth muscle disruption in a rat model of OAB. METHODS: Fifty-eight age-matched Sprague-Dawley rats underwent PBOO and daily gavage with PDE4i alone (roflumilast; 1mg/kg), PDE5i alone (tadalafil;10mg/kg), high dose combination (PDE4i 1mg/kg, PDE5i 10mg/kg), low dose combination (PDE4i 0.2mg/kg, PDE5i 10mg/kg), or vehicle for 28 days. Fourteen animals underwent sham PBOO with vehicle. Rats underwent conscious and anesthetized cystometry 28 days after PBOO and were euthanized for qualitative bladder histology. One-way ANOVA on ranks with a Dunn's post hoc test was used to indicate statistically significant differences between groups (p<0.05). RESULTS: Bladder & urethral weight was significantly increased after PBOO with vehicle, PDE4i alone, and PDE5i alone, but not with either combination treatment. Frequency of non-voiding contractions during both conscious and anesthetized cystometry increased significantly after PBOO with vehicle, but not after PDE4i or high dose combination treatments compared to sham PBOO. Threshold pressure for voiding was significantly decreased with high dose combination compared to vehicle. PBOO treated with PDE4i alone or high dose combination showed less bladder smooth muscle fibrosis than vehicle, PDE5i alone, or low dose combination treatments. CONCLUSION: A PDE4i and PDE5i combination treatment has potential benefit in reducing OAB symptoms, but future research is needed.


Assuntos
Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Animais , Quimioterapia Combinada , Feminino , Contração Muscular/efeitos dos fármacos , Ratos Sprague-Dawley , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/fisiopatologia , Micção/efeitos dos fármacos
18.
Eur J Pharm Biopharm ; 143: 24-34, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31419584

RESUMO

Low permeability of the urinary bladder epithelium, poor retention of the chemotherapeutic agents due to dilution and periodic urine voiding as well as intermittent catheterisations are the major limitations of intravesical drug delivery used in the treatment of bladder cancer. In this work, maleimide-functionalised poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG-Mal) nanoparticles were developed. Their physicochemical characteristics, including morphology, architecture and molecular parameters have been investigated by means of dynamic light scattering, transmission electron microscopy and small-angle neutron scattering techniques. It was established that the size of nanoparticles was dependent on the solvent used in their preparation and molecular weight of PEG, for example, 105 ±â€¯1 nm and 68 ±â€¯1 nm particles were formed from PLGA20K-PEG5K in dimethyl sulfoxide and acetone, respectively. PLGA-PEG-Mal nanoparticles were explored as mucoadhesive formulations for drug delivery to the urinary bladder. The retention of fluorescein-loaded nanoparticles on freshly excised lamb bladder mucosa in vitro was evaluated and assessed using a flow-through fluorescence technique and Wash Out50 (WO50) quantitative method. PLGA-PEG-Mal nanoparticles (NPs) exhibited greater retention on urinary bladder mucosa (WO50 = 15 mL) compared to maleimide-free NPs (WO50 = 5 mL). The assessment of the biocompatibility of PEG-Mal using the slug mucosal irritation test revealed that these materials are non-irritant to mucosal surfaces.


Assuntos
Portadores de Fármacos/química , Maleimidas/administração & dosagem , Maleimidas/química , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Animais , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Peso Molecular , Membrana Mucosa/metabolismo , Tamanho da Partícula , Ovinos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo
19.
Radiat Oncol ; 14(1): 149, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429773

RESUMO

BACKGROUND: The present prospective study evaluated the safety and efficacy of the rectum following KUSHEN Ningjiaos in cervical cancer. We compared rectal wall changes during brachytherapy with or without KUSHEN Ningjiaos in cervical cancer patients and analyzed the difference in spatial dose distribution, including whole rectum-wall (R-w), anterior rectum-wall (R-a) and posterior rectum-wall (R-p). METHODS AND MATERIALS: One hundred cervical cancer patients with and without KUSHEN Ningjiaos were treated with brachytherapy (600 cGy). The whole R-w was divided into two areas of R-a and R-p, and R-w dose surface map were constructed. The volume of each R-w was compared in patients pre- and post-KUSHEN Ningjiaos. RESULTS: When the pre- vs. post-KUSHEN groups were compared the volume of R-w increased. In the post-KUSHEN group, a significantly higher proportion of the D2cc of VR-w and VR-a compared with the pre-KUSHEN group showed that the D2ccmean increased from 532.45 cGy to 564.7 cGy and 533.51 cGy to 565.26 cGy, respectively; however, results demonstrated a decrease in the D2ccmean of R-p from 260.5 cGy to 240.0868 cGy (P < 0.05). The insertion of KUSHEN Ningjiaos resulted in a reduction of the relative volume of R-p exposed to high doses, and regressive analysis showed that the DR-p-max correlated most strongly with VR-w and D2ccR-p (P < 0.01 and P < 0.05, respectively). CONCLUSION: The insertion of KUSHEN Ningjiaos can protect the rectum. KUSHEN Ningjiaos appears to be safe and well tolerated; therefore, we believe that there will be fewer adverse events after brachytherapy for patients. TRIAL REGISTRATION: A multi-center, prospective clinical trial for KUSHEN Ningjiaos was inserted into rectum to reduce the rate of radiation proctitis in three-dimensional brachytherapy of cervical cancer. ChiCTR1900021631 . 2 Mar 2019-Retrospectively registered.


Assuntos
Braquiterapia/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Proctite/prevenção & controle , Lesões por Radiação/prevenção & controle , Reto/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Neoplasias do Colo do Útero/radioterapia , Feminino , Humanos , Proctite/etiologia , Prognóstico , Estudos Prospectivos , Lesões por Radiação/etiologia , Dosagem Radioterapêutica , Reto/efeitos da radiação , Estudos Retrospectivos , Bexiga Urinária/efeitos da radiação , Neoplasias do Colo do Útero/patologia
20.
Strahlenther Onkol ; 195(10): 934-939, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31363801

RESUMO

PURPOSE: The urinary bladder is one major organ at risk in radiotherapy of pelvic malignancies. The radiation response manifests in early and chronic changes in bladder function. These are based on inflammatory effects and changes in urothelial cell function and proliferation. This study evaluates the effect of bortezomib as an anti-proliferative and anti-inflammatory compound in an established mouse bladder model. The early radiation-induced bladder dysfunction in the mouse occurs in two phases during the first month after irradiation (phase I: day 0-15, phase II: days 16-30). MATERIALS AND METHODS: Daily bortezomib injections (0.02 mg/ml, subcutaneously) were administered between days 0-15 or 15-30 in separate groups. Single graded radiation doses were administered in five dose groups. Cystometry was carried out before (individual control) and during the first month after irradiation. When bladder capacity was decreased by ≥50%, mice were considered as responders. Statistical analysis was performed by the SPSS software version 24. RESULTS: Daily bortezomib injections between days 0-15 resulted in a significant decrease in responders for phase I. There was no significant effect with daily bortezomib injections between days 16-30. CONCLUSION: Two separate waves of acute radiation-induced urinary bladder dysfunction have distinct mechanisms that need further biological studies.


Assuntos
Bortezomib/farmacologia , Lesões Experimentais por Radiação/tratamento farmacológico , Bexiga Urinária/efeitos da radiação , Animais , Relação Dose-Resposta à Radiação , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C3H , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/efeitos da radiação , Órgãos em Risco/efeitos da radiação , Bexiga Urinária/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos , Urodinâmica/efeitos da radiação
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