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1.
Biomed Chromatogr ; 34(2): e4744, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31725908

RESUMO

We proposed a biochemometrics strategy for tracing diuretic components of herbs based on quantitative determination and pharmacological evaluation. First, a sensitive and robust liquid chromatography coupled with tandem mass spectrometry approach was established for simultaneous quantification of six major triterpenoids in crude and salt-processed Alisma orientale. The separation of triterpenoids was achieved on a BEH C18 column with a mobile phase consisting of acetonitrile and water spiked with 0.1% formic acid. Six major triterpenoids were detected by multiple reaction monitoring in the negative ion mode. Glycyrrhetinic acid was used as the internal standard. The approach showed good linearity. Intra- and inter-day precisions were all within 2.9%. The recovery rates of each triterpenoid ranged from 97.9% to 103.2%. The approach was then successfully employed for quantitative analysis of six triterpenoids in ten batches of crude and salt-processed A. orientale. Second, the diuretic effects of crude and salt-processed A. orientale were evaluated in mice. Third, principal component analysis and canonical correlation analysis were used to uncover the relationship between the contents of six major triterpenoids and the diuretic effect of different crude and salt-processed samples. Alisol B, alisol F, and alisol A have a close positive correlation with the diuretic effect.


Assuntos
Alisma/química , Diuréticos , Extratos Vegetais/química , Animais , Cromatografia Líquida , Diuréticos/química , Diuréticos/farmacologia , Diuréticos/urina , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Triterpenos/química , Triterpenos/farmacologia , Triterpenos/urina , Micção/efeitos dos fármacos
2.
Med Sci Monit ; 25: 6782-6787, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31498783

RESUMO

BACKGROUND This study aimed to investigate effects of intra-operative administration with dexmedetomidine (Dex) on hemodynamics and renal function in patients with malignant obstructive jaundice. MATERIAL AND METHODS Our randomized, double-blinded, placebo-controlled study was conducted among 40 patients with malignant obstructive jaundice between August 2009 and March 2011 in The Affiliated Hospital of Inner Mongolia Medical University. The 40 patients were randomly divided into 2 groups: the Dex group (receiving Dex 0.5 µg/kg 10-minutes before induction and then a 0.5 µg/kg/hour maintenance infusion until end of operation 30 minutes) and the Control group (receiving normal saline of same amount and at same rate). The adverse events, including incidence of cardiovascular complications and nausea and vomiting, and length of hospital stay were determined. The level of cystatin C (CysC), retinol-binding protein (RBP), creatinine (Scr), and blood urea nitrogen (BUN) were also evaluated. RESULTS Dexmedetomidine administration significantly decreased heart rate (HR) and stroke volume variation (SVV) and significantly increased capital venous pressure (CVP) and mean arterial pressure (MAP) values compared to that in the Control group (P<0.05). Dexmedetomidine administration significantly upregulated urine volume and significantly downregulated atropine levels compared to the Control group (P<0.05). Dexmedetomidine administration significantly improved renal functions, by modulating CysC, RBP, Scr and BUN levels compared to the Control group (P<0.05). Dexmedetomidine administration demonstrated no additional side-effects. Dexmedetomidine administration significantly shortened length of hospitalization in the Dex group compared to the Control group (P<0.05). CONCLUSIONS Dexmedetomidine plays preventive effects on renal dysfunction and hemodynamic stability in malignant obstructive jaundice patients during peri-operative period.


Assuntos
Dexmedetomidina/uso terapêutico , Hemodinâmica , Icterícia Obstrutiva/fisiopatologia , Icterícia Obstrutiva/cirurgia , Rim/fisiopatologia , Atropina/urina , Transfusão de Sangue , Dexmedetomidina/administração & dosagem , Dexmedetomidina/farmacologia , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Micção/efeitos dos fármacos
3.
Urology ; 133: 72-77, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31465791

RESUMO

OBJECTIVE: To assess whether intraurethral anesthesia decreased voiding efficiency (VE), reduced catheterization pain, and impacted urodynamic parameters in healthy adult females. METHODS: In a randomized, double-blind, placebo-controlled trial, participants received two 5 mL doses of either intraurethral aqueous gel or 4% lidocaine gel. The primary outcome was VE during randomized condition uroflow, defined as voided volume/(voided volume + residual volume). The secondary outcomes were pain during catheterization and to confirm previously reported pressure-flow changes. A sample size of 10 per group was planned to detect a clinically significant decrease in VE with a power (1-ß) of 0.99. RESULTS: From October to December 2018, 23 women were screened and 18 were randomized to receive placebo (n = 10) or lidocaine (n = 8). Baseline uroflow VE was similar between the placebo and lidocaine groups (88 ± 6.6% vs 91 ± 5.8%, P = .33). After study drug administration, the changes in VE (post-pre) were similar between placebo and lidocaine groups (-5.4 ± 14% vs 1.7 ± 6.4%, P = .21). Visual analog scores were similar following catheterizations (26.7 ± 12.8 mm vs 36.9 ± 26.8 mm, P = .34). The lidocaine group exhibited lower average flow rates per voided volume (0.04 ± 0.02 s-1 vs 0.02 ± 0.01 s-1, P = .04). CONCLUSION: Intraurethral administration of 4% lidocaine did not decrease VE compared to placebo and did not change pain scores following catheterization. In the lidocaine group, the average flow rate per voided volume was lower. The decrease in flow rate after local anesthesia to the urethra may indicate that urethral sensory feedback contributes to voiding in human micturition.


Assuntos
Anestésicos Locais/administração & dosagem , Lidocaína/administração & dosagem , Dor/prevenção & controle , Cateterismo Urinário , Micção/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos , Administração Tópica , Adulto , Anestésicos Locais/farmacologia , Método Duplo-Cego , Feminino , Humanos , Lidocaína/farmacologia , Uretra , Cateterismo Urinário/efeitos adversos
4.
Neuropeptides ; 77: 101956, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31324387

RESUMO

The effects of the neurokinin NK2 receptor agonist [Lys5,MeLeu9,Nle10]-NKA(4-10) (LMN-NKA) on bladder and colorectal function were examined in minipigs. In anesthetized animals, subcutaneous (SC) administration of 30-100 µg/kg increased peak bladder and colorectal pressures. Increases in bladder and colorectal pressure were inhibited by a 15 min pretreatment with the NK2 receptor antagonist GR 159897 (1 mg/kg intravenously (IV)). Bladder and colorectal pressures were also increased after IV (0.3 µg/kg), intranasal (IN; 100 µg/kg) and sublingual administration (SL; 5 mg/kg). There was a nonsignificant trend for hypotension (16 or 12% decrease in mean arterial pressure) after 100 µg/kg SC and 0.3 µg/kg IV, respectively, but not after 100 µg/kg IN or 5 mg/kg SL. In conscious minipigs, 30-300 µg/kg SC caused a dose-related increase in defecation that was accompanied by emesis in 38% of subjects receiving 300 µg/kg. Urination was increased after 100 µg/kg SC but not lower or higher doses. The peak plasma exposure (Cmax) after 100 µg/kg SC was 123 ng/mL, and area under the curve (AUC) was 1790 min * ng/mL. Defecation response rates (~82%) were maintained after SC administration of LMN-NKA (30 µg/kg) given 3 times daily over 5 consecutive days. Defecation rates were higher after a single dose of 100 µg/kg IN compared with vehicle, but this did not reach significance. After 7-10 mg/kg SL, 83% of animals urinated and defecated, and none had emesis. The data support the feasibility of developing a convenient and well-tolerated route of administration of LMN-NKA for human use. Minipigs may be a suitable species for toxicology studies with LMN-NKA due to the relatively low rate of emesis in this species.


Assuntos
Colo/efeitos dos fármacos , Defecação/efeitos dos fármacos , Receptores da Neurocinina-2/agonistas , Reto/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Animais , Indóis/farmacologia , Piperidinas/farmacologia , Pressão , Receptores da Neurocinina-2/antagonistas & inibidores , Suínos , Porco Miniatura
5.
Int Urol Nephrol ; 51(9): 1507-1515, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31289981

RESUMO

PURPOSE: To compare hydrogen sulfide (H2S)-induced relaxation on the bladder between normotensive and spontaneously hypertensive rat (SHR), we evaluated the effects of H2S donors (GYY4137 and NaHS) on the micturition reflex and on the contractility of bladder tissues. We also investigated the content of H2S and the expression levels of enzymes related to H2S biosynthesis [cystathionine ß-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (MPST), and cysteine aminotransferase (CAT)] in the bladder. METHODS: Eighteen-week-old male normotensive Wistar rats and SHRs were used. Under urethane anesthesia, the effects of intravesically instilled GYY4137 (10-8, 10-7 and 10-6 M) on the micturition reflex were evaluated by cystometry. The effects of NaHS (1 × 10-8-3 × 10-4 M) were evaluated on carbachol (10-5 M)-induced pre-contracted bladder strips. Tissue H2S content was measured by the methylene blue method. The expression levels of these enzymes were investigated by Western blot. RESULTS: GYY4137 significantly prolonged intercontraction intervals in Wistar rats, but not in SHRs. NaHS-induced relaxation on pre-contracted bladder strips was significantly attenuated in SHRs compared with Wistar rats. The H2S content in the bladder of SHRs was significantly higher than that of Wistar rats. CBS, MPST and CAT were detected in the bladder of Wistar rats and SHRs. The expression levels of MPST in the SHR bladder were significantly higher than those in the Wistar rat bladder. CONCLUSION: H2S-induced bladder relaxation in SHRs is impaired, thereby resulting in a compensatory increase of the H2S content in the SHR bladder.


Assuntos
Sulfeto de Hidrogênio/farmacologia , Hipertensão/fisiopatologia , Relaxamento Muscular/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologia , Animais , Masculino , Ratos Endogâmicos SHR , Ratos Wistar , Micção/efeitos dos fármacos
7.
J Med Food ; 22(6): 551-559, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017505

RESUMO

Majority of men are affected by symptomatic benign prostatic hyperplasia (BPH) from a certain age. Botanical extracts are frequently used in the early management of the symptoms. In a single-arm, mono-center pilot study, the effects of a proprietary oil-free hydroethanolic pumpkin seed extract on the symptoms of BPH were investigated. A total of 60 men (62.3 years [95% confidence interval (CI): 60.3-64.3 years]) with a total International Prostate Symptom Score (IPSS) of 14.8 (95% CI: 13.5-16.1) participated between January 2017 and October 2017 in the study by ingesting the oil-free hydroethanolic pumpkin seed extract once daily before going to bed during 3 months. Change in IPSS within treatment period was assessed. Frequency of nocturia was recorded by bladder diary, and postvoid residual urine volume was determined through ultrasound. Between baseline and after 12 weeks of supplementation, a significant symptom reduction of an average 30.1% (95% CI: 23.1-37.1) was seen for the total IPSS. Symptom alleviation had a high impact on quality of life (P < .0001) and was significant after 8 and 12 weeks of intervention (P < .001). Nocturia significantly decreased over time (P < .0001), as confirmed by IPSS questionnaire and bladder diary. Postvoid residual urine volume was significantly reduced at the end of intervention (baseline: 83.67 mL [95% CI: 58.02-109.3]; after 12 weeks: 63.11 mL [95% CI: 45.37-80.85]; P = .0394). These results indicate that the oil-free hydroethanolic pumpkin seed extract seems to be a very well tolerable, appropriate plant extract to support health benefits in a collective suffering from BPH related symptoms without the need of medical treatment.


Assuntos
Cucurbita/química , Extratos Vegetais/administração & dosagem , Hiperplasia Prostática/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/patologia , Hiperplasia Prostática/fisiopatologia , Qualidade de Vida , Sementes/química , Micção/efeitos dos fármacos
8.
Heart Vessels ; 34(10): 1684-1691, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30993439

RESUMO

Conventional diuretic therapy for low-flow (LF) severe aortic stenosis (SAS) often has an inadequate effect or causes hemodynamic instability. Tolvaptan is used for acute heart failure in addition to conventional diuretics, and it does not cause intravascular dehydration. This study aimed to retrospectively investigate the safety and efficacy of tolvaptan in the acute phase in 56 consecutive patients with SAS and compared LF-SAS with normal-flow (NF) SAS. The primary endpoints were adverse clinical events (death, worsening heart failure, worsening renal failure, fatal arrhythmia, cardiogenic or hypovolemic shock, and use of inotropic agents) and the volume of urine within 48 h of tolvaptan administration. Among 56 patients, 16 had LF-SAS (29%), and 40 had NF-SAS (71%). Severe adverse clinical events were not observed 48 h after tolvaptan administration. In both groups, the urine volume significantly increased after tolvaptan administration in comparison to 24 h before tolvaptan administration (both, p < 0.01). There were no changes in the urine volume during the initial 24 and 48 h. In the LF-SAS group, tolvaptan resulted in a significant decrease in fluid balance during the initial 24 and 48 h compared to 24 h before tolvaptan administration (p < 0.05). Adding tolvaptan to conventional treatment is safe and effective without renal dysfunction and hypotension in patients with SAS, including those with LF.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Estenose da Valva Aórtica/complicações , Insuficiência Cardíaca/tratamento farmacológico , Tolvaptan/uso terapêutico , Micção/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Feminino , Taxa de Filtração Glomerular , Insuficiência Cardíaca/etiologia , Humanos , Japão , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
9.
J Urol ; 202(3): 564-573, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31009289

RESUMO

PURPOSE: We evaluated the efficacy and safety of a combination of 2 mg tolterodine and 9 mg pilocarpine, vs tolterodine monotherapy in patients with overactive bladder. MATERIALS AND METHODS: We enrolled patients with overactive bladder symptoms in a multicenter, randomized, double-blind, parallel, active control study. Patients were randomized to the combination or 2 mg tolterodine twice daily for 12 weeks. After the double-blind period finished all patients were started on the combination for 12 weeks. Study co-primary end points were the change from baseline in the mean number of daily micturitions and cumulative incidence of dry mouth at the end of 12 weeks. Secondary end points were other overactive bladder symptoms, the total xerostomia inventory score and results of a visual analogue scale for dry mouth at the end of 12 and 24 weeks. RESULTS: The mean change in the number of daily micturitions from baseline to 12 weeks was -1.49 and -1.74 in the combination and tolterodine monotherapy groups, respectively. The mean difference was -0.26 (95% CI -0.79-0.27), confirming noninferiority. At 12 weeks the incidence of dry mouth was lower in the combination group than in the tolterodine monotherapy group (30.0% vs 42.9%, p = 0.009). All secondary and other efficacy outcomes related to overactive bladder symptoms improved in each group with no significant differences between the groups at 12 weeks. Changes from baseline in the total xerostomia inventory score and the visual analogue scale for dry mouth were significantly lower in the combination group than in the tolterodine monotherapy group. CONCLUSIONS: Tolterodine and pilocarpine alleviated dry mouth in patients with overactive bladder while maintaining anticholinergic efficacy similar to that of tolterodine.


Assuntos
Antagonistas Colinérgicos/administração & dosagem , Agonistas Muscarínicos/administração & dosagem , Pilocarpina/administração & dosagem , Tartarato de Tolterodina/administração & dosagem , Bexiga Urinária Hiperativa/tratamento farmacológico , Xerostomia/epidemiologia , Idoso , Antagonistas Colinérgicos/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Agonistas Muscarínicos/efeitos adversos , Pilocarpina/efeitos adversos , Tartarato de Tolterodina/efeitos adversos , Resultado do Tratamento , Micção/efeitos dos fármacos , Xerostomia/induzido quimicamente , Xerostomia/prevenção & controle
10.
Urol Int ; 102(4): 468-475, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30889607

RESUMO

BACKGROUND: A medical device containing xyloglucan-gelose-hibiscus-propolis (referred to hereafter as xyloglucan + gelose) acts as a mucosal barrier protector and urinary acidifier. The safety and efficacy of this device were investigated as adjuvant therapy to first-line antimicrobials for treatment of uncomplicated urinary tract infection (UTI) in adults. PATIENTS AND METHODS: In this multicentre, randomised, parallel group, double-blind, phase IV study, xyloglucan + gelose (n = 20) or placebo (n = 20) were administered orally in combination with an antimicrobial agent (e.g., ciprofloxacin) for 5 days, then alone for 5 days, then beginning on Day 30 of the study for 15 days per month for 2 months. RESULTS: Frequency of adverse events (AEs) was 5 and 45% in the xyloglucan + gelose and placebo groups respectively. All AEs were unrelated to study products. Xyloglucan + gelose reduced uroculture positivity (defined as a bacterial count ≥103 CFU/mL) from 100% of patients at baseline to 0% at Day 11, with recurrence in 3 patients (15%) by Day 76. Corresponding results with placebo were 100% uroculture positive patients at baseline reduced to 45% at Day 11, with recurrence in 14 patients (70%) by Day 76. Xyloglucan + gelose significantly reduced the frequency of urinary incontinence and urgency of micturition compared with placebo (both p < 0.05), with symptom resolution in all patients by Day 90. CONCLUSIONS: The xyloglucan + gelose medical device was safe, well tolerated, and it reduced bacteriological and symptomatic parameters in adults with uncomplicated UTI.


Assuntos
Anti-Infecciosos/administração & dosagem , Quimioterapia Adjuvante/métodos , Glucanos/administração & dosagem , Infecções Urinárias/tratamento farmacológico , Xilanos/administração & dosagem , Adolescente , Adulto , Idoso , Ciprofloxacino/administração & dosagem , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/efeitos dos fármacos , Segurança do Paciente , Recidiva , Resultado do Tratamento , Micção/efeitos dos fármacos , Adulto Jovem
11.
J Med Food ; 22(5): 529-537, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864860

RESUMO

Prostatism and erectile dysfunction (ED) are highly prevalent and closely comorbid. Prescription treatments are limitingly expensive but robust in mechanisms of action (MoA). Nutritional supplements (NS) are low-cost but inadequately supported by evidence. Do any NS use robust MoA? Could their efficacy be amplified via dosing, concentration of active principles, and/or use in combination? The goal is to develop an effective NS for prostatism and ED using the MoA of prescription treatments. Literature reviews were conducted on dietary supplements for prostatism or ED and MoA of relevant drugs. The most promising NS employing these MoA were chosen. A pilot study of a prototype combination was conducted. A protocol was created for an adequate dose-response trial to test the NS combination in men with ED and prostatism. The main measures were response rates, International Prostate Symptom Score, and International Index of Erectile Function. For drugs, the MoAs best proven for prostatism and ED were nitric oxide augmentation, mild androgen inhibition, and anti-inflammatory effects. The following NS best simulate these MoA and are best supported for efficacy; for prostatism: beta sitosterol; for ED: panax ginseng, arginine, and citrulline. Pilot clinical data provided support. A plan for a formal dose-response clinical trial was approved by a central institutional review board. NS using effective MoA might suffice for prostatism and ED. Pilot testing of a combination NS with the best-supported MoA supported further development. A dose-response trial should be conducted using adequate doses of L-citrulline, beta-sitosterol, ginseng, and vitamin D3.


Assuntos
Suplementos Nutricionais/análise , Disfunção Erétil/tratamento farmacológico , Prostatismo/tratamento farmacológico , Arginina/administração & dosagem , Colecalciferol/administração & dosagem , Citrulina/administração & dosagem , Ensaios Clínicos como Assunto , Disfunção Erétil/fisiopatologia , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Panax/química , Projetos Piloto , Extratos Vegetais/administração & dosagem , Prostatismo/fisiopatologia , Sitosteroides/administração & dosagem , Micção/efeitos dos fármacos
12.
Urology ; 129: 172-179, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30880074

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of Serenoa repens among patients with benign prostatic hyperplasia (lower urinary tract symptoms/benign prostatic hyperplasia [LUTS/BPH]) in China. METHODS: We conducted a double blind, placebo-controlled study of 354 patients with LUTS/BPH from 19 institutions, to evaluate the efficacy and safety of Serenoa repens. Participants were randomly assigned (1:1) into the Serenoa repens extract (320 mg) or placebo groups for 24 weeks. Primary efficacy parameters were changes in International Prostate Symptom Score and peak urinary flow from baseline to each assessment. Secondary efficacy parameters included improvement of storage symptom and voiding symptom scores, prostate volume, urinary frequency, and total prostate-specific antigen level. Other parameters assessed were quality of life score, a four-item male sexual function questionnaire score, and International Index of Erectile Function score across the consecutive double-blind visits. RESULTS: Statistically significant improvement in the peak urinary flow, International Prostate Symptom Score, scores of storage symptoms and voiding symptoms, quality of life score, four-item male sexual function questionnaire score, and International Index of Erectile Function score were observed in the Serenoa repens extract group compared with those in the placebo group (P <.05). Two (1.18%) of 169 patients in the placebo group and 3 (1.89) of 159 patients in the Serenoa repens extract group experienced 1 or more adverse events. CONCLUSION: The Serenoa repens extract was effective, safe, well-tolerated, and clinically and statistically superior to placebo in the target LUTS/BPH population.


Assuntos
Ereção Peniana/fisiologia , Extratos Vegetais/administração & dosagem , Hiperplasia Prostática/tratamento farmacológico , Micção/fisiologia , Idoso , China/epidemiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Ereção Peniana/efeitos dos fármacos , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/epidemiologia , Serenoa , Resultado do Tratamento , Micção/efeitos dos fármacos , Agentes Urológicos/administração & dosagem
13.
Eur J Pharmacol ; 853: 11-17, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30853531

RESUMO

Bladder dysfunctions associated with benign prostatic hyperplasia are not sufficiently alleviated by current pharmacotherapies. Lysophosphatidic acid (LPA) is a phospholipid with diverse biological effects. LPA modulates prostate and urethral contraction via the type 1 LPA (LPA1) receptor, suggesting the potential of the LPA1 receptor as a therapeutic target. However, the role of LPA and the LPA1 receptor in bladder function has not been studied in vivo. We investigated the effects of LPA and the novel LPA1 receptor antagonist ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamido]methyl}- 1,3-thiazole-4-carbonyl)- 3-ethyl-2,2-dioxo-2λ6-diazathian-1-ide) on the micturition reflex in conscious rats using cystometry. Intravenous infusion of LPA decreased the micturition interval and threshold pressure with no apparent changes in baseline pressure or maximum intravesical pressure. ASP6432 inhibited the LPA-induced decrease in MI. In contrast, ASP6432 had no effect on the LPA-induced decrease in threshold pressure. Similarly, ASP6432 had no effect on either baseline pressure or maximum intravesical pressure. We also evaluated the effect of ASP6432 on the urinary frequency induced by the nitric oxide synthase inhibitor L-Nω-nitro arginine methyl ester (L-NAME). Intravenous L-NAME administration decreased the micturition interval. ASP6432 dose-dependently reversed the L-NAME-induced decrease in micturition interval. Our findings demonstrate for the first time that LPA causes bladder overactivity in rats. ASP6432 inhibited the LPA- and L-NAME-induced decrease in micturition interval, suggesting a significant role for the LPA1 receptor in regulating the functional capacity of the bladder. Our results also suggest the potential of ASP6432 as a novel therapy for the treatment of bladder dysfunction associated with lower urinary tract diseases.


Assuntos
Estado de Consciência , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Tiazóis/farmacologia , Micção/efeitos dos fármacos , Animais , Benzamidas , Relação Dose-Resposta a Droga , Feminino , Ratos , Ratos Sprague-Dawley , Bexiga Urinária Hiperativa/fisiopatologia
14.
Acta Cir Bras ; 34(2): e201900205, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30843938

RESUMO

PURPOSE: To evaluate the impact of the combination of BRL 37344 and tadalafil (TDF) on the reduction of overactive bladder (OB) symptoms. METHODS: Thirty mice were randomized into 5 groups (G) of 6 animals each. L-NAME was used to induce DO. G1: Control; G2: L-NAME; G3: L-NAME + TDF; G4: L-NAME + BRL 37344; G5: L-NAME + TDF + BRL 37344. After 30 days of treatment, the animals were submitted to cystometry to evaluate non-voiding contractions (NVC), threshold pressure (TP), baseline pressure (BP), frequency of micturition (FM) and threshold volume (TV). Differences between the groups were analyzed with ANOVA followed by the Tukey test. RESULTS: NVC increased in G2 (4.33±2.58) in relation to G1 (1.50±0.55). NVC decreased in G3 (2.00±1.10), G4 (1.50±1.52) and G5 (2.00±1.26) compared to G2 (p<0.05). FM decreased in G3 (0.97±0.71), G4 (0.92±0.38) and G5 (1.05±0.44) compared to G2 (p<0.05). However, the combination of TDF and BRL37344 was not more effective at increasing NVC and improving FM than either drug alone. The five groups did not differ significantly with regard to TV. CONCLUSION: The combination of BRL 37344 and TDF produced no measurable additive effect on reduction of OB symptoms.


Assuntos
Etanolaminas/administração & dosagem , Tadalafila/administração & dosagem , Bexiga Urinária Hiperativa/tratamento farmacológico , Agentes Urológicos/administração & dosagem , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Masculino , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Distribuição Aleatória , Micção/efeitos dos fármacos
15.
Gynecol Obstet Invest ; 84(5): 472-476, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30897579

RESUMO

AIMS: To determine if findings at urodynamics prognosticate improvements in overactive bladder symptoms among women receiving mirabegron treatment. METHODS: Before treatment, women completed a urodynamic investigation, a micturition diary and the Urinary Distress Inventory (UDI) with the irritative subscale UDIOAB. After 6 months mirabegron treatment, patients were clinically evaluated and completed the UDI. Associations were tested using regression analyses and nonparametric statistics. RESULTS: Testing urodynamic variables for association with treatment effects in multiple linear regression analysis showed that lower volumes at first sensation to void significantly correlated with greater improvement in the UDIOAB after 6 months mirabegron treatment (B = 0.026, 95% CI 0.002-0.049, p = 0.034). Improvements in UDIOAB showed no correlation with presence of nocturia (p = 0.65), previous use of anticholinergics (p = 1), menopausal status (p = 1), any detrusor overactivity during filling (p = 1), phasic detrusor contractions during filling (p = 1), or detrusor overactivity during inhibition (p = 1). CONCLUSIONS: We found limited support for clinically relevant associations between findings at urodynamics and subsequent treatment outcomes for mirabegron in routine clinical practice. Our findings do not support the role of these investigations as predictors of outcomes in patients with overactive bladder symptoms.


Assuntos
Acetanilidas/uso terapêutico , Técnicas de Diagnóstico Urológico/estatística & dados numéricos , Tiazóis/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Urodinâmica/efeitos dos fármacos , Agentes Urológicos/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Resultado do Tratamento , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos
16.
Horm Behav ; 109: 10-17, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30708030

RESUMO

The behavioral and endocrine activation of sexual behaviors exhibited by male goats, especially self-enurination (SE), is poorly understood. In the first experiment, to assess the influence of socio-sexual context on SE in bucks, the effects of distance from does, the presence of estrous versus non-estrous does and the presence of another buck on SE and courtship frequencies of intact male goats (bucks; n = 12) were tested using a unique behavior test apparatus. For experiments 2 and 3, to test the relative contributions of sex steroid hormones and socio-sexual context on SE, castrated male goats (wethers; n = 20) were randomly divided into five groups and injected for seven weeks with one of the following: 25 mg testosterone propionate (T), 25 mg dihydrotestosterone propionate (DHT), 100 µg estradiol benzoate (E), 100 µg E and 25 mg DHT (E + DHT), or oil (CON). The effects of these treatments on frequency of SE and courtship were assessed using the behavior test apparatus (social scenarios) adapted from the findings in experiment 1. In one scenario, a wether could observe (from 4.6 m) a buck and estrous female (doe) together in a wire mesh holding pen. In a different scenario, the wether could observe (from the same distance) a buck that could only court the estrous doe through a wire mesh barrier. Finally, to observe the effects of steroid treatment on mounting and ejaculation frequencies, in addition to SE and courtship, each wether was placed in a pen with an estrous doe for 10 min. After a five-week, treatment-washout period, wethers were randomly assigned to different treatment groups and retested. In experiment 1, bucks that were distanced from females displayed more SEs than those with fence-line contact, while those with fence-line contact displayed more bouts of courtship (P < 0.05). In experiments 2 and 3, courtship frequencies displayed in all three scenarios were greater than CON only for groups exposed to estrogen directly or via aromatization (T, E + DHT, E; P < 0.05). Frequencies of SE exhibited during behavior tests in which the wether was watching were greater than CON only for androgen-treated groups (T, E + DHT, DHT; P < 0.05). In contrast, when the wether was free to interact with the female, only the DHT group displayed SE at a higher frequency than CON (P < 0.05). Treatment had no effect on mount frequencies in this test scenario, however ejaculation frequencies were highest for T and E + DHT (P < 0.05). These studies suggest that the courtship behaviors of the male goat are estrogen-dependent. However, SE appears to be activated by androgens. It was also demonstrated that social context contributes as much to behavior expression as steroid treatment, as in social scenario 2 some sexual behaviors were displayed in similar frequencies across groups, despite differing sex steroid treatments.


Assuntos
Androgênios/farmacologia , Estrogênios/farmacologia , Cabras , Orquiectomia/veterinária , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Corte , Di-Hidrotestosterona/análogos & derivados , Di-Hidrotestosterona/farmacologia , Ejaculação/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Cabras/fisiologia , Masculino , Comportamento Sexual Animal/fisiologia , Comportamento Social , Testosterona/farmacologia , Micção/efeitos dos fármacos
17.
BJU Int ; 124(1): 163-173, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30636087

RESUMO

OBJECTIVES: To investigate the influence of low-dose sildenafil, a phosphodiesterase type 5 inhibitor (PDE5-I), on the function of the mouse lower urinary tract (LUT). MATERIALS AND METHODS: Adult male mice were decerebrated and arterially perfused with a carbogenated Ringer's solution to establish the decerebrate arterially perfused mouse (DAPM). To allow distinction between central neural and peripheral actions of sildenafil, experiments were conducted in both the DAPM and in a 'pithed' DAPM, which has no functional brainstem or spinal cord. The action of systemic and intrathecal sildenafil on micturition was assessed in urethane-anaesthetised mice. RESULTS: In the DAPM, systemic perfusion of sildenafil (30 pm) decreased the voiding threshold pressure [to a mean (sem) 84.7 (3.8)% of control] and increased bladder compliance [to a mean (sem) 140.2 (8.3)% of control, an effect replicated in the pithed DAPM]. Sildenafil was without effect on most voiding variables but significantly increased the number of bursts of the external urethral sphincter (EUS) per void in DAPM [to a mean (sem) 130.1 (6.9)% of control at 30 pm] and in urethane-anaesthetised mice [to a mean (sem) 117.5 (5.8)% of control at 14 ng/kg]. Sildenafil (10 and 30 pm) increased pelvic afferent activity during both bladder filling and the isovolumetric phase [to a mean (sem) 205.4 (30.2)% of control at 30 pm]. Intrathecal application of sildenafil (5 µL of either 150 pm or 1.5 nm) did not alter cystometry and EUS-electromyography variables in urethane-anaesthetised mice. CONCLUSIONS: Low-dose sildenafil increases bladder compliance, increases pelvic nerve afferent activity, and augments the bursting activity of the EUS. We propose that the novel actions on afferent traffic and sphincter control may contribute to its beneficial actions to restore storage and voiding efficiency in LUT dysfunction.


Assuntos
Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Uretra/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Vias Aferentes/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Estimulação Elétrica , Masculino , Camundongos , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Inibidores da Fosfodiesterase 5/administração & dosagem , Pressão , Citrato de Sildenafila/administração & dosagem , Bexiga Urinária/fisiologia
18.
Complement Ther Med ; 42: 429-437, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30670279

RESUMO

INTRODUCTION: It is believed that tubulointerstitial inflammation plays a role in the formation of renal scarring secondary to acute pyelonephritis (APN). Vitamin A is an anti-inflammatory agent that is involved in the re-epithelialization of damaged mucosal surfaces. OBJECTIVE: The aim of this study was to evaluate the efficacy of vitamin A supplementation in combination with antibiotics for improving urinary tract infections (UTIs) symptoms and preventing renal scarring in girls with APN. STUDY DESIGN: This randomized, double-blind, placebo-controlled clinical trial was conducted on 90 girls aged 2 to 12 years old between 2015 and 2017. Patients with UTIs and first episode of APN diagnosed based on 99 mTc-DMSA scintigraphy (uptake defect) were assessed for eligibility. Patients were randomly divided into two groups that either received 10 days of oral vitamin A (intervention group) or 10 days of placebo (control group) in addition to antibiotics during the acute phase of infection. The clinical response was considered as the primary outcome [duration (positive days) of UTI symptoms during trial treatment period] and secondary outcomes (no change, improving and or worsening of 99 mTc-DMSA scan results 6 months after treatment from baseline). P < 0.05 was considered to be statistically significant. RESULTS: Seventy-four patients (vitamin A group: 36 patients, placebo: 38 patients) were included in the analysis. The mean age was 5.25 ± 1 year old. Three patients (7.89%) in the placebo group and 2 patients (5.55%) in the vitamin A group had vesicoureteral reflux (VUR) (p = 0.114). Duration of fever (vitamin A group: 1.8 days, placebo: 3.1 days, p = 0.0026), urinary frequency (1.3 days vs. 2.8 days, p = 0.003) and poor feeding (2.3 days vs. 4.2 days, p = 0.005) were significantly lower in the vitamin A group. Following the second 99 mTc-DMSA scan, worsening of lesions was observed among 8 (22.2%) and 17 (44.7%) patients in the vitamin A and placebo groups, respectively (p = 0.003). 63.8% (23 patients) of the vitamin A group and 21% (8 patients) of placebo group showed lesion improving in the photopenic region. (P < 0.0001) There was no evidence of vitamin A intolerance. DISCUSSION: Our results show the efficacy of vitamin A supplementation on reducing renal scarring secondary to APN and on fever, urinary frequency and poor feeding duration in girls with APN. CONCLUSION: Vitamin A supplementation is effective for improving the clinical symptoms of UTI and reducing renal injury and scarring following APN in girls with first APN. However, larger randomized clinical trials (RCTs) with longer follow up are needed to confirm these effects.


Assuntos
Cicatriz/prevenção & controle , Suplementos Nutricionais , Rim/efeitos dos fármacos , Pielonefrite/tratamento farmacológico , Infecções Urinárias/tratamento farmacológico , Vitamina A/uso terapêutico , Vitaminas/uso terapêutico , Doença Aguda , Criança , Pré-Escolar , Cicatriz/etiologia , Método Duplo-Cego , Comportamento Alimentar/efeitos dos fármacos , Feminino , Febre/prevenção & controle , Humanos , Lactente , Rim/patologia , Pielonefrite/complicações , Resultado do Tratamento , Infecções Urinárias/complicações , Micção/efeitos dos fármacos , Vitamina A/farmacologia , Vitaminas/farmacologia
19.
Eur Urol ; 75(2): 274-282, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30661513

RESUMO

BACKGROUND: Antimuscarinics have shown modest efficacy with unwanted side effects in patients with overactive bladder (OAB). Efficacy of vibegron, a new ß3-adrenergic receptor agonist, for OAB is unknown. OBJECTIVE: To evaluate the efficacy of once-daily oral vibegron in OAB patients (primary), and its safety, tolerability, and efficacy when administered alone or concomitantly with tolterodine (secondary). DESIGN, SETTING, AND PARTICIPANTS: International, phase IIb, randomized, double-blind, placebo- and active comparator-controlled, two-part superiority trial (2011-2013) in OAB-wet or OAB-dry patients aged 18-75 yr (NCT01314872). INTERVENTIONS: Part 1: once-daily oral vibegron monotherapy (3 [V3], 15 [V15], 50 [V50], or 100 [V100] mg), tolterodine extended release 4mg (TER4), or placebo for 8 wk, or combination V50/TER4 for 4 wk and then V50 for 4 wk; part 2: V100/TER4, V100, TER4, or placebo for 4 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Average daily micturitions at week 8 of part 1 (primary); urge incontinence episodes, total incontinence episodes, and urgency episodes (secondary). RESULTS AND LIMITATIONS: Overall, 1395 patients were randomized. From baseline to week 8, V50 and V100 significantly decreased average daily micturitions (least square mean difference [95% confidence interval], -0.64 [-1.11, -0.18]; p=0.007 and -0.91 [-1.37, -0.44]; p<0.001, respectively) and the number of urge incontinence episodes (-0.72 [-1.11, -0.33] and -0.71 [-1.10, -0.32], respectively; both p<0.001) versus placebo. All vibegron doses were well tolerated. The incidence of dry mouth was higher with TER4 than with vibegron monotherapy. Results are limited by the relatively short treatment duration. CONCLUSIONS: Once-daily V50 and V100 improved OAB symptoms; vibegron was well tolerated as monotherapy and concomitantly with tolterodine. Further development is warranted. PATIENT SUMMARY: Antimuscarinics, commonly used to treat overactive bladder, produce modest efficacy and unwanted side effects. In this study, a different type of drug (vibegron) was efficacious and safe, alone or with an antimuscarinic (tolterodine).


Assuntos
Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Pirimidinonas/administração & dosagem , Pirrolidinas/administração & dosagem , Tartarato de Tolterodina/administração & dosagem , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Administração Oral , Adolescente , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Adulto , Idoso , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Pirimidinonas/efeitos adversos , Pirrolidinas/efeitos adversos , Recuperação de Função Fisiológica , Fatores de Tempo , Tartarato de Tolterodina/efeitos adversos , Resultado do Tratamento , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/diagnóstico , Bexiga Urinária Hiperativa/fisiopatologia , Micção/efeitos dos fármacos , Adulto Jovem
20.
BJU Int ; 123(4): 718-725, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29781566

RESUMO

OBJECTIVES: To examine the effect of intrathecal (i.t.) serotonin (5-hydroxytryptamine) 5-HT7 agonist administration on voiding function in the urethane-anesthetised rat, and the change in 5-HT7 receptor (5-HT7 R) expression in the lumbosacral cord Onuf's nucleus after spinal cord injury (SCI). MATERIALS AND METHODS: In all, 32 female Sprague-Dawley (SD) rats were equally divided into a spinally intact (SI) group and SCI group (n = 16 each). At 8 weeks after transection, half of the rats underwent continuous cystometry under urethane anaesthesia, and the 5-HT7 R-selective agonist LP44 was given (i.t.). The remaining rats were used for pseudorabies (PRV) retrograde tracing, immunofluorescence, and Western Blot. RESULTS: LP44 administered i.t. had no effect in the SI rats. In SCI rats, LP44 (1-30 µg/kg) induced significant dose-dependent increases in micturition volume, voiding efficiency, number of high-frequency oscillations per micturition; and decreases in residual volume, bladder capacity, peak bladder pressure, threshold pressure and non-voiding contractions. The 5-HT7 R antagonist, SB-269970 (10 µg/kg), partially reversed LP44-induced changes. Using PRV retrograde tracing and immunofluorescence, 5-HT7 Rs were found in the L6-S1 spinal cord Onuf's nucleus in both SI and SCI rats, but the expression was significantly greater in the SCI rats. Western blot showed significantly more 5-HT7 Rs in the ventral L6-S1 spinal cord in SCI rats. CONCLUSION: A 5-HT7 R agonist, given i.t., improved voiding efficiency in urethane-anesthetised SCI rats, and the 5-HT7 R was significantly up-regulated in the lumbosacral cord Onuf's nucleus. If valid for humans, these findings suggest that the 5-HT7 R could be a target for therapeutic interventions.


Assuntos
Receptores de Serotonina/efeitos dos fármacos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Traumatismos da Medula Espinal/fisiopatologia , Micção/efeitos dos fármacos , Animais , Western Blotting , Doença Crônica , Modelos Animais de Doenças , Feminino , Injeções Espinhais , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/fisiologia , Traumatismos da Medula Espinal/patologia , Micção/fisiologia
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