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1.
Neurourol Urodyn ; 39(3): 916-925, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32040866

RESUMO

AIMS: The urethral dysfunction produced by a rat model of peripheral neurogenic detrusor underactivity (DU) using pelvic nerve crush (PNC) injury was characterized and then tested with the administration of tadalafil, a phosphodiesterase type 5 (PDE 5) inhibitor. METHODS: Ten days after producing PNC rats, awake cystometrograms (CMGs) and isovolumetric cystometrograms with urethral perfusion pressure (IC-UPP) measurements were performed. Also, in control rats, IC-UPP was recorded before and after intravenous atropine administration to determine if the reduction of bladder contraction pressure affects urethral relaxation during voiding. Then, CMG and IC-UPP measurements in PNC rats were recorded after intravenous administration of tadalafil. Lastly, real-time polymerase chain reaction was used to measure transcript levels of neuronal nitric oxide synthases (nNOS), endothelial nitric oxide synthases, and PDE 5 in urethral specimens from PNC and control rats. RESULTS: PNC rats demonstrated the characteristics of DU in CMG. Also, PNC rats exhibited significant decreases in isovolumetric bladder contraction amplitudes and urethral relaxation. Atropine attenuated the amplitude of isovolumetric bladder contractions; however, atropine did not affect urethral relaxation in control rats. Tadalafil decreased postvoid residual and increased voiding efficiency without changing bladder contraction amplitude in PNC rats. Also, tadalafil improved the amplitude of urethral relaxation during bladder contraction in PNC rats. Urethral nNOS transcript levels were upregulated in PNC rats compared to control rats. CONCLUSIONS: PNC rats revealed both DU and impaired urethral relaxation. PDE 5 inhibition in PNC rats enhanced urethral relaxation during voiding, resulting in improved voiding efficiency. Thus, urethral dysfunction could be a potential target for the treatment of inefficient voiding associated with neurogenic DU.


Assuntos
Traumatismos dos Nervos Periféricos/fisiopatologia , Inibidores da Fosfodiesterase 5/farmacologia , Tadalafila/farmacologia , Uretra/efeitos dos fármacos , Bexiga Urinaria Neurogênica/fisiopatologia , Bexiga Inativa/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Animais , Lesões por Esmagamento/fisiopatologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Feminino , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Pelve , Ratos , Ratos Sprague-Dawley , Uretra/inervação , Uretra/metabolismo , Uretra/fisiopatologia , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Micção/fisiologia
2.
Am J Physiol Renal Physiol ; 318(4): F1006-F1016, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32003596

RESUMO

Corticotropin-releasing factor (CRF) regulates diverse physiological functions, including bladder control. We recently reported that Crf expression is under genetic control of Aoah, the locus encoding acyloxyacyl hydrolase (AOAH), suggesting that AOAH may also modulate voiding. Here, we examined the role of AOAH in bladder function. AOAH-deficient mice exhibited enlarged bladders relative to wild-type mice and had decreased voiding frequency and increased void volumes. AOAH-deficient mice had increased nonvoiding contractions and increased peak voiding pressure in awake cystometry. AOAH-deficient mice also exhibited increased bladder permeability and higher neuronal firing rates of bladder afferents in response to stretch. In wild-type mice, AOAH was expressed in bladder projecting neurons and colocalized in CRF-expressing neurons in Barrington's nucleus, an important brain area for voiding behavior, and Crf was elevated in Barrington's nucleus of AOAH-deficient mice. We had previously identified aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor-γ as transcriptional regulators of Crf, and conditional knockout of AhR or peroxisome proliferator-activated receptor-γ in Crf-expressing cells restored normal voiding in AOAH-deficient mice. Finally, an AhR antagonist improved voiding in AOAH-deficient mice. Together, these data demonstrate that AOAH regulates bladder function and that the AOAH-Crf axis is a therapeutic target for treating voiding dysfunction.


Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Neurônios/enzimologia , Bexiga Urinária/inervação , Transtornos Urinários/enzimologia , Micção , Urodinâmica , Animais , Compostos Azo/farmacologia , Núcleo de Barrington/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hidrolases de Éster Carboxílico/deficiência , Hidrolases de Éster Carboxílico/genética , Hormônio Liberador da Corticotropina/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Contração Muscular , Neurônios/efeitos dos fármacos , PPAR gama/genética , PPAR gama/metabolismo , Pressão , Pirazóis/farmacologia , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Transtornos Urinários/tratamento farmacológico , Transtornos Urinários/genética , Transtornos Urinários/fisiopatologia , Urodinâmica/efeitos dos fármacos
3.
BJU Int ; 125(5): 718-724, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32012409

RESUMO

OBJECTIVE: To compare the efficacy and safety of tamsulosin vs the combination of tamsulosin and tadalafil in male lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: This was a double-blinded, parallel-arm randomised controlled trial. Men aged >45 years with moderate LUTS and a maximum urinary flow rate (Qmax ) of 5-15 mL/s were included. One arm received 0.4 mg tamsulosin only (Group-A), while the second received 5 mg tadalafil with tamsulosin (Group-B). The primary outcome was the International Prostate Symptom Score (IPSS). Secondary outcomes were IPSS quality of life (QoL) score, five-item version of the International Index of Erectile Function (IIEF-5) score, Qmax , and post-void residual urine (PVR). Block randomisation was used. Placebo was used for blinding and allocation concealment. Intention-to-treat analysis was used for outcome measures. RESULTS: Of the 183 men screened, 140 were randomised (71 in Group-A, 69 in Group-B); 116 (82.85%) (61 in Group-A, 55 in Group-B) completed the study. Baseline characteristics were comparable. The improvements in the IPSS, IPSS QoL score, IIEF score and Qmax were -1.69 (95% confidence interval [CI] -1.4 to -2.0), -0.70 (95% CI -0.60 to -0.80), 3.8 (95% CI 3.4-4.2) and 1.8 mL/s (95% CI 1.1-2.4) respectively, in favour of the combination group. The difference in PVR was not significant. There were no serious adverse events (AEs). The dropout rate due to AEs was 2.85%. Myalgia (five patients) was the commonest AE in the combination group. CONCLUSION: The combination of tamsulosin and tadalafil produced significantly better improvements in LUTS, QoL, erectile function and Qmax compared to monotherapy with tamsulosin, without an increase in AEs.


Assuntos
Sintomas do Trato Urinário Inferior/tratamento farmacológico , Qualidade de Vida , Tadalafila/uso terapêutico , Tansulosina/uso terapêutico , Micção/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Seguimentos , Humanos , Sintomas do Trato Urinário Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 5/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
4.
J Pharmacol Exp Ther ; 373(2): 239-247, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32102918

RESUMO

Transient receptor potential (TRP) melastatin 8 (TRPM8) is a temperature-sensing ion channel mainly expressed in primary sensory neurons (Aδ-fibers and C-fibers in the dorsal root ganglion). In this report, we characterized KPR-5714 (N-[(R)-3,3-difluoro-4-hydroxy-1-(2H-1,2,3-triazol-2-yl)butan-2-yl]-3-fluoro-2-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]benzamide), a novel and selective TRPM8 antagonist, to assess its therapeutic potential against frequent urination in rat models with overactive bladder (OAB). In calcium influx assays with HEK293T cells transiently expressing various TRP channels, KPR-5714 showed a potent TRPM8 antagonistic effect and high selectivity against other TRP channels. Intravenously administered KPR-5714 inhibited the hyperactivity of mechanosensitive C-fibers of bladder afferents and dose-dependently increased the intercontraction interval shortened by intravesical instillation of acetic acid in anesthetized rats. Furthermore, we examined the effects of KPR-5714 on voiding behavior in conscious rats with cerebral infarction and in those exposed to cold in metabolic cage experiments. Cerebral infarction and cold exposure induced a significant decrease in the mean voided volume and increase in voiding frequency in rats. Orally administered KPR-5714 dose-dependently increased the mean voided volume and decreased voiding frequency without affecting total voided volume in these models. This study demonstrates that KPR-5714 improves OAB in three different models by inhibiting exaggerated activity of mechanosensitive bladder C-fibers and suggests that KPR-5714 may provide a new and useful approach to the treatment of OAB. SIGNIFICANCE STATEMENT: TRPM8 is involved in bladder sensory transduction and plays a role in the abnormal activation in hypersensitive bladder disorders. KPR-5714, as a novel and selective TRPM8 antagonist, may provide a useful treatment for the disorders related to the hyperactivity of bladder afferent nerves, particularly in overactive bladder.


Assuntos
Vias Aferentes/efeitos dos fármacos , Canais de Cátion TRPM/antagonistas & inibidores , Bexiga Urinária/efeitos dos fármacos , Vias Aferentes/fisiologia , Animais , Infarto Cerebral/fisiopatologia , Feminino , Células HEK293 , Humanos , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPM/fisiologia , Bexiga Urinária/inervação , Bexiga Urinária Hiperativa/tratamento farmacológico , Micção/efeitos dos fármacos
5.
BJU Int ; 125(5): 709-717, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31991511

RESUMO

OBJECTIVE: To evaluate the efficacy of a novel and selective ß3-adrenoreceptor agonist vibegron on urgency urinary incontinence (UUI) in patients with overactive bladder (OAB). PATIENTS AND METHODS: A post hoc analysis was performed in patients with UUI (>0 episodes/day) who were assigned to receive vibegron or placebo in a vibegron phase 3 study. Patients were subclassified into mild/moderate (>0 to <3 UUI episodes/day) or severe UUI (≥3 UUI episodes/day) subgroup. Changes from baseline in number of UUI episodes/day, in number of urgency episodes/day, and in voided volume/micturition were compared between the groups. The percentage of patients who became UUI-free ('diary-dry' rate) and the response rate (percentage of patients with scores 1 [feeling much better] or 2 [feeling better] assessed by the Patient Global Impression scale [PGI]) were evaluated. RESULTS: Changes in numbers of UUI episodes at week 12 in the vibegron 50 mg, vibegron 100 mg and placebo groups, respectively, were -1.35, -1.47 and -1.08 in all patients, -1.04, -1.13 and -0.89 in the mild/moderate UUI subgroup, and -2.95, -3.28 and -2.10 in the severe UUI subgroup. The changes were significant in the vibegron 50 and 100 mg groups vs placebo regardless of symptom severity. Change in number of urgency episodes/day was significant in the vibegron 100 mg group vs placebo in all patients and in both severity subgroups. In the vibegron 50 mg group, a significant change vs placebo was observed in all patients and in the mild/moderate UUI subgroup. Change in voided volume/micturition was significantly greater in the vibegron 50 and 100 mg groups vs placebo in all patients, as well as in the both severity subgroups. Diary-dry rates in the vibegron 50 and 100 mg groups were significantly greater vs placebo in all patients and in the mild/moderate UUI subgroup. In the severe UUI subgroup, however, a significant difference was observed only in the vibegron 50 mg group. Response rates assessed by the PGI were significantly higher in the vibegron groups vs placebo in all patients and in the both severity subgroups. Vibegron administration, OAB duration ≤37 months, mean number of micturitions/day at baseline <12.0 and mean number of UUI episodes/day at baseline <3.0 were identified as factors significantly associated with normalization of UUI. CONCLUSIONS: Vibegron, a novel ß3-adrenoreceptor agonist, significantly reduced the number of UUI episodes/day and significantly increased the voided volume/micturition in patients with OAB including those with severe UUI, with the response rate exceeding 50%. These results suggest that vibegron can be an effective therapeutic option for OAB patients with UUI.


Assuntos
Pirimidinonas/uso terapêutico , Pirrolidinas/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Incontinência Urinária/tratamento farmacológico , Micção/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Bexiga Urinária Hiperativa/complicações , Bexiga Urinária Hiperativa/fisiopatologia , Incontinência Urinária/etiologia , Incontinência Urinária/fisiopatologia
7.
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
8.
Neurourol Urodyn ; 39(1): 158-169, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31729056

RESUMO

PURPOSE: Cannabinoids have been shown to exert analgesic and anti-inflammatory effects, and the effects of cannabinoids are mediated primarily by cannabinoid receptors 1 and 2 (CB1 and CB2). The objective of this study was to determine efficacy and mechanism of CB2 activation on cyclophosphamide (CYP)-induced cystitis in vivo. METHODS: Cystitis was induced by intraperitoneal (IP) injection of CYP in female C57BL/6J mice. Mice were pretreated with CB2 agonist JWH-133 (1 mg/kg, intraperitoneally), CB2 antagonist AM-630 (1 mg/kg, intraperitoneally) or autophagy inhibitor 3-methyladenine (3-MA) (50 mM, intraperitoneally) before IP injection of CYP. Peripheral nociception and spontaneous voiding were investigated in these mice. Bladders were collected, weighed, and processed for real-time polymerase chain reaction, immunoblotting analysis, histological and immunohistochemical analysis. RESULTS: Twenty-four hours after IP injection of CYP, the bladder of CYP-treated mice showed histological evidence of inflammation. The expression of CB2 in bladder was significantly increased in CYP-treated mice. Mechanical sensitivity was significantly increased in CYP-treated mice and CB2 agonist JWH-133 attenuated this effect (P < .05). The number of urine spots was significantly increased after CYP treatment and it was decreased in JWH-133 treated mice (P < .05). Activating CB2 with JWH-133 significantly alleviated bladder tissue inflammatory responses and oxidative stress induced by CYP. Activation of CB2 by JWH-133 increased the expression of LC3-II/LC3-I ratio, and decreased the expression of SQSTM1/p62 in the bladder of cystitis mice, whereas AM-630 induced inverse effects. Further study indicated that JWH-133 could promote autophagy and blocking autophagy by 3-MA dismissed the effort of CB2 in alleviating bladder tissue inflammatory responses and oxidative stress injury. Furthermore, treatment with 3-MA decreased the expression of p-AMPK and induced the phosphorylation of mTOR in the presence of JWH-133 stimulation in cystitis model. CONCLUSIONS: Activation of CB2 decreased severity of CYP-induced cystitis and ameliorated bladder inflammation. CB2 activation is protective in cystitis through the activation of autophagy and AMPK-mTOR pathway may be involved in the initiation of autophagy.


Assuntos
Autofagia/efeitos dos fármacos , Cistite/metabolismo , Receptor CB2 de Canabinoide/agonistas , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Canabinoides/farmacologia , Ciclofosfamida , Cistite/induzido quimicamente , Feminino , Indóis/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Receptor CB2 de Canabinoide/antagonistas & inibidores , Micção/efeitos dos fármacos
9.
Neurourol Urodyn ; 39(1): 144-157, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31663175

RESUMO

AIMS: Sensory information from the lower urinary tract (LUT) is conveyed to the spinal cord to trigger and co-ordinate micturition. However, it is not fully understood how spinal dorsal horn neurons are excited during the voiding reflex. In this study, we developed an in vivo technique allowing recording of superficial dorsal horn (SDH) neurons concurrent with intravesical pressure (IVP) during the micturition cycle in both normal and diabetic rats. METHODS: Lumbosacral dorsal horn neuronal activity and IVP were recorded from urethane-anesthetized naive and streptozotocin (STZ)-induced diabetic rats. Saline was continuously perfused into the urinary bladder through a cannula to induce micturition. RESULTS: We classified SDH neurons into bladder- and urethral-responsive neurons, based on their responsiveness during the voiding reflex. Bladder-responsive SDH neurons responded to the rapid increase in IVP at the start of voiding. In contrast, urethral-responsive SDH neuronal firing increased at the peak IVP and their firing lasted during the voiding phase (the high-frequency oscillations). Urethral-responsive SDH neurons were more sensitive to capsaicin, received C afferent fiber inputs, and were rarely detected in STZ-diabetes rats. Administration of a cyclohexenoic long-chain fatty alcohol (TAC-302), which is reported to promote neurite outgrowth of peripheral nerves in STZ-diabetic rats, prevented the functional loss of spinal urethral response. CONCLUSIONS: Sensory information from the bladder and urethra is conveyed separately to different groups of SDH neurons. Functional loss of spinal urethral sensory information through unmyelinated C afferent fibers may contribute to diabetic bladder dysfunction.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Células do Corno Posterior/fisiologia , Reflexo/fisiologia , Uretra/fisiopatologia , Micção/fisiologia , Animais , Capsaicina/farmacologia , Modelos Animais de Doenças , Feminino , Masculino , Células do Corno Posterior/efeitos dos fármacos , Ratos , Reflexo/efeitos dos fármacos , Traumatismos da Medula Espinal/fisiopatologia , Uretra/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologia , Micção/efeitos dos fármacos
10.
Biomed Res Int ; 2019: 6927374, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886241

RESUMO

Lagopsis supina is a well-known traditional Chinese medicine and used as an agent for diuresis in China for centuries. This is the first time to evaluate the diuretic activity of the ethanol extract of L. supina (LS) and its four fractions (LSA, LSB, LSC, and LSD) in normal rats. After the administration of LS-H, LS-M, LSB-H, and LSC-L, the urine output of the rats was significantly increased, while the urine excretion was significantly reduced after treatment with LSB-L. The urine Na+ excretion was remarkably increased with LS-H, LS-M, LSA-H, LSA-L, LSB-H, LSC-L, and LSD-L, and the urine K+ excretion was significantly increased after administration of LS-H and LSB-H. Moreover, the urine Na+ and K+ excretion was significantly reduced after treatment with LSC-H and LSD-H. However, the urine pH values and urine and serum Na+-K+-ATPase levels did not show remarkable change after administration of LS or its four fractions in comparison with the control group. On the contrary, LS and its four fractions can suppress the renin-angiotensin-aldosterone system (RAAS), including ADH arrest by LSB-H, LSB-L, LSC-L, LSD-L, and LSD-H and ALD arrest by LSD-L, as well as promote ANP release by LS-M, LSB-H, LSC-H, and LSD-H, while furosemide can suppress only arrest of ADH within 24 h compared with the control group. In addition, LS and its four fractions did not change the urine and serum TNF-α and IL-6 levels in normal rats within 24 h. This study will provide a quantitative basis for explaining the natural medicinal use of LS as a diuretic agent for edema and promoting the diuretic process.


Assuntos
Antidiuréticos , Diuréticos , Lamiaceae/química , Extratos Vegetais , Animais , Antidiuréticos/química , Antidiuréticos/farmacologia , Diuréticos/química , Diuréticos/farmacologia , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Sódio/urina , Urinálise , Micção/efeitos dos fármacos
11.
Biomed Res Int ; 2019: 9828397, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828153

RESUMO

Aims: To assess the efficacy of a micronized-palmitoylethanolamide-polydatin (m-PEA-Pol) based product on chronic pelvic pain and severity of other symptoms in interstitial cystitis/bladder pain syndrome (IC/BPS) patients refractory to conventional therapies. Methods: A pilot, open-label bicentric study was carried out involving 32 IC/BPS patients. Chronic, oral m-PEA-Pol treatment lasted 6 months. Bladder pain was evaluated using the visual analog scale, while changes from baseline in other urinary symptoms were evaluated by means of the O'Leary-Sant Interstitial Cystitis Symptom and Problem Index and the Pelvic Pain and Urgency/Frequency (PUF) symptom scale questionnaires. The generalized linear mixed model was used to evaluate significant mean changes across time. Results: A significant and progressive reduction of pain intensity was observed during m-PEA-Pol treatment (p < 0.0001 for reduction over time). The effect was associated with a reduction in severity of patients' symptoms evaluated with the O'Leary-Sant questionnaire (p=0.0110 and p=0.0014 for cystitis symptoms and problem mean scores, respectively) and the PUF scale (p=0.0163 and p=0.0005 for symptom and bother mean scores, respectively). m-PEA-Pol therapy elicited a significant reduction over time in the urinary frequency evaluated with voiding diary (p=0.0005) and a small but not significant improvement of bladder capacity. Conclusions: These data highlight the potential benefit of m-PEA-Pol in patients with rare pathology such as IC/BPS and confirm the good safety profile of micronized PEA-based products.


Assuntos
Cistite Intersticial/tratamento farmacológico , Etanolaminas/administração & dosagem , Glucosídeos/administração & dosagem , Ácidos Palmíticos/administração & dosagem , Dor Pélvica/tratamento farmacológico , Estilbenos/administração & dosagem , Administração Oral , Adulto , Idoso , Amidas , Dor Crônica/tratamento farmacológico , Dor Crônica/patologia , Cistite Intersticial/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Dor Pélvica/patologia , Projetos Piloto , Micção/efeitos dos fármacos
12.
Biol Pharm Bull ; 42(11): 1877-1882, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31685769

RESUMO

Intracerebroventricular (icv) injection of transient receptor potential vanilloid 4 (TRPV4) agonists 4α-phorbol-12, 13-didecanoate (4α-PDD) and GSK101690A increased urinary excretion under the physiological condition. TRPV4 antagonists ruthenium red and HC-067047 significantly blocked increased urinary volume after intragastric administration of water and 4α-PDD-induced diuresis. Administration of the TRPV4 agonists did not significantly change the plasma concentration of vasopressin or atrial natriuretic factor. Pretreatment with indomethacin inhibited the diuresis induced by 4α-PDD. Moreover, icv injection of prostaglandin (PG) F2α produced diuretic effects. These findings indicate that central TRPV4 regulates urine excretion, which contributes to systemic water homeostasis in vivo. The underlying mechanisms are suggested to involve PG synthesis, but not release of vasopressin or atrial natriuretic factor.


Assuntos
Diurese/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Ésteres de Forbol/farmacologia , Canais de Cátion TRPV/agonistas , Micção/efeitos dos fármacos , Animais , Fator Natriurético Atrial/sangue , Dinoprosta/farmacologia , Indometacina/farmacologia , Masculino , Morfolinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Wistar , Rutênio Vermelho/farmacologia , Vasopressinas/sangue
13.
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
14.
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
15.
J Pediatr Urol ; 15(6): 642.e1-642.e6, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31526515

RESUMO

BACKGROUND: Functional overactive bladder disorder is one of the most prevalent presentations of bladder and bowel dysfunction in children, and it is associated with lower overall cardiac autonomic and parasympathetic activity. Antimuscarinics are the most frequently used pharmacological agents for treatment of children with functional overactive bladder disorder; however, there is a gap in the literature in describing the effect of antimuscarinics on the autonomic profile of this population. OBJECTIVE: The aim of the study was to assess the cardiac parasympathetic activity before and after 12 weeks of oxybutynin treatment in children with overactive bladder. METHODS: This was a single-institution prospective cohort study. Cardiac autonomic activity was assessed during storage and voiding phases of the bladder function via spectral analysis of heart rate variability and impedance cardiography. The primary outcome measure was high frequency, a proxy for parasympathetic nervous system activity. Parameters of uroflow study, severity of symptoms, and quality of life outcomes were also assessed. RESULTS: Ten children (7 females) diagnosed with overactive bladder with a median age of 10 years (range = 6-14) were followed up for a median treatment duration of 11.8 weeks (range = 6-19.4). After treatment, there was a significant reduction in high frequency during the storage phase (median change = -24.17%, p = 0.047). No change was observed in the other outcome measures except for the overall Symptom Score for Dysfunctional Elimination Syndrome after treatment (5-point decrease, p = 0.034) (Summary Table). DISCUSSION: The findings of the present follow-up study suggest that the use of oxybutynin in children with overactive bladder is associated with a significant reduction in the activity of the parasympathetic nervous system. The clinical implications of this finding are important because similar autonomic profiles (as markers of chronic stress) have been shown to be associated with increased inflammation and are found in major chronic diseases. The authors caution making a clinical connection between the heart rate variability profile of the patients in this study and patients with chronic diseases because oxybutynin is usually not administered as long-term treatment for overactive bladder. CONCLUSION: Use of oxybutynin was associated with reduction in cardiac parasympathetic activity of children with functional overactive bladder. Further investigation into the role of the autonomic nervous system as a treatment target in the management of these children is warranted.


Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Antagonistas Muscarínicos/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária/fisiopatologia , Micção/efeitos dos fármacos , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Qualidade de Vida , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/inervação , Bexiga Urinária Hiperativa/fisiopatologia , Micção/fisiologia
16.
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
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.
Neurourol Urodyn ; 38(8): 2112-2120, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31436351

RESUMO

AIMS: The goal of this study was to test whether central corticotropin-releasing factor (CRF) was involved in angiotensin II (Ang II) and Ang II type 1 (AT1) receptor-mediated facilitation of micturition reflex and to investigate whether peripherally administered telmisartan, AT1 receptor antagonist, suppresses the central Ang II-induced facilitation of micturition reflex in rats. METHODS: Urethane anesthetized male Wistar rats were placed under continuous cystometry before and after intracerebroventricular administration of each drug. Rats were intracerebroventricularly administered telmisartan (AT1 receptor antagonist), CP154526 (CRF1 receptor antagonist), or K41498 (CRF2 receptor antagonist) 30 minutes before intracerebroventricular administration of Ang II. Some male Wistar rats were perorally pretreated with either vehicle, AT1 receptor antagonist telmisartan or valsartan, once daily for 8 days, then measured blood pressure. Thereafter, Ang II was intracerebroventricularly administered for continuous cystometry. RESULTS: Intracerebroventricularly administered telmisartan or CP154526 dose-dependently suppressed the central Ang II-induced intercontraction interval (ICI) reduction. In contrast, intracerebroventricularly administered K41498 did not affect the central Ang II-induced response compared to vehicle pretreatment. Peripherally administered telmisartan but not valsartan suppressed the central Ang II-induced ICI reduction in rats compared to vehicle administration without altering blood pressure. CONCLUSIONS: Central Ang II induced facilitation of the micturition reflex through AT1 and CRF1 receptors. Peripherally administered telmisartan suppressed central Ang II-induced facilitation of micturition reflex.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Telmisartan/farmacologia , Micção/efeitos dos fármacos , Proteínas de Anfíbios/farmacologia , Angiotensina II/administração & dosagem , Animais , Masculino , Hormônios Peptídicos/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Wistar , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores
19.
Sci Rep ; 9(1): 9828, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285518

RESUMO

Stress-related peptide corticotropin-releasing factor (CRF) and CRF-related peptides are distributed in the peripheral viscera such as the bladder. We investigated the contribution of psychological stress (PS) and CRF on bladder function. Male rats received sham stress (SS) or PS using a communication box method for 120 min every day for 7 days. One group of rats received the intraperitoneal CRF-R1 antagonist antalarmin for 7 days during stress exposure. Mean voided volume per micturition was significantly lower in PS rats compared to SS rats, which was antagonized by antalarmin treatment. Increases in plasma and bladder CRF, and mRNA expressions of bladder CRF, CRF-R1, and M2/3 muscarinic receptors, were found in PS rats. CRF did not influence bladder contraction in itself; however, stress increased the response of muscarinic contraction of bladder strips. These changes were antagonized by antalarmin treatment. In conclusion, PS reinforces M3 receptor-mediated contractions via CRF-R1, resulting in bladder storage dysfunction.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Estresse Psicológico/tratamento farmacológico , Bexiga Urinária/fisiopatologia , Animais , Estudos de Casos e Controles , Hormônio Liberador da Corticotropina/sangue , Modelos Animais de Doenças , Injeções Intraperitoneais , Masculino , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M2/genética , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Micção/efeitos dos fármacos
20.
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
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