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1.
Anticancer Res ; 40(1): 335-339, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892584

RESUMO

BACKGROUND/AIM: The novel taxane cabazitaxel has been shown to exert excellent anticancer effects after androgen receptor axis-targeting (ARAT) agents in clinical data, but not in in vitro data. We investigated the clinical outcome of cabazitaxel chemotherapy after docetaxel according to use of ARAT agents. PATIENTS AND METHODS: Prostate specific antigen (PSA) response, progression-free survival, and overall survival were compared between cases with and without prior use of ARAT agents in 74 Japanese patients with metastatic castration-resistant prostate cancer treated with cabazitaxel chemotherapy. RESULTS: Background characteristics were comparable between patients with and without prior use of ARAT agents. PSA response, progression-free survival, and overall survival in cabazitaxel chemotherapy were comparable between patients with and without prior use of ARAT agents. CONCLUSION: No detrimental effects of prior ARAT agents on clinical outcome were observed for cabazitaxel chemotherapy in the post-docetaxel setting, suggesting that cabazitaxel can be expected to remain active even after ARAT agent therapy.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Docetaxel/farmacologia , Terapia de Alvo Molecular , Receptores Androgênicos/metabolismo , Taxoides/farmacologia , Idoso , Antagonistas de Receptores de Andrógenos/uso terapêutico , Docetaxel/uso terapêutico , Humanos , Masculino , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/uso terapêutico , Resultado do Tratamento
2.
Anticancer Drugs ; 31(3): 298-303, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31913197

RESUMO

This multi-institutional study aimed to identify prognostic factors for cabazitaxel treatment of castration-resistant prostate cancer (CRPC). This study included 74 Japanese patients with CRPC who were treated with cabazitaxel between 2014 and 2017. Associations between clinicopathological factors including serum markers and progression-free survival (PFS) and overall survival (OS) were investigated. On multivariate analysis, high Gleason score [≥9 vs. ≤7; hazard ratio (HR), 95% confidence interval (CI): 2.00 (1.01-4.34); P = 0.047], presence of pain [HR, 95% CI: 2.02 (1.14-3.58); P = 0.016], and lactate dehydrogenase (LDH) level [HR, 95% CI: 47.31 (3.79-577.49); P = 0.0019] were significantly associated with PFS. Similarly, number of docetaxel cycles [HR, 95% CI: 0.050 (0.0037-0.45); P = 0.0057], performance status [≥2 vs. 0; HR, 95% CI: 5.07 (1.57-16.24); P < 0.0001], and LDH level [HR, 95% CI: 2946 (50-420994); P = 0.0001] were significantly associated with OS. This study showed that LDH level is robustly prognostic for both PFS and OS in cabazitaxel chemotherapy for CRPC.

3.
Anticancer Res ; 39(8): 4411-4414, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366538

RESUMO

BACKGROUND/AIM: Cabazitaxel use has usually been limited to up to 10 cycles in most countries according to the protocol in the TROPIC trial. Therefore, clinical data on cabazitaxel use beyond 10 cycles is limited. The aim of this study was to report the therapeutic outcome of cabazitaxel chemotherapy administered for >10 cycles. PATIENTS AND METHODS: This study included 74 Japanese patients with prostate cancer between 2014 and 2017. Patients background, and treatment outcomes including PSA decline, progression-free survival, treatment-failure-free survival, overall survival, and adverse events were investigated, comparing patients treated with ≤10 and >10 cycles. RESULTS: Patients characteristics were favorable as indicated by the higher number of cycles of prior docetaxel chemotherapy, absence of pain, and absence of bony and visceral metastases among men who received >10 cycles of cabazitaxel. PSA response, progression-free survival, treatment-failure-free survival and overall survival were better among patients treated with >10 cycles of cabazitaxel compared to those treated with ≤10 cycles. The incidence of severe adverse events was similar between the two groups. CONCLUSION: Taken together, this study suggested that continuous chemotherapy with cabazitaxel beyond 10 cycles may be beneficial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Docetaxel/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/efeitos adversos , Esquema de Medicação , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/efeitos adversos , Resultado do Tratamento
4.
Cancer Chemother Pharmacol ; 84(3): 561-566, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31115605

RESUMO

OBJECTIVE: This study aimed to reveal the efficacy and safety profiles of 4-weekly cabazitaxel in patients with castration-resistant prostate cancer (CRPC). METHODS: The study included 62 Japanese patients who were treated for CRPC with ≥ 2 courses of cabazitaxel between 2014 and 2017. The oncological outcomes and adverse events were compared between 16 (25.8%) and 46 (74.2%) men who were treated with standard 3-weekly and alternative 4-weekly regimens, respectively. RESULTS: The prostate-specific antigen (PSA) response was comparable between the 3-weekly and 4-weekly regimens (median [interquartile range]: - 9.9% [- 64.5 to 13.0%] and - 30.7% [- 52.8 to 10.9%], P = 0.89), respectively. For patients on the 4-weekly regimen, the risks of progression (hazard ratio [HR], 95% confidence interval [CI] 1.27, 0.71-2.43, P = 0.44), treatment failure (HR, 95% CI 0.84, 0.48-1.55, P = 0.57) and any-cause mortality (HR, 95% CI 1.09, 0.58-2.17, P = 0.79) were comparable to those for patients on the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens. CONCLUSIONS: 3-weekly and 4-weekly regimens of cabazitaxel showed similar efficacy and safety profiles in a real-world clinical setting. These data suggest that a 4-weekly regimen may be acceptable for selected patients.

5.
Med Oncol ; 36(4): 32, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30815799

RESUMO

This multi-institutional study aimed to investigate the efficacy and safety profiles of cabazitaxel after prior docetaxel chemotherapy in patients with castration-resistant prostate cancer (CRPC). This study included 63 Japanese patients with CRPC who were treated with cabazitaxel from 2014 to 2017. The oncological outcomes and adverse events (AEs) were documented, and prognostic factors for oncological outcomes and predictive factors for AEs were analysed. PSA decline was observed in 68.3% of patients, including 25.4% who achieved a ≥ 50% decline. The median progression-free survival, treatment failure-free survival, and overall survival were 4.3, 4.1, and 9.0 months, respectively. More cycles of prior docetaxel therapy was identified as common favourable prognostic factors for progression-free survival, treatment failure-free survival, and overall survival. Severe neutropenia, febrile neutropenia, and severe non-haematological AEs were observed in 73.0%, 33.3%, and 23.8% of patients, respectively. However, > 10 cycles of docetaxel was not associated with increased incidence of AEs. In conclusion, cabazitaxel chemotherapy was still active in Japanese CRPC patients treated with > 10 cycles of docetaxel chemotherapy, with an acceptable risk of AE burden. Treatment with cabazitaxel after > 10 cycles of docetaxel may be an appropriate option when it can be administered.


Assuntos
Docetaxel/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Esquema de Medicação , Humanos , Masculino , Resultado do Tratamento
6.
Jpn J Clin Oncol ; 47(3): 233-238, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27940489

RESUMO

Objective: To assess the characteristics of biochemical recurrence in the late period (>5 years after radical prostatectomy) and the differences in the predictors of biochemical recurrence in different periods, we conducted a multicenter retrospective study. Methods: We reviewed 478 men who underwent radical prostatectomy for clinically localized prostate cancer. All of the patients were followed up for at least 5 years. The cohort was then divided into three groups; no recurrence group, recurrence <5 years after surgery group and recurrence ≥5 years after surgery group. The background characteristics of each group were compared using the χ2 test. A Cox multivariate regression analysis was performed to determine the predictors of biochemical recurrence in each period. Results: Biochemical recurrence occurred in 135 men. In 113 (84%) of the patients, biochemical recurrence occurred at <5 years after surgery; in 22 (16%), it occurred at ≥5 years after surgery. The proportion of men with a low preoperative prostate-specific antigen level was significantly larger in the latter group (P = 0.0023). A preoperative prostate-specific antigen level and a positive surgical margin were significant predictors of biochemical recurrence at <5 years after surgery (hazard ratio: 1.03 and 3.20). A positive surgical margin was also a significant predictor of biochemical recurrence at ≥5 years after surgery (hazard ratio: 3.03); however, a high preoperative prostate-specific antigen level was not. Conclusions: Biochemical recurrence occurred at ≥5 years after surgery in 16% of the patients. A positive surgical margin predicted biochemical recurrence in both the early and late periods.


Assuntos
Antígeno Prostático Específico/metabolismo , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias da Próstata/patologia , Estudos Retrospectivos
8.
Naunyn Schmiedebergs Arch Pharmacol ; 376(5): 309-19, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18071674

RESUMO

The effects of ZD0947, a novel urinary bladder selective ATP-sensitive potassium channel (K(ATP) channel) opener, on carbachol-induced contractions of isolated guinea pig urinary bladder strips were investigated to compare its ability to relax norepinephrine-induced contraction of the aorta. Electrophysiological techniques were also utilized to compare the effects of ZD0947 on membrane currents between guinea pig detrusor and aortic myocytes. ZD0947 caused a significant reduction of the carbachol-induced contractile activity, demonstrating a biphasic relaxation (the first and second components). Although glibenclamide antagonized the effects of two components for the ZD0947-induced relaxation, gliclazide, a selective sulphonylurea receptor 1 (SUR1) antagonist, reduced the effects of the first component but not the second component of the ZD0947-induced relaxation. ZD0947 also reduced the norepinephrine-induced contraction of the aorta. ZD0947 reduced electrical excitability of detrusor smooth muscles, inhibiting spike discharges and also hyperpolarizing the membrane as measured with microelectrodes. In conventional whole-cell configuration, ZD0947 caused a glibenclamide-sensitive K(+) current (i.e., K(ATP) current) at a holding potential of -60 mV in guinea pig detrusor and aortic myocytes. The current density of ZD0947-induced K(ATP) currents in guinea pig detrusor myocytes was significantly larger than that in aortic smooth muscle cells. These results show that ZD0947 caused a significant relaxation through the activation of K(ATP) channels in detrusor muscle.


Assuntos
Di-Hidropiridinas/farmacologia , Canais KATP/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Carbacol/farmacologia , Eletrofisiologia , Cobaias , Contração Isométrica/efeitos dos fármacos , Canais KATP/metabolismo , Masculino , Miócitos de Músculo Liso/metabolismo , Norepinefrina/farmacologia , Bexiga Urinária/citologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária Hiperativa/tratamento farmacológico
9.
Neurourol Urodyn ; 27(3): 222-5, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17580358

RESUMO

AIMS: To investigate the associations of symptoms and the quality of life (QOL) with objective variables in a strictly selected large cohort of subjects with symptomatic benign prostatic obstruction (BPO). METHODS: A retrospective study was conducted in 557 males with BPO in whom a symptomatic improvement had been achieved by transurethral resection of the prostate (TURP), thus suggesting that their lower urinary tract symptoms were primarily due to BPO. The association between the preoperative International Prostate Symptom Score (IPSS) and QOL score with objective variables including the residual volumes, prostate size and urodynamic parameters was statistically analyzed. RESULTS: Maximum flow rate (Q(max)) positively and a residual urine volume (PVR) negatively correlated with symptoms and QOL score. Detrusor overactivity (DO) also was weakly, but broadly associated with the symptoms. Degree of detrusor contractility and bladder capacity had a weak association with only some storage symptoms. The degree of bladder outlet obstruction (BOO) positively related to the scores on urgency, straining and total IPSS. Patients' age had positive correlation with the score on nocturia. The prostate volume was only negligibly correlated with either any symptoms or the QOL score. CONCLUSIONS: Parameters, such as Q(max) or PVR, obtained from the noninvasive urodynamics were most widely correlated with symptoms and QOL. Despite a large group with strict selection of men with LUTS possibly relating to BPO being studied, only weak association between the symptoms or QOL and objective parameters including urodynamics was confirmed.


Assuntos
Hiperplasia Prostática/cirurgia , Qualidade de Vida , Ressecção Transuretral da Próstata , Obstrução do Colo da Bexiga Urinária/etiologia , Bexiga Urinária Hiperativa/etiologia , Transtornos Urinários/etiologia , Urodinâmica , Idoso , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Hiperplasia Prostática/complicações , Hiperplasia Prostática/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Obstrução do Colo da Bexiga Urinária/cirurgia , Bexiga Urinária Hiperativa/fisiopatologia , Bexiga Urinária Hiperativa/cirurgia , Transtornos Urinários/fisiopatologia , Transtornos Urinários/cirurgia
10.
Naunyn Schmiedebergs Arch Pharmacol ; 376(3): 195-203, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17909749

RESUMO

The inhibitory effects of flavoxate hydrochloride (piperidinoethyl-3-methylflavone-8-carboxylate; hereafter referred as flavoxate) on voltage-dependent nifedipine-sensitive inward Ba2+ currents (I Ba) in human detrusor myocytes were investigated at different temperatures using conventional whole-cell patch-clamp techniques. When the bath-solution temperature was increased from 22 degrees C to 30 degrees C, I Ba peak amplitude was enhanced by approximately twice at several test potentials. Neither the I Ba threshold nor the membrane potentials for the I Ba maximum peak amplitude was affected by the temperature change. The concentration-response curves of flavoxate at both 30 degrees C (Ki = 5.1 microM) and 37 degrees C (Ki = 4.6 microM) were slightly shifted to the left in comparison with that at 22 degrees C (Ki = 10.3 microM). Similar results were also obtained in the presence of nifedipine (Ki = 14 nM at 22 degrees C vs. Ki = 2.5 nM at 30 degrees C and Ki = 2.1 nM at 37 degrees C). Altering the bath-solution temperature from 22 degrees C to 30 degrees C shifted the steady-state inactivation curve of I Ba at -90 mV to the left. At 30 degrees C, the steady-state inactivation curve of I Ba in the presence of flavoxate was also shifted to the left in comparison with that in the absence of flavoxate. Either 3-isobutyl-1-methylxanthine (IBMX) or theophylline, a phosphodiesterase inhibitor, caused little effects on I Ba, although cyclic nucleotides (dibutyryl cAMP and 8-Br-cGMP) inhibited I Ba. These results suggest that the inhibitory actions of flavoxate on I Ba in human detrusor myocytes were slightly changed at different experimental temperatures and that flavoxate directly blocked voltage-dependent L-type Ca2+ channels, not through the inhibition of phosphodiesterase activity pathway.


Assuntos
Bário/metabolismo , Flavoxato/farmacologia , Células Musculares/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Células Cultivadas , Feminino , Humanos , Masculino , Células Musculares/efeitos dos fármacos , Nifedipino/farmacologia , Parassimpatolíticos/farmacologia , Técnicas de Patch-Clamp , Inibidores de Fosfodiesterase/farmacologia , Temperatura Ambiente
11.
Neurourol Urodyn ; 26(4): 547-551, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17304522

RESUMO

AIMS: The contractile mechanisms of prostatic smooth muscle have been extensively investigated at the receptor level. However, the intracellular mechanisms have not yet been fully elucidated, especially in human tissue. In the present study, we examined the functional role of RhoA/Rho kinase (ROCK), one of the major intracellular molecules involved in smooth muscle contraction, in the contraction of the human prostate. METHODS: Ring preparations made of cultured human prostatic stromal cells (CHPSCs) or fresh human prostatic tissue was used for an isometric tension study. Gene transfer using baculovirus vector and alpha-toxin permeabilized preparations were also used. RESULTS: RhoA, ROCK I and ROCK II proteins were all expressed in CHPSCs and fresh human prostatic tissue. In CHPSCs ring preparations, the contraction induced by endothelin (ET)-1 was enhanced by over-expression of RhoA and inhibited by ROCK inhibitor. In alpha-toxin permeabilized preparations, ET-1 or GTP-gammaS induced an additional contraction at a constant [Ca2+]i, that was inhibited by ROCK inhibitor. In fresh human prostatic tissue, norepinephrine (NE)-induced contraction was inhibited by ROCK inhibitor at a constant [Ca2+]i in alpha-toxin permeabilized preparations. CONCLUSIONS: These results suggested that RhoA/ROCK-mediated Ca2+ sensitization is likely involved in the contraction of the human prostate. The antagonisms of this pathway may thus be useful as an alternative target in the treatment of benign prostatic hyperplasia (BPH).


Assuntos
Cálcio/fisiologia , Próstata/fisiologia , Proteína rhoA de Ligação ao GTP/fisiologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Amidas/farmacologia , Western Blotting , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Contração Muscular/fisiologia , Piridinas/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fosfolipases Tipo C/farmacologia , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/genética
12.
Eur J Pharmacol ; 531(1-3): 34-40, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16438954

RESUMO

Electorophysiological and pharmacological properties of the levcromakalim-induced inward ATP-sensitive K+ currents (K(ATP) currents) in pig proximal urethra were investigated by use of two different whole-cell patch-clamp techniques, namely conventional whole-cell and nystatin-perforated patch recordings. In conventional whole-cell configuration, the levcromakalim (100 microM)-induced K(ATP) current decayed by about 30% in 8 min at a holding potential of -50 mV. In contrast, with the nystatin-perforated patch, 96% of the levcromakalim-induced K(ATP) current still remained even after 8 min application of levcromakalim. The peak amplitude of the levcromakalim-induced inward K(ATP) currents in nystatin-perforated patch was approximately half of those observed in conventional whole-cell configuration. When cytosolic extract of pig urethra was included in the pipette solution, approximately 90% of the levcromakalim (100 microM)-induced K(ATP) current remained at 8 min, even after the establishment of conventional whole-cell configuration. In conventional whole-cell configuration, glibenclamide suppressed the levcromakalim-induced K(ATP) currents in a concentration-dependent manner (Ki=175 nM). Inclusion of 1 mM uridine 5'-diphosphate (UDP) in the pipette solution shifted the glibenclamide-sensitivity (Ki=640 nM) to the right in comparison with that in the absence of UDP (i.e., control). In contrast, using nystatin-perforated patch, glibenclamide inhibited the levcromakalim-induced K(ATP) currents with two affinity sites (high-affinity site, Ki1=10 nM; low-affinity site, Ki2=9 microM). The concentration response curves regarding the inhibitory effects of K(ATP) channel pore blockers (Ba2+ and flecainide) on the levcromakalim-induced K(ATP) currents in conventional whole-cell recording nearly overlapped with those in nystatin-perforated patch recording. These results indicate that the glibenclamide-sensitivity of pig urethral K(ATP) channels in nystatin-perforated patch recording was significantly different from that in a conventional whole-cell configuration, and that the glibenclamide-sensitivity may be modified by some cytosolic factor(s).


Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Glibureto/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Algoritmos , Animais , Bário/farmacologia , Extratos Celulares/farmacologia , Cromakalim/farmacologia , Relação Dose-Resposta a Droga , Feminino , Flecainida/farmacologia , Canais KATP , Potenciais da Membrana/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Técnicas de Patch-Clamp/métodos , Suínos , Fatores de Tempo , Uretra/citologia
13.
Eur J Pharmacol ; 524(1-3): 1-10, 2005 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-16242124

RESUMO

The effects of U-37883A, a vascular ATP-sensitive K(+) channel (K(ATP) channel) blocker, on membrane currents were investigated in pig urethral myocytes by use of patch-clamp techniques (conventional whole-cell recordings, nystatin-perforated patches and cell-attached configuration). Tension measurement was also performed to study the effects of U-37883A on the levcromakalim-induced urethral relaxation and the urethral resting tone in the absence and presence of Bay K 8644. Although cumulative application of U-37883A produced a concentration-dependent inhibitory effect on the levcromakalim-induced urethral relaxation, U-37883A did not abolish the relaxation. In nystatin-perforated patch recording, K(ATP) currents activated by levcromakalim were inhibited by U-37883A in a concentration-dependent manner (K(i), 4.7 microM). Approximately 10% of the K(ATP) currents still remained even in the presence of 300 microM U-37883A. In cell-attached mode, extracellular application of U-37883A (100 microM) irreversibly inhibited the activity of the levcromakalim-induced K(ATP) channels. In whole-cell configuration, U-37883A suppressed the peak amplitude of voltage-dependent Ba(2+) currents in a concentration- and voltage-dependent manner, and at 30 microM, shifted the steady-state inactivation curve of the Ba(2+) currents to the left at -90 mV. These results demonstrate that U-37883A reduces not only the activities of K(ATP) channels but also voltage-dependent Ca(2+) channels. Therefore, it is not appropriate to define U-37883A as solely a vascular K(ATP) channel blocker.


Assuntos
Adamantano/análogos & derivados , Morfolinas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Uretra/efeitos dos fármacos , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Adamantano/farmacologia , Trifosfato de Adenosina/fisiologia , Análise de Variância , Animais , Bário/farmacologia , Agonistas dos Canais de Cálcio , Cromakalim/farmacologia , Relação Dose-Resposta a Droga , Feminino , Glibureto/farmacologia , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Células Musculares/efeitos dos fármacos , Células Musculares/fisiologia , Nitroprussiato/farmacologia , Técnicas de Patch-Clamp , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Suínos , Fatores de Tempo , Uretra/citologia , Uretra/fisiologia , Vasodilatadores/farmacologia
14.
Br J Pharmacol ; 146(1): 25-32, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15965499

RESUMO

The effects of flavoxate hydrochloride (Bladderon, piperidinoethyl-3-methylflavone-8-carboxylate; hereafter referred as flavoxate) on voltage-dependent nifedipine-sensitive inward Ba(2+) currents in human detrusor myocytes were investigated using a conventional whole-cell patch-clamp. Tension measurement was also performed to study the effects of flavoxate on K(+)-induced contraction in human urinary bladder. Flavoxate caused a concentration-dependent reduction of the K(+)-induced contraction of human urinary bladder. In human detrusor myocytes, flavoxate inhibited the peak amplitude of voltage-dependent nifedipine-sensitive inward Ba(2+) currents in a voltage- and concentration-dependent manner (K(i) = 10 microM), and shifted the steady-state inactivation curve of Ba(2+) currents to the left at a holding potential of -90 mV. Immunohistochemical studies indicated the presence of the alpha(1C) subunit protein, which is a constituent of human L-type Ca(2+) channels (Ca(V)1.2), in the bundles of human detrusor smooth muscle. These results suggest that flavoxate caused muscle relaxation through the inhibition of L-type Ca(2+) channels in human detrusor.


Assuntos
Canais de Cálcio Tipo L/efeitos dos fármacos , Flavoxato/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Bário/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/fisiologia , Humanos , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Pessoa de Meia-Idade , Contração Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Parassimpatolíticos/farmacologia , Potássio/farmacologia , Bexiga Urinária/fisiologia
15.
Br J Pharmacol ; 144(7): 919-25, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15723098

RESUMO

The effects of mefenamic acid and Bay K 8644 on voltage-dependent nifedipine-sensitive inward Ba2+ currents in pig urethral myocytes were investigated by use of conventional whole-cell configuration patch clamp. Mefenamic acid increased the peak amplitude of voltage-dependent nifedipine-sensitive inward Ba2+ current without shifting the position of the current-voltage relationship. Mefenamic acid (300 microM) caused little shift in the activation curve although the voltage dependence of the steady-state inactivation was shifted to more positive potentials by 11 mV in the presence of mefenamic acid. Bay K 8644 (> or = 100 nM) enhanced voltage-dependent nifedipine-sensitive inward Ba2+ currents in a concentration- and voltage-dependent manner, shifting the maximum of the current-voltage relationship by 10 mV in the hyperpolarizing direction. Bay K 8644 (1 microM) significantly shifted the voltage dependence of the activation curve to more negative potentials by approximately 9 mV although Bay K 8644 caused little shift in the steady-state inactivation curve. These results indicate that mefenamic acid increased voltage-dependent nifedipine-sensitive inward Ba2+ currents through the activation of L-type Ca2+ channels with different kinetics from those of Bay K 8644 in pig urethral myocytes.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Ácido Mefenâmico/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Uretra/efeitos dos fármacos , Animais , Feminino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Miócitos de Músculo Liso/fisiologia , Suínos , Uretra/fisiologia
16.
Eur J Pharmacol ; 506(1): 1-7, 2004 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-15588618

RESUMO

Kinetic studies of U-37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl-hydrochloride), a vascular ATP-sensitive K+ channel (KATP channel) blocker, were performed on pig urethral myocytes to investigate inhibitory effects on large-conductance intracellular Ca2+ -sensitive K+ channels (i.e., BKCa channels; 225 pS K+ channels) by use of single-channel recordings (outside-out and inside-out configuration). BKCa channels in pig urethral smooth muscles showed extracellular iberiotoxin (300 nM) sensitivity and voltage dependency. The alpha subunit of BKCa channel proteins was detected in the membrane fraction by use of Western blot technique. Application of U-37883A (> or =10 microM) reduced the activity of BKCa channels in a concentration-dependent manner, not only by decreasing mean openlife time but also by prolonging the mean closed time. These results shows that U-37883A affects channels other than the vascular KATP channel, and demonstrates how it inhibits the activities of BKCa channels in urethral smooth muscles.


Assuntos
Adamantano/análogos & derivados , Adamantano/farmacologia , Morfolinas/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Canais de Potássio Cálcio-Ativados/fisiologia , Uretra/efeitos dos fármacos , Animais , Cálcio/farmacologia , Células Cultivadas , Cinética , Potenciais da Membrana/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Suínos , Fatores de Tempo , Uretra/citologia , Uretra/fisiologia
17.
Life Sci ; 72(4-5): 475-85, 2002 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-12467888

RESUMO

Patch-clamp experiments have been performed to investigate the effects of endoproteases (such as trypsin, carboxypeptidase B) on both membrane currents and unitary currents in isolated smooth muscle cells from pig proximal urethra (conventional whole-cell configuration, cell-attached configuration, and inside-out patches). Application of either trypsin (1 mg/mL) or carboxypeptidase B (0.1 mg/mL) to the intracellular surface of the excised membrane patches stimulated the activity of a 2.1 pA K+ channel (in symmetrical 140 mM K+ conditions) at a holding potential of -50 mV. The trypsin-induced K+ channels in inside-out configuration exhibited the same amplitude and similar channel opening kinetics to the levcromakalim-induced ATP-sensitive K+ channel (i.e. K ATP channel) in cell-attached patches of the same membrane; however, the sensitivity of the channels to glibenclamide was greatly reduced after the trypsin-treatment. The activity of the trypsin-induced K+ channel was reversibly inhibited by cibenzoline in an inside-out configuration (Ki = 5 microM). It is concluded that trypsin and carboxypeptidase B reactivate the channel with an intact pore activity but the different pharmacological properties of the channels may reflect some change in the conformation in channel proteins after proteolysis.


Assuntos
Endopeptidases/farmacologia , Músculo Liso/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Uretra/efeitos dos fármacos , Transportadores de Cassetes de Ligação de ATP , Algoritmos , Animais , Eletrofisiologia , Feminino , Técnicas In Vitro , Canais KATP , Cinética , Técnicas de Patch-Clamp , Canais de Potássio Corretores do Fluxo de Internalização , Suínos , Tripsina/farmacologia
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