RESUMEN
PURPOSE: We aimed to evaluate the therapeutic efficacy and safety of TAS-303, a highly selective noradrenaline reuptake inhibitor, in Japanese women with stress urinary incontinence (SUI). MATERIALS AND METHODS: A double-blind, placebo-controlled, phase 2 study randomized women with SUI symptoms to once-daily oral administration of TAS-303 18 mg or placebo for 12 weeks. The primary endpoint was percent change from baseline to Week 12 in mean SUI episode frequency per 24 hours (SUIEF) in the per-protocol set. The secondary endpoints were the proportion of patients with ≥ 50% reduction in mean SUIEF, incontinence episode frequency, incontinence amount, health-related quality of life, and safety in the full analysis set. RESULTS: In total, 231 patients were randomized to TAS-303 (n = 116) or placebo (n = 115). At Week 12, TAS-303 had superior efficacy to placebo, with a least squares mean percent change in mean SUIEF of -57.7% vs -46.9%, respectively, in the per-protocol set (least squares mean difference -10.8%; P = .036). TAS-303 showed some evidence of improved incontinence episode frequency, incontinence amount, and health-related quality of life (although not statistically significant) at Week 12 vs placebo in the full analysis set. The between-group difference in SUIEF improvement was more clearly confirmed in patients with ≥ 2 SUI episodes daily at baseline. All adverse events (AEs) with TAS-303 were mild or moderate; there were no serious AEs, AEs leading to discontinuation, or nervous system- or gastrointestinal-related (eg, nausea or vomiting) adverse drug reactions. CONCLUSIONS: Once-daily TAS-303 18 mg showed superior efficacy to placebo for the treatment of SUI in Japanese women, with an adequate safety profile. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04512053; Japan Registry of Clinical Trials: jRCT2080225307 (JapicCTI-205403 before site integration).
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Incontinencia Urinaria de Esfuerzo , Humanos , Método Doble Ciego , Femenino , Incontinencia Urinaria de Esfuerzo/tratamiento farmacológico , Persona de Mediana Edad , Adulto , Resultado del Tratamiento , Calidad de Vida , Anciano , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Pirrolidinas/uso terapéutico , PirimidinonasRESUMEN
PURPOSE: We developed a simple self-checkable screening tool for chronic prostatitis (S-CP) and internally validated it to encourage men (in the general population) with possible chronic prostatitis to consult urologists. METHODS: The expert panel proposed the S-CP, which comprises three domains: Area of pain or discomfort (6 components), accompanying Symptom (6 components), and Trigger for symptom flares (4 components). We employed logistic regression to predict chronic prostatitis prevalence with the S-CP. We evaluated the predictive performance using data from a representative national survey of Japanese men aged 20 to 84. We calculated the optimism-adjusted area under the curve using bootstrapping. We assessed sensitivity/specificity, likelihood ratio, and predictive value for each cutoff of the S-CP. RESULTS: Data were collected for 5,010 men-71 (1.4%) had a chronic prostatitis diagnosis. The apparent and adjusted area under the curve for the S-CP was 0.765 [95% confidence interval (CI) 0.702, 0.829] and 0.761 (0.696, 0.819), respectively. When the cutoff was two of the three domains being positive, sensitivity and specificity were 62.0% (95% CI 49.7, 73.2) and 85.4% (95% CI 84.4, 86.4), respectively. The positive/negative likelihood ratios were 4.2 (95% CI 3.5, 5.2) and 0.45 (95% CI 0.33, 0.60), respectively. The positive/negative predictive values were 5.7 (95% CI 4.2, 7.6) and 99.4 (95% CI 99.1, 99.6), respectively. CONCLUSION: The reasonable predictive performance of the S-CP indicated that patients (in the general population) with chronic prostatitis were screened as a first step. Further research would develop another tool for diagnostic support in actual clinical settings.
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Prostatitis , Masculino , Humanos , Prostatitis/diagnóstico , Prostatitis/complicaciones , Dolor Pélvico/epidemiología , Enfermedad Crónica , Valor Predictivo de las Pruebas , Modelos LogísticosRESUMEN
This Asia-Pacific (AP) AMS 800™ artificial urinary sphincter (AUS) consensus statement aims to provide a set of practical recommendations to assist surgeons with the AMS 800 device surgery. The AP consensus committee consisted of key opinion leaders with extensive experience with AMS 800 surgery across several AP countries. The panel reviewed and discussed relevant findings with emphasis on locoregional and specific clinical challenges relevant to the AP region. Recommendations were made in key areas namely (1) patient selection and informed consent process; (2) preoperative assessment; (3) dealing with co-existing urological disorders; (4) surgical principles and intraoperative troubleshooting; (5) postoperative care; (6) special populations; and (7) cost analysis and comparative review. The AMS 800 device should be offered to males with moderate to severe stress urinary incontinence (SUI). Full informed consent should be undertaken, and emphasis is placed on surgical contraindications and high-risk candidates. The presence of a surgical mentor or referral to experts is recommended in complex AUS candidates. Preoperative cystoscopy with or without multichannel urodynamic study is necessary and patients with pre-existing urological disorders should be treated adequately and clinically stable before surgery. Adherence to strict patient selection and safe surgical principles are critical to ensure excellent clinical outcomes and minimize complications. Given that InhibiZone-coated device is not available in many AP countries, the use of prophylactic antibiotics pre-and post-operatively are recommended. The AMS 800 device should be prepared according to the manufacturer's guidelines and remains a cost-effective treatment for male SUI. The AMS 800 device remains the surgical benchmark for male SUI but is associated with certain mechanical limitations and a unique set of complications.
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Incontinencia Urinaria de Esfuerzo , Esfínter Urinario Artificial , Humanos , Masculino , Incontinencia Urinaria de Esfuerzo/cirugía , Resultado del Tratamiento , Cuidados Posoperatorios , AsiaRESUMEN
OBJECTIVES: To estimate the surgical and quality-of-life outcomes of artificial urinary sphincter implantation in patients with diabetes mellitus (DM). Subanalyses were performed using the same population as that in our previous multicenter, prospective, observational study. METHODS: A total of 135 male patients who underwent primary artificial urinary sphincter implantation were divided into two groups: those with and without DM. The revision-free rates, that is, the percentage of patients who did not require revision surgery, were compared between patients with and without DM. The number of urinary pads required per day, International Consultation on Incontinence Questionnaire-Short Form, and King's Health Questionnaire were used to compare the continence status and quality of life (QOL) between the two groups preoperatively and at 1, 3, and 12 months after surgery. RESULTS: Revision-free rates were significantly lower in the DM group (83.9%, 77.4%, and 67.8% at 1, 2, and 3 years after implantation, respectively) than in the non-DM group (95.5%, 92.5%, and 85.5% at 1, 2, and 3 years after implantation, respectively). Both continence status and QOL, assessed by questionnaires, markedly improved after surgery in patients with and without DM. CONCLUSIONS: Despite differences in the durability of the artificial urinary sphincters, patients with DM can obtain as much benefit from artificial urinary sphincter implantation regarding continence and quality-of-life improvement as patients without DM. Therefore, DM was not considered a comorbidity that contraindicated artificial urinary sphincter implantation. Additional large-scale studies are required to verify our findings.
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Diabetes Mellitus , Incontinencia Urinaria de Esfuerzo , Esfínter Urinario Artificial , Humanos , Masculino , Esfínter Urinario Artificial/efectos adversos , Calidad de Vida , Estudios Prospectivos , Resultado del Tratamiento , Diabetes Mellitus/epidemiología , Incontinencia Urinaria de Esfuerzo/cirugía , Estudios Retrospectivos , Implantación de Prótesis/efectos adversosRESUMEN
AIM: To examine the symptoms and noninvasive test parameters that clinically differentiate detrusor underactivity (DU) from bladder outlet obstruction (BOO) without using a pressure-flow study (PFS) in male patients with lower urinary tract symptoms. METHODS: We examined 909 men who underwent PFS and also had the following data: International Prostate Symptom Score (IPSS), free uroflowmetry, postvoid residual (PVR), and prostate volume (PV). Using these data, significant symptoms and noninvasive test parameters that clinically differentiate DU from BOO were examined. RESULTS: Significant parameters between DU patients and BOO patients were older age, smaller PV, and lower urgency symptom score (IPSS Q4). Optimal cutoff values were determined using receiver operating characteristic curves (≥74 years old, PV ≤ 34.8, and IPSS Q4 ≤ 1) and patients were categorized on the basis of the number of significant factors. The probability of DU or BOO in patients with three significant factors were 77% and 34%, respectively. CONCLUSION: Three factors (older age, smaller PV, and fewer urgency symptom) were the predictive factors to differentiate DU from BOO, which might be useful for estimating the probability of DU in clinical practice without a PFS.
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Síntomas del Sistema Urinario Inferior/diagnóstico , Obstrucción del Cuello de la Vejiga Urinaria/diagnóstico , Vejiga Urinaria de Baja Actividad/diagnóstico , Urodinámica/fisiología , Anciano , Humanos , MasculinoRESUMEN
OBJECTIVE: To carry out an exploratory assessment of the efficacy and safety of TAS-303, a noradrenaline reuptake inhibitor, in women with stress urinary incontinence. METHODS: In a double-blind, placebo-controlled, early phase II study, women with stress urinary incontinence and stress urinary incontinence-predominant mixed urinary incontinence were randomized to a placebo or TAS-303 (3 or 6 mg) once daily for 8 weeks. The main efficacy end-points were mean percentage change in incontinence episode frequency per 24 h from baseline to week 8 (the primary end-point) and week 4. RESULTS: At week 8, the mean percentage change in incontinence episode frequency per 24 h was -34.73% in the TAS-303 3 mg group, -35.41% in the TAS-303 6 mg group and -28.07% in the placebo group (differences vs placebo, not significant). In patients with stress urinary incontinence, or incontinence episode frequency less than two episodes per 24 h at baseline, TAS-303 significantly reduced incontinence episode frequency versus placebo after 4 weeks; some secondary end-points also showed a tendency to improve in the same subgroups. No serious adverse events (e.g. central nervous system or cardiovascular effects) were observed; TAS-303 was well tolerated and had a favorable safety profile. CONCLUSION: These findings suggest that TAS-303 is effective for improving stress urinary incontinence symptoms in some subgroups of patients with stress urinary incontinence. Therefore, further research is warranted.
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Incontinencia Urinaria de Esfuerzo , Método Doble Ciego , Clorhidrato de Duloxetina , Femenino , Humanos , Norepinefrina , Tiofenos , Resultado del Tratamiento , Incontinencia Urinaria de Esfuerzo/tratamiento farmacológicoRESUMEN
The present article is an abridged English translation of the Japanese Clinical Guidelines for Female Lower Urinary Tract Symptoms (second edition), published in September 2019. These guidelines consist of a total of 212 pages and are unique worldwide in that they cover female lower urinary tract symptoms other than urinary incontinence. They contain two algorithms for "primary treatment" and "specialized treatment," respectively. These guidelines, consisting of six chapters, address a total of 26 clinical questions including: (i) treatment algorithms; (ii) what are female lower urinary tract symptoms?; (iii) epidemiology and quality of life; (iv) pathology and illness; (v) diagnosis; and (vi) treatment. When the patient's symptoms mainly involve voiding and post-micturition symptoms, specialized treatment should be considered. In the event of voiding symptoms concurrent with storage symptoms, residual urine should be measured; if the residual urine volume is <100 mL, then diagnosis and treatment for storage symptoms is prioritized, and if the volume is ≥100 mL, then specialized treatment should be considered. When storage symptoms are the primary condition, then the patient is subject to the primary treatment algorithm. Specialized treatment for refractory overactive bladder includes botulinum toxin injection and sacral nerve stimulation. For stress urinary incontinence, surgical treatment is indicated, such as urethral slings. The two causes of voiding symptoms and post-micturition symptoms are lower urinary tract obstruction and detrusor underactivity (underactive bladder). Mechanical lower urinary tract obstruction, such as pelvic organ prolapse, is expected to improve with surgery.
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Síntomas del Sistema Urinario Inferior , Prolapso de Órgano Pélvico , Vejiga Urinaria Hiperactiva , Femenino , Humanos , Síntomas del Sistema Urinario Inferior/diagnóstico , Síntomas del Sistema Urinario Inferior/epidemiología , Síntomas del Sistema Urinario Inferior/etiología , Masculino , Calidad de Vida , UrodinámicaRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of intravesical KRP-116D, 50% dimethyl sulfoxide solution compared with placebo, in interstitial cystitis/bladder pain syndrome patients. METHODS: Japanese interstitial cystitis/bladder pain syndrome patients with an O'Leary-Sant Interstitial Cystitis Symptom Index score of ≥9, who exhibited the bladder-centric phenotype of interstitial cystitis/bladder pain syndrome diagnosed by cystoscopy and bladder-derived pain, were enrolled. Patients were allocated to receive either KRP-116D (n = 49) or placebo (n = 47). The study drug was intravesically administered every 2 weeks for 12 weeks. RESULTS: For the primary endpoint, the change in the mean O'Leary-Sant Interstitial Cystitis Symptom Index score from baseline to week 12 was -5.2 in the KRP-116D group and -3.4 in the placebo group. The estimated difference between the KRP-116D and placebo groups was -1.8 (95% confidence interval -3.3, -0.3; P = 0.0188). Statistically significant improvements for KRP-116D were also observed in the secondary endpoints including O'Leary-Sant Interstitial Cystitis Problem Index score, micturition episodes/24 h, voided volume/micturition, maximum voided volume/micturition, numerical rating scale score for bladder pain, and global response assessment score. The adverse drug reactions were mild to moderate, and manageable. CONCLUSIONS: This first randomized, double-blind, placebo-controlled trial shows that KRP-116D improves symptoms, voiding parameters, and global response assessment, compared with placebo, and has a well-tolerated safety profile in interstitial cystitis/bladder pain syndrome patients with the bladder-centric phenotype.
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Cistitis Intersticial , Administración Intravesical , Cistitis Intersticial/tratamiento farmacológico , Dimetilsulfóxido/uso terapéutico , Método Doble Ciego , Humanos , Japón , Resultado del TratamientoRESUMEN
PURPOSE: We sought to identify the symptoms and noninvasive test parameters associated with detrusor underactivity and develop a prediction model of detrusor underactivity. We analyzed clinical data on male patients with lower urinary tract symptoms who underwent pressure-flow studies. MATERIALS AND METHODS: Included in analysis were 909 men who met study criteria and whose data included the International Prostate Symptom Score, free uroflowmetry, post-void residual urine volume and prostate volume. Using these data we examined the significant symptoms and noninvasive test parameters associated with detrusor underactivity and developed a prediction model of detrusor underactivity. RESULTS: Of the 909 patients 454 (50%) were classified with detrusor underactivity. On logistic regression analysis older patient age, smaller prostate volume, a lower urgency symptom score, a higher weak stream symptom score and a lower maximum flow rate were selected as independent predictors of detrusor underactivity. The prediction model of detrusor underactivity consisting of these 5 factors showed satisfactory performance (C statistic 0.724). CONCLUSIONS: We developed a prediction model of detrusor underactivity in male patients with nonneurogenic lower urinary tract symptoms. The model was based on 5 predictive factors, namely older age, smaller prostate volume, 2 symptoms (less urgency and a weak stream) and a lower maximum flow rate. The model helps estimate the probability of detrusor underactivity in clinical practice without an invasive pressure-flow study.
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Modelos Biológicos , Vejiga Urinaria de Baja Actividad/epidemiología , Vejiga Urinaria/fisiopatología , Urodinámica/fisiología , Factores de Edad , Anciano , Bases de Datos Factuales/estadística & datos numéricos , Humanos , Modelos Logísticos , Masculino , Tamaño de los Órganos , Próstata/patología , Estudios Retrospectivos , Medición de Riesgo/métodos , Factores de Riesgo , Vejiga Urinaria de Baja Actividad/diagnóstico , Vejiga Urinaria de Baja Actividad/fisiopatologíaRESUMEN
BACKGROUND: Anorexia is a serious problem in patients with gastric cancer who have undergone gastrectomy. Ghrelin, an orexigenic hormone primarily secreted from the stomach, has been proposed to prevent anorexia. Significant reduction in plasma ghrelin levels after gastrectomy may contribute to lack of appetite and weight loss. In this study, we investigated the effects of Z-505, a ghrelin receptor agonist, on anorexia after total gastrectomy (TG) in a rat model. METHODS AND MATERIALS: Male Sprague-Dawley rats were used to establish a TG model, and then sham-operated (control) and TG rats were randomly assigned to four subgroups receiving administration of Z-505 (100 mg/kg, p.o., once daily) or vehicle for 14 d from day 14 to day 27 after TG. The food intake, body weight, and fat weight were evaluated during the test period. Moreover, the neuronal activity in the hypothalamus was evaluated on day 21 to investigate the mechanism of action of Z-505. RESULTS: In TG rats, Z-505 significantly improved the decrease in cumulative food intake induced by the surgery over 14 d (TG + vehicle; 213.8 ± 15.3 g, n = 12 versus TG + Z-505; 258.2 ± 13.1 g, n = 14, P < 0.05). Z-505 also significantly increased fat weight and had a milder effect on body weight over 14 d. In addition, Z-505 significantly increased the number of c-Fos-positive cells in the hypothalamic arcuate nucleus (TG + vehicle; 17.8 ± 2.0, n = 12 versus TG + Z-505; 72.2 ± 11.8, n = 12, P < 0.001). CONCLUSIONS: Z-505 may be a useful therapeutic treatment for anorexia after TG.
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Amidas/administración & dosificación , Anorexia/tratamiento farmacológico , Gastrectomía/efectos adversos , Ghrelina/sangre , Pirrolidinas/administración & dosificación , Receptores de Ghrelina/agonistas , Animales , Anorexia/sangre , Anorexia/etiología , Núcleo Arqueado del Hipotálamo/citología , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/metabolismo , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , Humanos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Neoplasias Gástricas/cirugíaRESUMEN
AIMS: To present the development of the International Consultation on Incontinence Questionnaire-underactive bladder (ICIQ-UAB) as the first patient reported outcome measure for the assessment of the symptoms and impact on the health-related quality of life of UAB developed in-line with the Food and Drug Administration Guidance for Industry. METHODS: Draft items were developed following 44 semi-structured concept elicitation interviews in the UK and refined using 36 cognitive interviews. A pilot study was designed to assess the draft ICIQ-UAB's initial psychometric properties with 54 patients recruited from European hospitals. Further concept elicitation interviews were also carried out with 11 patients in the US and 10 patients in Japan. All participants had a prior urodynamic diagnosis of detrusor underactivity. RESULTS: The cognitive interviews confirmed the initial items to be understood and interpreted as intended. Pilot testing showed that both internal consistency (Cronbach's α ≥ 0.85) and test-retest reliability (stable patients; intraclass correlation coefficient ≥ 0.88) were high. The interviews in the US and Japan elicited symptoms and impacts that support previous findings in the UK and provided further insight into the experiences of patients in those countries. The developmental ICIQ-UAB was refined using the evidence from all substudies. CONCLUSIONS: The validity and reliability of the ICIQ-UAB were supported in a pilot study setting and the wider cultural applicability by the additional interviews in the US and Japan. Following further validation in future clinical trials, the developmental ICIQ-UAB is envisaged as an important tool for the monitoring of future UAB treatment strategies.
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Vejiga Urinaria de Baja Actividad/terapia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Proyectos Piloto , Psicometría , Calidad de Vida , Reproducibilidad de los Resultados , Autoinforme , Resultado del Tratamiento , Vejiga Urinaria de Baja Actividad/psicología , Incontinencia Urinaria/psicología , Incontinencia Urinaria/terapia , UrodinámicaRESUMEN
PURPOSE: We performed a multicenter, prospective, observational study to assess outcomes, including changes in continence status and quality of life, after artificial urinary sphincter implantation. MATERIALS AND METHODS: Prospectively enrolled in this study were 135 patients who underwent primary AMS 800™ implantation between 2011 and 2014 at 1 of 5 institutions. Perioperative complications were categorized according to the Clavien-Dindo classification. We estimated the revision-free rate, that is the incidence of patients who did not undergo artificial urinary sphincter revision surgery. Cox regression analysis was performed to identify patient risk factors for revision surgery. The number of pads needed per day, ICIQ-SF (International Consultation on Incontinence Questionnaire-Short Form) and KHQ (King's Health Questionnaire) were used to estimate continence status and quality of life preoperatively, and 1, 3 and 12 months postoperatively. RESULTS: The artificial urinary sphincter was implanted without major complications. The revision-free rate 1, 2 and 3 years after implantation was 94%, 88% and 81%, respectively. Diabetes mellitus and poor preoperative American Society of Anesthesiologists® physical status were significant risk factors for revision surgery. Continence status and quality of life were markedly improved after surgery. However, ICIQ-SF and some KHQ items showed slight but significant deterioration at 12 months compared with scores 1 month after surgery. CONCLUSIONS: Artificial urinary sphincter implantation is a safe and durable procedure that substantially improves patient continence status and quality of life soon after surgery. Our results indicate that patients start to experience slight but noticeable deterioration in continence status and quality of life relatively early (within 1 year) after surgery. This finding might be helpful with appropriately counseling patients who undergo artificial urinary sphincter implantation.
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Complicaciones Intraoperatorias/epidemiología , Medición de Resultados Informados por el Paciente , Complicaciones Posoperatorias/epidemiología , Incontinencia Urinaria de Esfuerzo/cirugía , Esfínter Urinario Artificial/efectos adversos , Procedimientos Quirúrgicos Urológicos/instrumentación , Anciano , Humanos , Incidencia , Pañales para la Incontinencia/estadística & datos numéricos , Masculino , Satisfacción del Paciente , Periodo Perioperatorio , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Calidad de Vida , Reoperación/estadística & datos numéricos , Factores de Tiempo , Resultado del Tratamiento , Procedimientos Quirúrgicos Urológicos/efectos adversos , Procedimientos Quirúrgicos Urológicos/métodosRESUMEN
Lymphatic metastasis is common in advanced-stage carcinoma and is associated with a poor prognosis. However, few effective treatments to inhibit it are available. Z-100 is an immunomodulatory extract of Mycobacterium tuberculosis strain Aoyama B that contains polysaccharides such as arabinomannan and mannan. Here, we investigated the inhibitory effect of Z-100 on spontaneous lymphatic metastasis. C57BL/6N mice injected subcutaneously with B16-BL6 melanoma cells in the right hind footpad were administered Z-100 subcutaneously in the right inguinal region on a daily basis. On day twenty-one after the injection, the right inguinal lymph nodes were excised, and the extent of metastasis, the number of immune cells, and the amount of granzyme B protein in the lymph nodes were examined. We also investigated the combined effect of Z-100 and irradiation in this model. Results showed that Z-100 reduced number of animals with metastasis, with respective metastasis rates of 85.7%, 42.9%, 7.1% and 0.0% in saline, 0.1 mg/kg Z-100, 1 mg/kg Z-100 and 10 mg/kg Z-100 group. Further, mice that had been given Z-100 were found to have more immune cells and granzyme B protein in the lymph nodes than control mice. The combination of low dose Z-100 and irradiation also inhibited spontaneous lymph node metastases. These findings suggest that Z-100 may be beneficial in preventing lymphatic metastasis by enhancing the immune response.
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Lípidos/uso terapéutico , Metástasis Linfática/prevención & control , Mananos/uso terapéutico , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Mycobacterium tuberculosis , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/uso terapéutico , Animales , Recuento de Células , Supervivencia Celular/efectos de los fármacos , Terapia Combinada , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Granzimas/metabolismo , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Irradiación Linfática , Metástasis Linfática/inmunología , Metástasis Linfática/patología , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Ratones , Subgrupos de Linfocitos T/efectos de los fármacosRESUMEN
BACKGROUND: Chronic prostatitis (CP) can impair health-related quality of life (QOL), but the full impact of CP, including the impact of CP-like symptoms in men who have no CP diagnosis (CPS), is unknown. We estimated the impact of diagnosed CP (DCP) and CPS on Health-related QOL. METHODS: From a representative nationwide survey of men aged 20-84 in Japan, we determined the prevalence of DCP and also of CPS. For CPS, we used Nickel's criteria, which were used previously to estimate the prevalence of CP and are based on the NIH Chronic Prostatitis Symptom Index. To test the robustness of Nickel's criteria, we used two other definitions of CPS (two sensitivity analyses). We measured QOL with the Short-Form 12-Item Health Survey. We compared the participants' QOL scores with the national-norm scores, and with the scores of men who had benign prostatic hyperplasia (BPH). RESULTS: Among the 5 010 participants, 1.4% had DCP and 3.7% had CPS. The sensitivity analyses resulted in CPS prevalence estimates of 3.1% and 4.5%. CPS was particularly common in younger participants (5.7% of those in their 30 s had CPS). QOL was very low among men with CP: In most areas (domains) of QOL, their scores were more than 0.5 standard deviation below the national-norm mean. Their mental-health scores were lower than those of men with BPH. The lowest scores among all 8 QOL domains were in role-functioning. CONCLUSIONS: CP is common, but it is underdiagnosed, particularly in younger men. Whether diagnosed or only suspected, CP's impact on QOL is large. Because CP is common, and because it substantially impairs individuals' QOL and can also reduce societal productivity, it requires more attention. Specifically, needed now is a simple tool for urologists and for primary care providers, to identify men, particularly young men, whose QOL is impaired by CP.
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Hiperplasia Prostática , Neoplasias de la Próstata , Prostatitis , Masculino , Humanos , Prostatitis/diagnóstico , Prostatitis/epidemiología , Calidad de Vida , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/epidemiología , Níquel , Enfermedad Crónica , Encuestas y CuestionariosRESUMEN
Acotiamide hydrochloride (acotiamide; N-[2-[bis(1-methylethyl) amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide monohydrochloride trihydrate, Z-338) has been reported to improve meal-related symptoms of functional dyspepsia in clinical studies. Here, we examined the gastroprokinetic effects of acotiamide and its antiacetylcholinesterase activity as a possible mechanism of action in conscious dogs. Acotiamide increased postprandial gastric motor activity in conscious dogs with chronically implanted force transducers and, like itopride, mosapride, and cisapride, exhibited gastroprokinetic activity in these dogs. Furthermore, acotiamide improved clonidine-induced hypomotility and delayed gastric emptying. Acotiamide-enhanced postprandial gastroduodenal motility was suppressed completely by pretreatment with atropine, a muscarinic receptor antagonist. In in vitro studies, acotiamide enhanced acetylcholine- but not carbachol-induced contractile responses of guinea pig gastric antrum strips. Moreover, like itopride and neostigmine, acotiamide inhibited recombinant human and canine stomach-derived acetylcholinesterase (AChE) activity in vitro. The mode of the AChE inhibitory action of acotiamide was selective and reversible. Unlike itopride or mosapride, acotiamide showed no affinity for dopamine D(2) or serotonin 5-HT(4) receptors. With regard to cardiovascular side effects, unlike cisapride, acotiamide did not affect myocardial monophasic action potential duration, QT interval, or corrected QT interval in anesthetized dogs. These results suggest that acotiamide stimulates gastric motility in vivo by inhibiting AChE activity without affecting QT interval. Acotiamide thus represents a beneficial new drug for the treatment of functional dyspepsia involving gastric motility dysfunction, with differences from other prokinetic agents.
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Benzamidas/farmacología , Compuestos de Bencilo/farmacología , Inhibidores de la Colinesterasa/farmacología , Cisaprida/farmacología , Motilidad Gastrointestinal/efectos de los fármacos , Morfolinas/farmacología , Tiazoles/farmacología , Animales , Benzamidas/química , Compuestos de Bencilo/química , Células CHO , Cisaprida/química , Cricetinae , Cricetulus , Perros , Motilidad Gastrointestinal/fisiología , Cobayas , Sistema de Conducción Cardíaco/efectos de los fármacos , Sistema de Conducción Cardíaco/fisiología , Humanos , Masculino , Morfolinas/químicaRESUMEN
Asacol, a medication that delivers delayed release 5-aminosalicylic acid (5-ASA), is a useful therapeutic agent for inflammatory bowel disease (IBD), but the relationship between its pharmacological actions and intestinal concentrations has not been studied in detail. Therefore, our aim was to assess 5-ASA's pharmacological actions as a function of its concentration at its target site. We first evaluated 5-ASA's release profiles in vitro by the paddle method and found that Asacol starts to release 5-ASA at pH ≥ 7. Orally administered Asacol pharmacokinetic parameters were evaluated in dogs. Asacol's T(max) was much longer than that of the time-dependent release 5-ASA formulation. We also determined 5-ASA's distribution in the intestinal mucosa and found that it is effectively delivered there by Asacol. These results indicated that Asacol released 5-ASA in a pH-dependent manner, resulting in efficient delivery to the large intestine. We also compared the mucosal 5-ASA concentrations with the IC(50) values for scavenging free radicals or suppressing LTB(4) production. The 5-ASA concentration in the large intestine was higher than IC(50) values necessary to suppress inflammatory processes. We also report the release characteristics of Asacol and the targeted delivery of 5-ASA to affected sites in IBD patients.
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Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mesalamina/farmacología , Mesalamina/farmacocinética , Administración Oral , Animales , Células Cultivadas , Química Farmacéutica , Perros , Concentración de Iones de Hidrógeno , Concentración 50 Inhibidora , Leucotrieno B4/metabolismo , Masculino , Mesalamina/administración & dosificación , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismoRESUMEN
OBJECTIVES: ⢠To assess the effect of α1-D/A adrenoceptor antagonist naftopidil on patients with neurogenic lower urinary tract dysfunction (NLUTD) and voiding difficulty. ⢠To explore the effectiveness of naftopidil in these patients by using urodynamic variables, including pressure flow study (PFS), and to find good and simple parameters (International Prostate Symptom Score (IPSS), Post-void residual urine (PVR), and uroflowmetry (UFM) parameters) as substitution of PFS for predicting the effect of naftopidil. PATIENTS AND METHODS: ⢠The main inclusion and exclusion criteria were, IPSS ≥8, voiding symptoms with IPSS ≥5, IPSS-quality of life (QOL) ≥2, PVR ≥50 mL, and without prostatic enlargement ≥ 20 mL. ⢠After initial assessment, patients were stepwisely administered for 12 weeks with the following: placebo for 2 weeks, naftopidil 25 mg/day for 2 weeks, naftopidil 50 mg/day for 2 weeks, and naftopidil 75 mg/day for 6 weeks. At the end of both placebo and 6 weeks' naftopidil 75 mg/day, their IPSS, UFM, PVR, and PFS were assessed. ⢠A total of 82 Japanese patients (men 40, women 42) with lower urinary tract symptoms complicated by NLUTD, with a mean age of 63.9 years, were included from private or institutional clinics. ⢠The lesions were spinal cord 42, and peripheral nervous system 40. The spinal cord lesions were all lumbar spine (injury or lumbar canal stenosis). RESULTS: ⢠In all patients, pressure at maximum urinary flow rate (P(det) Q(max) ) in PFS significantly decreased (P < 0.05), and maximum urinary flow rate in UFM significantly increased (P < 0.01). Analysis of data for men and for women also showed a significant decrease in PVR, %PVR, and total IPSS score. ⢠The degree of improvement of voided volume, PVR (%), and IPSS in patients with PVR <300 mL was significantly greater than those in patients with PVR ≥300 mL. ⢠The degree of improvement of P(det) Q(max) in PFS, and IPSS in patients with bladder contractility was significantly greater than that in patients without bladder contractility. CONCLUSIONS: ⢠α1-D/A adrenoceptor antagonist naftopidil has a significant effect on both symptoms and urodynamic variables of patients of both genders with NLUTD in Japan. ⢠PVR <300 mL and bladder contractility are predictive factors for the efficacy of naftopidil on patients with NLUTD.
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Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Naftalenos/uso terapéutico , Enfermedades del Sistema Nervioso/complicaciones , Piperazinas/uso terapéutico , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Urodinámica/efectos de los fármacos , Enfermedades Urológicas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Métodos Epidemiológicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores Adrenérgicos alfa 1/fisiología , Reología , Resultado del Tratamiento , Urodinámica/fisiología , Enfermedades Urológicas/etiología , Enfermedades Urológicas/fisiopatología , Adulto JovenRESUMEN
OBJECTIVES: The aim of this study was to identify the urodynamic features of women with stress urinary incontinence (SUI) or with high-stage (stage 3 or greater) cystocele (HSC) as compared with symptom-free women. METHODS: Fifty-six neurologically intact women with SUI and 47 women with HSC but without SUI were prospectively evaluated. All patients underwent full urodynamics, in addition to basic clinical evaluations. The urodynamic parameters of SUI and HSC were compared to the ones obtained from 78 urologically symptom-free normal women over the same period. RESULTS: Patients with HSC, after correction of cystocele using a temporary vaginal pessary, had consistently lower maximum urinary flow rate with a lower detrusor pressure during micturition than the controls or those with SUI. On the other hand, patients with SUI had an equivalent to higher maximum urinary flow rate, normal detrusor contraction strength with a lower detrusor pressure during micturition than the controls. Both maximum Watts factor and bladder contractility index were significantly lower in the whole HSC cohort in comparison to the controls and patients with SUI. The urodynamic characteristics observed among the three groups were all maintained even after adjusting for age. CONCLUSIONS: Women with SUI demonstrate voiding with low-pressure, normal contraction strength with an equivalent to high urinary flow rate. Women with HSC demonstrate voiding with low pressures with weak contraction strengths and low urinary flow rates, suggesting a higher prevalence of detrusor underactivity. Chronically decreased or increased urethral resistance might alter voiding dynamics and performance.
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Cistocele/complicaciones , Cistocele/fisiopatología , Incontinencia Urinaria de Esfuerzo/etiología , Incontinencia Urinaria de Esfuerzo/fisiopatología , Micción/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Contracción Muscular/fisiología , Presión , Uretra/fisiología , Adulto JovenRESUMEN
BACKGROUND: Z-360 is an orally active cholecystokinin-2 (CCK2)/gastrin receptor antagonist currently under development as a therapeutic drug for pancreatic cancer. It was previously reported that Z-360 treatment in combination with gemcitabine prolonged the survival period in a lethal pancreatic cancer xenograft model in mice. In a phase Ib/IIa clinical study, Z-360 treatment displayed a trend of reduced pain in patients with advanced pancreatic cancer in combination with gemcitabine including analgesics such as opioids. Here, we investigated the mechanism of analgesic action of Z-360 in a severe cancer-induced pain model in mice, which is considered to be opioid-resistant, by examining ephrin B1 gene expression, N-methyl-D-aspartate receptor NR2B subunit phosphorylation, and interleukin-1ß (IL-1ß) production. RESULTS: In a mouse model of cancer-induced pain, ephrin B1 gene expression in dorsal root ganglia (DRGs) and the phosphorylation of NR2B in the spinal cord were induced. Z-360 treatment inhibited both ephrin B1 gene expression and the phosphorylation of NR2B. In addition, IL-1ß production increased in the cancer-inoculated hind paw of mice, but could be suppressed by treatment with Z-360. Moreover, we observed that the CCK1 receptor antagonist devazepide similarly suppressed up-regulation of ephrin B1 gene expression and IL-1ß production, and that the intraperitoneal injection of sulfated CCK-8 induced the production of IL-1ß in the cancer-inoculated region. CONCLUSIONS: We have identified a novel pain cascade, in which IL-1ß production in cancer-inoculated regions induces ephrin B1 gene expression in DRGs and then ephrin B1 enhances the tyrosine phosphorylation of NR2B via Eph B receptor in the spinal cord. Notably, Z-360 relieves cancer-induced pain by preventing this pain cascade through the suppression of IL-1ß production, likely via the blockade of CCK1 receptor. The pre-clinical results presented here support the analgesic action of Z-360 in pancreatic cancer patients with severe, opioid-resistant pain. Pre-clinical and clinical results have demonstrated that Z-360 combined with gemcitabine represents a promising pancreatic cancer therapy approach with characteristic analgesic effects in addition to the prolongation of survival.