RESUMEN

To assess the pharmacologically relevant and selective muscarinic receptor occupancy in the bladder mucosa, we considered not only plasma drug concentrations but also urinary drug concentrations. The purpose of this study was to predict muscarinic receptor occupancy in the human bladder mucosa based on urinary concentrations in response to clinical dosages of antimuscarinic agents used to treat overactive bladder. The calculated mean plasma or serum unbound steady state concentrations were 0.06-11 nM in clinical dosages of five antimuscarinic agents. Urinary concentrations calculated from the mean plasma or serum and renal clearance ranged between 19 nM and 2 µM, which were >10-fold higher than the Ki values for bladder muscarinic receptors excluding propiverine. Bladder mucosal muscarinic receptor occupancy estimated from the urinary concentrations and the Ki values was >90 % at a steady state in clinical dosages of five antimuscarinic agents. The bladder muscarinic receptor occupancy was higher than that in the parotid gland calculated based on the mean plasma or serum unbound concentrations and Ki values for muscarinic receptors in the parotid gland. These results suggest that sufficient and selective muscarinic receptor occupancy by antimuscarinic agents, to exert pharmacological effects, in the bladder mucosa can be predicted using urinary concentrations.

Asunto(s)

Membrana Mucosa , Antagonistas Muscarínicos , Receptores Muscarínicos , Vejiga Urinaria Hiperactiva , Vejiga Urinaria , Humanos , Antagonistas Muscarínicos/farmacocinética , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/metabolismo , Vejiga Urinaria Hiperactiva/orina , Receptores Muscarínicos/metabolismo , Vejiga Urinaria/metabolismo , Vejiga Urinaria/efectos de los fármacos , Membrana Mucosa/metabolismo , Membrana Mucosa/efectos de los fármacos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano

RESUMEN

PURPOSE: Previous studies have included a limited number of randomized controlled trials (RCTs) and compared limited parameters after treatment with imidafenacin and other anticholinergic drugs (ADs) for overactive bladder syndrome (OAB), and controversy about the superiority of these ADs still remains. We aim to update the evidence and provide better clinical guidance. METHODS: A systematic search of PubMed, Embase, ClinicalTrial.gov and Cochrane Library Central Register of Controlled Trials was conducted from January 2007 to April 2019. Meta-analysis of all published RCTs comparing imidafenacin with other ADs in patients with OAB was performed. The primary outcomes were the changes in OAB symptoms and OAB symptom score (OABSS). Secondary outcomes included adverse events (AEs) and the dropout rate related to AEs. RESULTS: A total of 6 studies including 7 RCTs involving 1430 patients with mean follow-up of 23.43 weeks were included. All ADs improved OAB symptoms. Regarding efficacy, these drugs had similar efficacy in voids, urgency episodes, urgency incontinence episodes, incontinence episodes and OABSS. However, imidafenacin performed better in the reduction of nocturia episodes (MD = -0.24, 95% CI -0.44 to -0.04, P = 0.02). Moreover, imidafenacin was associated with a statistically lower dry mouth rate (RR = 0.87, 95% CI 0.75-1.00, P = 0.04), lower constipation rate (RR = 0.68, 95% CI 0.50-0.93, P = 0.01) and lower AE-related withdrawal rate (RR = 0.51, 95% CI 0.29-0.89, P = 0.02). There was no significant difference in terms of other complications. CONCLUSIONS: In conclusion, imidafenacin was comparable to other ADs in the treatment of OAB. Moreover, imidafenacin presented a lower dry mouth rate, lower constipation rate and higher adherence and persistence.

Asunto(s)

Preparaciones Farmacéuticas , Vejiga Urinaria Hiperactiva , Humanos , Imidazoles , Antagonistas Muscarínicos , Resultado del Tratamiento

RESUMEN

Urgency is regarded as a core symptom of overactive bladder (OAB) and may correspond to detrusor overactivity (DO). One of the causes of OAB in men is bladder outlet obstruction (BOO) associated with benign prostatic hyperplasia (BPH). Vibegron is a novel selective ß3-adrenoceptor agonist recently approved for the treatment of OAB. However, in OAB patients with BPH (BPH/OAB), the effects of vibegron on storage functions, especially DO and voiding functions have not been fully investigated. In this study, we evaluated the effects of a single administration of vibegron on storage function (particularly focusing on non-voiding contractions [NVC] considered a surrogate marker for DO) and voiding functions, using a rat model of partial BOO as a model for BPH/OAB. Furthermore, the utility of vibegron in combination with imidafenacin (an antimuscarinic) or silodosin (an α1A-adrenoceptor blocker) was evaluated. Six weeks after establishment of BOO, the frequency and amplitude of NVC, evaluated by cystometrography, increased. Vibegron inhibited the frequency of NVC without affecting voiding function (micturition pressure, residual volume, and voiding efficiency). Imidafenacin and silodosin also inhibited the frequency of NVC; however, the inhibitory effects of vibegron were stronger than those of imidafenacin or silodosin. The combination of vibegron with imidafenacin or silodosin additively inhibited the frequency of NVC without worsening the voiding function. These results suggest the possibility that vibegron is effective as a single agent for the amelioration of storage symptoms in BPH/OAB patients and is useful in combination with either antimuscarinics or α1-adrenoceptor blockers.

Asunto(s)

Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos beta 3/farmacología , Antagonistas Muscarínicos/farmacología , Hiperplasia Prostática/tratamiento farmacológico , Obstrucción del Cuello de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada , Femenino , Humanos , Imidazoles/farmacología , Indoles/farmacología , Masculino , Pirimidinonas , Pirrolidinas , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos/metabolismo , Vejiga Urinaria/efectos de los fármacos , Obstrucción del Cuello de la Vejiga Urinaria/complicaciones , Micción/fisiología

RESUMEN

PURPOSE: The aim of this meta-analysis was to evaluate the efficacy and safety of imidafenacin for overactive bladder (OAB) induced by benign prostatic hyperplasia (BPH) in men receiving alpha-blocker monotherapy. METHODS: We performed a systematic research of the PubMed, Embase, and Cochrane Library databases, and searched for studies about alpha-blocker with or without imidafenacin treatment for OAB in patients with BPH. We also investigated the original references of the included texts. RESULTS: Four randomized controlled trials including 779 participants with BPH (389 in the alpha-blocker+imidafenacin group and 390 in the alpha-blocker only group) were studied. The main efficacy endpoint was the Overactive Bladder Symptom Score, which showed a mean difference of -1.88 (95% confidence interval, -2.32 to -1.44; P<0.00001), suggesting that alpha-blocker and imidafenacin treatment was effective in treating men with OAB. As other primary efficacy end points, the International Prostate Symptom Score (IPSS) total score (P=0.47), the IPSS storage symptom score (P=0.07), the IPSS voiding symptom score (P=0.60), and the IPSS quality of life score (P=0.18) indicated that 2 methods had no significant differences in treating men with OAB. In terms of safety, which was assessed using postvoid residual volume (P=0.05) and maximum flow rate (P=0.53), the analysis suggested that combination treatment was very well tolerated. CONCLUSION: This study suggested that imidafenacin plus alpha-blocker was an efficacious and safe treatment for OAB symptoms in BPH patients.

RESUMEN

Background: Although long-acting muscarinic receptor antagonists are central to the management of chronic obstructive pulmonary disease (COPD), inhaled medicines may have technical difficulty in some patients and adherence barriers. Methods: A multicenter, randomized, double-blind, placebo-controlled 3×3 crossover Phase II trial was performed to evaluate the efficacy and safety of oral administration of the antimuscarinic agent imidafenacin in patients with COPD. Twenty-seven male COPD patients with % forced expiratory volume in 1 s (FEV1) ≥30% and <80% predicted were randomized to single oral dose of imidafenacin 0.1 mg, imidafenacin 0.2 mg, or placebo. Results: Maximum change in FEV1 with both doses of imidafenacin significantly improved from baseline to 24 hrs after administration when compared with a placebo. Area under the curve in FEV1 during 24 hrs after administration with 0.2 mg, but not 0.1 mg dose, was significantly improved when compared with a placebo, and the improvement was significantly based on dose-dependent manners. Plasma imidafenacin level was positively correlated with change in FEV1. All subjects with both doses of imidafenacin completed without moderate nor severe adverse events. Conclusion: A single oral dose of imidafenacin 0.1 mg or imidafenacin 0.2 mg may contribute to the improvement of pulmonary function with excellent safety and tolerability in patients with COPD. Trial registration: JapicCTI-121760 (Japan Pharmaceutical Information Center - Clinical Trials Information [JapicCTI]; http://www.clinicaltrials.jp/user/cteSearch_e.jsp).

Asunto(s)

Imidazoles/administración & dosificación , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Antagonistas Muscarínicos/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Administración Oral , Anciano , Estudios Cruzados , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento

RESUMEN

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

Asunto(s)

Agonistas de Receptores Adrenérgicos beta 3/farmacología , Imidazoles/farmacología , Antagonistas Muscarínicos/farmacología , Pirimidinonas/farmacología , Pirrolidinas/farmacología , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/fisiología , Anestesia , Animales , Interacciones Farmacológicas , Femenino , Ratas , Ratas Sprague-Dawley

RESUMEN

BACKGROUND: The role of the selective antimuscarinic imidafenacin in Caucasian patients with overactive bladder (OAB) has not been previously assessed. OBJECTIVE: To evaluate the safety and efficacy of imidafenacin 0.2 mg vs tolterodine 4 mg per day in patients with OAB. DESIGN SETTING AND PARTICIPANTS: This study was a randomized, open-label, tolterodine-controlled, comparative multicenter trial of 300 randomized patients with OAB symptoms for 12 weeks with full analysis of 289 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Based on 5-day bladder diaries, the primary efficacy endpoint was the change in the mean number of micturitions per day. The secondary endpoints were the change in the mean incontinence episodes, voiding frequency, the OAB Awareness Tool score, and the European Quality of Life Questionnaire (EQ-5D) score. The superiority of tolterodine over imidafenacin in the mean number of micturitions/24 hours was the null hypothesis. RESULTS AND LIMITATION: The median age was 46.6 years, and 82% of patients were female. After treatment, the change in the mean number of incontinence episodes was -2.1 ± 2.2 in the imidafenacin group and -1.9 ± 1.8 in the tolterodine group (P = .001). The change in the mean number of daytime incontinence episodes was -1.7 ± 1.7 and -1.5 ± 1.4 ( P = .01). The OAB Awareness Tool score decreased by 14.2 ± 8.5 and 14.5 ± 8.0, respectively ( P = 0.5). Most adverse events were mild and resolved without treatment. CONCLUSIONS: The clinical efficacy and safety of imidafenacin are not inferior to those of tolterodine for the treatment of Caucasian patients with OAB. PATIENT SUMMARY: Imidafenacin is as effective as tolterodine for the treatment of OAB.

Asunto(s)

Imidazoles/uso terapéutico , Antagonistas Muscarínicos/uso terapéutico , Tartrato de Tolterodina/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Agentes Urológicos/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto Joven

RESUMEN

@#A sensitive and selective method for the determination of imidafenacin in human plasma using liquid chromatography combined with mass spectrometry was established, and was applied to the pharmacokinetic and bioequivalence studies of imidafenacin in healthy Chinese volunteers. After the liquid-liquid extraction pretreatment, samples were separated by UPLC on BEH C8(2. 1 mm×50 mm, 1. 7 μm)column with mobile phase 2 mmol/L ammonium acetate solution with 0. 2% acetic acid and acetonitrile using gradient elution. The mass instrument was operated in the positive ion mode, and the monitored transition was set at m/z 320. 2→238. 1 and m/z 330. 2→248. 2 for imidafenacin and IS(imidafenacin-d10), respectively. In the single-dose, double cycle, self-crossover clinical trial, 24 healthy Chinese volunteers received 0. 1 mg reference or test imidafenacin tablet orally under fasting condition. Drug concentration in plasma was determined by this method and the pharmacokinetic parameters were calculated by DAS 3. 2. 8 software. The linear range of the analysis method is 10. 0 pg/mL to 1 000 pg/mL. The extraction recoveries of the low medium and high concentration samples were 84. 0%, 88. 0% and 90. 0%, respectively. The matrix effects of low medium and high concentration samples were 105%, 100% and 101%, respectively. The pharmacokinetic parameters of imidafenacin for the reference and test tablets were as follows: cmax 524. 8 pg/mL vs 612. 6 pg/mL, tmax 1. 250 h vs 1. 063 h, AUC0-∞ 2 229 pg ·h/mL vs 2 466 pg ·h/mL. The reference and test tablets of imidafenacin were bioequivalent. This method proved to be rapid and accurate for the pharmacokinetic and bioequivalence studies of imidafenacin.

RESUMEN

The objective of this study was to formulate once-a-day extended-release (ER) pellet system of imidafenacin (IDN), a recently approved urinary antispasmodic agent with twice-a-day dosing regimen. The sugar sphere pellets were firstly layered with IDN and hypromellose and then coated with Eudragit RS (copolymers of acrylic and methacrylic acid esters), employed as a release modifier, using a fluid-bed coater. Solid-state characterizations using solid-state X-ray diffraction and differential scanning calorimeter indicated that the antispasmodic agent was homogeneously layered onto the pellets in an amorphous state. Drug release from multiple-unit ER system was effectively retarded in proportion to the amount of Eudragit RS in the outer layer, with a high correlation value above 0.86. In a pharmacokinetic evaluation in beagle dogs, the plasma concentration profile of IDN was markedly protracted by ER pellets, exhibiting delayed the time needed to reach the maximum drug concentration and the elimination half-life in plasma, compared to the commercial immediate release form (Uritos® tablet, Kyorin Pharmaceutical Co., Ltd., Japan). Therefore, the novel ER pellets can be a promising tool for oral IDN therapy, providing a once-a-day dosing regimen, and thus, improving patient compliance.

Asunto(s)

Química Farmacéutica/métodos , Liberación de Fármacos , Imidazoles/sangre , Imidazoles/síntesis química , Resinas Acrílicas/síntesis química , Resinas Acrílicas/farmacocinética , Animales , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/farmacocinética , Perros , Liberación de Fármacos/fisiología , Derivados de la Hipromelosa/síntesis química , Masculino , Polímeros/síntesis química , Polímeros/farmacocinética , Solubilidad

RESUMEN

INTRODUCTION: The analysis of the results of a multicenter, open, randomized comparative phase III clinical trial on the use of imidafenacin for treating patients with OAB was carried out. A clinical study was conducted according to GCP standards in 12 urological centers of the Russian Federation with the support of company AO "R-Pharm". MATERIALS AND METHODS: A total of 296 patients (men and women) aged from 18 to 65 years with OAB and urgent urinary incontinence were included in the study. All patients were randomized into two groups. In Group 1 (n=148) patients received -cholinoblocker imidafenacin 1 tablet (0,1 mg) twice a day. Group 2 patients (n=148) were prescribed a comparison drug tolterodine 1 tablet (2 mg) twice a day, as well. The duration of treatment was 12 weeks. RESULTS: The analysis of results showed a significant decrease in the OAB symptoms in both groups. In Group 1 a decrease of episodes of urge urinary incontinence was more pronounce compared to Group 2, as well as amount of day-time and night-time of episodes of urge urinary incontinence by the 2nd, 4th, 8th and 12th weeks of treatment in comparison with baseline scores. There were no differences between two groups in the severity of reducing average urinary frequency per day. Reducing the severity of urinary disturbances in patients of both groups was accompanied by an improvement in the quality of life. There was a significant and similar decrease in the average total score of both OAB Awareness Tool and EQ-5D questionnaires. Tolerability of treatment was satisfactory in both groups and there were no differences in the adverse events in Group 1 and 2. CONCLUSION: Imidafenacin showed high clinical efficacy for treating patients with OAB, which is not inferior, and in some values, is superior in comparison to tolterodine. Both drugs had a similar safety and tolerability profile.

Asunto(s)

Imidazoles/uso terapéutico , Vejiga Urinaria Hiperactiva , Incontinencia Urinaria , Adolescente , Adulto , Anciano , Compuestos de Bencidrilo , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos , Calidad de Vida , Federación de Rusia , Tartrato de Tolterodina , Resultado del Tratamiento , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Incontinencia Urinaria/tratamiento farmacológico , Adulto Joven

RESUMEN

Imidafenacin, an antimuscarinic agent for treating overactive bladder, has an antidiuretic effect, but the detailed mechanisms of action remain unclear. The cholinergic and vasopressin systems are known to interact, for example, in the suppression of vasopressin-induced water reabsorption through muscarinic stimulation in the renal collecting duct. We, therefore, investigated whether vasopressin signaling pathway would participate in the antidiuretic effect of imidafenacin. In female Sprague-Dawley rats, urine production was measured by collecting urine from cystostomy chatheter using a Bollman restraining cage for 2h after drug i.v. injection and water load (25ml/kg p.o.). Both imidafenacin and a vasopressin V2 receptor agonist desmopressin acetate (desmopressin) dose-dependently suppressed urine production. The combination of imidafenacin and desmopressin at the minimum effective doses suppressed the urine production more strongly than each alone. Mozavaptan hydrochloride (mozavaptan, 3mg/kg), a vasopressin V2 receptor antagonist, completely inhibited the antidiuretic effects of imidafenacin and desmopressin at their respective minimum effective doses. The antidiuretic effect of desmopressin emerged at the maximum antidiuretic dose level (0.1µg/kg) even under mozavaptan-treatment, whereas that of imidafenacin (300µg/kg) was still kept suppressed by mozavaptan. When 300µg/kg imidafenacin was added to the combination of mozavaptan 3mg/kg and desmopressin 0.1µg/kg, the antidiuretic effect was further enhanced. The present study suggests that vasopressin signaling pathway participates in the antidiuretic effect of imidafenacin, and that imidafenacin exerts its antidiuretic effects by enhancing some part of the vasopressin signaling pathway in orally water-loaded rats.

Asunto(s)

Fármacos Antidiuréticos/farmacología , Imidazoles/farmacología , Vasopresinas/metabolismo , Agua/administración & dosificación , Agua/farmacología , Administración Oral , Animales , Desamino Arginina Vasopresina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Compuestos de Piridinio/farmacología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Micción/efectos de los fármacos

RESUMEN

The present study aimed to directly characterize specific binding sites of tritium ([(3)H])-labeled imidafenacin, a new radioligand for labeling muscarinic receptors, in the bladder and other peripheral or central nervous tissues of rats. Muscarinic receptors in rat tissues were measured by radioligand binding assay using [(3)H]imidafenacin. Specific [(3)H]imidafenacin binding in rat tissues was saturable, reversible, and of high affinity. Estimated dissociation constants (Kd values) were significantly lower in submaxillary gland and prostate and higher in heart than in bladder, indicating lower Kd values in M1 and M3 subtype- than M2 subtype-dominating tissues. Unlabeled imidafenacin and clinically used antimuscarinic agents competed with [(3)H]imidafenacin for binding sites in bladder and other tissues in a concentration-dependent manner, which indicated pharmacological specificity of [(3)H]imidafenacin binding sites. Pretreatment with N-(2-chloroethyl)-4-piperidinyl diphenylacetate (4-DAMP mustard), an irreversible inactivating agent of M3 subtype, significantly decreased the number of [(3)H]imidafenacin binding sites in bladder, submaxillary gland, and colon, but not in heart. [(3)H]imidafenacin labeled muscarinic receptors in M1 and M3 subtype-dominating tissues with higher affinity than [N-methyl-(3)H]scopolamine methyl chloride (NMS). [(3)H]imidafenacin is a useful radioligand to label muscarinic receptors in M1- and M3-dominating tissues with high affinity.

Asunto(s)

Imidazoles/metabolismo , Receptores Muscarínicos/metabolismo , Vejiga Urinaria/metabolismo , Animales , Imidazoles/farmacocinética , Masculino , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Distribución Tisular , Tritio

RESUMEN

Antimuscarinics are the first-line choice of treatment for overactive bladder (OAB). Imidafenacin distributes in the bladder more selectively than in the submaxillary gland and colon, and hence, this drug is considered more useful for OAB than other antimuscarinics. However, the examination of imidafenacin selectivity to bladder over colon using in vivo models is limited. Thus, the author examined whether imidafenacin could induce more selective blockade of the bladder over colon in conscious rats using two pharmacological indices (colonic transit and neostigmine-induced fecal pellet output) and compared its bladder selectivity with propiverine. In the bladder study, the inhibitory doses of antimuscarinics were calculated using the area under the curve of the distension-induced rhythmic contraction in conscious rats. The relative bladder selectivity of imidafenacin to propiverine was 50-fold and 61-fold, respectively, in a dye marker colonic transit model and in a neostigmine-induced fecal pellet output model. This comparative study shows that the functional bladder selectivity of imidafenacin is higher than that of propiverine tested under the present conditions in conscious rats.

Asunto(s)

Bencilatos/farmacología , Colon/efectos de los fármacos , Imidazoles/farmacología , Antagonistas Muscarínicos/farmacología , Vejiga Urinaria/efectos de los fármacos , Animales , Colon/fisiología , Defecación/efectos de los fármacos , Tránsito Gastrointestinal/efectos de los fármacos , Masculino , Neostigmina/farmacología , Ratas Sprague-Dawley , Vejiga Urinaria/fisiología

RESUMEN

PURPOSE: Imidafenacin and fesoterodine are used to treat overactive bladder. Imidafenacin, fesoterodine and its active metabolite 5-hydroxymethyl tolterodine are muscarinic receptor antagonists. It is believed that these agents act on afferent nerves in addition to smooth muscle. We investigated the effects of imidafenacin and 5-hydroxymethyl tolterodine on single unit afferent activity of mechanosensitive capsaicin sensitive and insensitive primary bladder afferent nerve fibers in rats. MATERIALS AND METHODS: Female Sprague Dawley® rats were anesthetized. Single unit afferent activity was recorded from the L6 dorsal roots and classified by conduction velocity as that of Aδ or C fibers. After measuring control single afferent activity during constant filling cystometry the procedure was repeated with intravenous administration of imidafenacin (0.3 to 30 µg/kg) or 5-hydroxymethyl tolterodine (0.01 to 1 mg/kg) at cumulative doses with or without intravesical capsaicin or oxotremorine-M instillation. RESULTS: A total of 139 single unit afferent fibers were isolated from 111 rats, including 19 Aδ and 120 C fibers. Neither imidafenacin nor 5-hydroxymethyl tolterodine significantly affected the overall single unit afferent activity of Aδ or C fibers. Based on capsaicin sensitivity C fibers were divided into capsaicin sensitive and insensitive groups. Each antimuscarinic inhibited the single unit afferent activity of capsaicin sensitive C fibers but not of capsaicin insensitive C fibers at the highest dose. Moreover, oxotremorine-M facilitated single unit afferent activity in a proportion of C fibers. The facilitated single unit afferent activity was significantly attenuated by the highest dose of imidafenacin. CONCLUSIONS: These findings demonstrate that imidafenacin and 5-hydroxymethyl tolterodine can selectively inhibit capsaicin sensitive C fibers among mechanosensitive bladder afferents by antagonizing bladder muscarinic receptors.

Asunto(s)

Compuestos de Bencidrilo/farmacología , Capsaicina/farmacología , Cresoles/farmacología , Imidazoles/farmacología , Antagonistas Muscarínicos/farmacología , Fibras Nerviosas Amielínicas/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/inervación , Animales , Femenino , Ratas , Ratas Sprague-Dawley

RESUMEN

OBJECTIVES: This study determined if muscarinic receptors could mediate the cold stress-induced detrusor overactivity induced in type 2 diabetes mellitus rats. METHODS: Ten-week-old female Goto-Kakizaki diabetic rats (n = 12) and Wister Kyoto non-diabetic rats (n = 12) were maintained on a high-fat diet for 4 weeks. Cystometric investigations of the unanesthetized rats were carried out at room temperature (27 ± 2°C) for 20 min. They were intravenously administered imidafenacin (0.3 mg/kg, n = 6) or vehicle (n = 6). After 5 min, the rats were transferred to a low temperature (4 ± 2°C) for 40 min where the cystometry was continued. The rats were then returned to room temperature for the final cystometric measurements. Afterwards, expressions of bladder muscarinic receptor M3 and M2 messenger ribonucleic acids and proteins were assessed by reverse transcription polymerase chain reaction and immunohistochemistry. RESULTS: In non-diabetic Wister Kyoto rats, imidafenacin did not reduce cold stress-induced detrusor overactivity. In diabetic Goto-Kakizaki rats, just after transfer to a low temperature, the cold stress-induced detrusor overactivity in imidafenacin-treated rats was reduced compared with vehicle-treated rats. Within the urinary bladders, the ratio of M3 to M2 receptor messenger ribonucleic acid in the diabetic Goto-Kakizaki rats was significantly higher than that of the non-diabetic Wister Kyoto rats. The proportion of muscarinic M3 receptor-positive area within the detrusor in diabetic Goto-Kakizaki rats was also significantly higher than that in non-diabetic Wister Kyoto rats. CONCLUSIONS: Imidafenacin partially inhibits cold stress-induced detrusor overactivity in diabetic Goto-Kakizaki rats. In this animal model, muscarinic M3 receptors partially mediate cold stress-induced detrusor overactivity.

Asunto(s)

Diabetes Mellitus Tipo 2/metabolismo , Imidazoles/farmacología , ARN Mensajero/análisis , Receptor Muscarínico M2/análisis , Receptor Muscarínico M3/análisis , Vejiga Urinaria Hiperactiva/fisiopatología , Animales , Frío , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Ratas , Ratas Endogámicas WKY , Receptor Muscarínico M2/antagonistas & inhibidores , Receptor Muscarínico M2/genética , Receptor Muscarínico M3/antagonistas & inhibidores , Receptor Muscarínico M3/genética , Estrés Fisiológico/efectos de los fármacos , Vejiga Urinaria Hiperactiva/complicaciones , Vejiga Urinaria Hiperactiva/metabolismo , Micción/efectos de los fármacos , Urodinámica/efectos de los fármacos

RESUMEN

OBJECTIVES: To investigate patient satisfaction with antimuscarinic treatment of overactive bladder syndrome, and to identify factors having a significant influence on satisfaction. METHODS: A cross-sectional questionnaire survey was carried out to assess treatment satisfaction among male and female patients with overactive bladder (age ≥20 years) in the Hokuriku district of Japan. The overactive bladder symptom scores, treatment efficacies, adverse events (dry mouth and constipation), and patient satisfaction scores were investigated and compared among patients using different antimuscarinic therapeutics. RESULTS: In total, 977 survey respondents (52.6% men; mean age 73.6 years) received antimuscarinic treatment. The mean overactive bladder symptom score of these patients was 6.17; in addition, 32.3% patients were satisfied with their treatment, but 33.1% were dissatisfied. Factors having a significant influence on treatment satisfaction were sex (men were less satisfied), efficacy, adverse events and the overactive bladder symptom score. Constipation negatively influenced patient satisfaction to a greater extent than did dry mouth. Patient satisfaction varied according to the drug used. Constipation was less severe with the immediate-release-type agents (imidafenacin and oxybutynin) than with the extended-release-type (propiverine, solifenacin or tolterodine). CONCLUSIONS: Just one-third of Japanese Hokuriku patients with overactive bladder seem to be satisfied with their antimuscarinic treatment. Patient satisfaction is impaired by poor efficacy and the presence of adverse events; furthermore, constipation should be recognized as an adverse event that negatively influences patient satisfaction to a greater extent than dry mouth. Patient satisfaction differs according to the antimuscarinic agent used, with higher patient satisfaction being associated with less severe constipation.

Asunto(s)

Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/efectos adversos , Cresoles/administración & dosificación , Cresoles/efectos adversos , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/efectos adversos , Satisfacción del Paciente , Fenilpropanolamina/administración & dosificación , Fenilpropanolamina/efectos adversos , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Bencilatos/administración & dosificación , Bencilatos/efectos adversos , Estudios Transversales , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Japón , Masculino , Ácidos Mandélicos/administración & dosificación , Ácidos Mandélicos/efectos adversos , Persona de Mediana Edad , Quinuclidinas/administración & dosificación , Quinuclidinas/efectos adversos , Succinato de Solifenacina , Tetrahidroisoquinolinas/administración & dosificación , Tetrahidroisoquinolinas/efectos adversos , Tartrato de Tolterodina , Resultado del Tratamiento

RESUMEN

OBJECTIVES: To assess the effect of imidafenacin on cognitive function, including the conversion rate of mild cognitive impairment (MCI) to dementia, in a period of one year. METHODS: Patients newly administered imidafenacin to treat overactive bladder (OAB), including those who had MCI or dementia, were surveyed across Japan (cognitive safety analysis set [CSAS]), on all of whom we performed the Mini-Mental State Examination (MMSE) at baseline, 24- and 48-weeks after treatment. From CSAS, we extracted well described cases of OAB change as well as drug-related adverse events of dry mouth etc. (efficacy analysis set [EAS]). From CSAS, we extracted MCI cases (MCI set [MCIS]) to analyze the conversion rate of MCI to dementia. MCI is defined by exclusion of normal individual and apparent dementia. RESULTS: The cognitive safety analysis set comprised 187 patients who were collected from 51 medical institutions, and no significant decrease was noted in the MMSE scores in the patients during follow-up. EAS comprised 176 patients. In this group, drug-related adverse events such as dry mouth were reported in 15 (8.5%). MCIS comprised 145 patients. In this group, the annual conversion rate of MCI to dementia was 3.6%, and this rate did not exceed those reported in past epidemiological studies (6.8-16.1% per year). CONCLUSIONS: The present findings suggest that imidafenacin can be used safely for cognitively vulnerable patients with OAB.

RESUMEN

Imidafenacin is an antimuscarinic agent with high affinity for the M(3) and M(1) muscarinic receptor subtypes and low affinity for the M(2) subtype, and is used to treat overactive bladder. Several animal studies have demonstrated that imidafenacin has organ selectivity for the bladder over the salivary glands, colon, heart, and brain. In Phase I studies in humans, the approximately 2.9-hour elimination half-life of imidafenacin was shorter than that of other antimuscarinics such as tolterodine and solifenacin. Imidafenacin was approved for clinical use in overactive bladder in Japan in 2007 after a randomized, double-blind, placebo-controlled Phase II study and a propiverine-controlled Phase III study conducted in Japanese patients demonstrated that imidafenacin 0.1 mg twice daily was clinically effective for treating overactive bladder and was not inferior to propiverine for reduction of episodes of incontinence, with a better safety profile than propiverine. Several short-term clinical studies have demonstrated that imidafenacin also improves sleep disorders, nocturia, and nocturia-related quality of life. In addition, it is speculated that addon therapy with imidafenacin is beneficial for men with benign prostatic hyperplasia whose overactive bladder symptoms are not controlled by alpha-1 adrenoceptor antagonists. No cognitive impairment or influence of imidafenacin on the QTc interval has been observed. Although there have been very few relevant long-term clinical studies, the available information suggests the long-term efficacy, safety, and tolerability of imidafenacin, with less frequent severe adverse events, such as dry mouth and constipation. In addition, imidafenacin can be used safely for a long time even for cognitively vulnerable elderly patients with symptoms of overactive bladder. Thus, it is highly likely that imidafenacin is safe, efficacious, and tolerable to control symptoms of overactive bladder even over the long term. However, it remains unknown if the practical effectiveness of imidafenacin is applicable to ethnic groups other than Japanese.

RESUMEN

Overactive bladder (OAB) is a chronic syndrome defined by symptoms of urinary urgency with no underlying medical causes. First-line treatment of OAB comprises fluid intake advice and bladder training, supplemented by anticholinergic drugs if necessary. Owing to the chronic nature of OAB, the ideal anticholinergic treatment should have good long-term efficacy and tolerability. There are many anticholinergics available, although some of these are not specific for the bladder and can cause adverse effects such as dry mouth, constipation, blurred vision or cognitive impairment. Imidafenacin (a newer anticholinergic which has been marketed in Japan since 2007) was developed to improve the tolerability of anticholinergic therapy. This article summarizes the pharmacological properties, pharmacokinetics, clinical efficacy and tolerability of imidafenacin in the treatment of OAB. Data from key clinical studies of imidafenacin show that it has a fast onset of action and is effective for the treatment of OAB. It selectively binds to muscarinic receptors in the bladder and is associated with a good safety profile compared with other anticholinergics. The clinical efficacy, superior tolerability and adjustable dosing of imidafenacin make it a good anticholinergic for the treatment of OAB.

RESUMEN

OBJECTIVES: Clinical efficacy, influence on quality of life (QOL), and safety of imidafenacin before sleeping were assessed in patients with overactive bladder (OAB) who suffered from nocturia. METHODS: A total of 60 OAB patients with a mean age of 74 years (45 men and 15 women) who mainly complained of nocturia were enrolled. Imidafenacin (0.1 mg) was administered once daily before sleeping for four weeks. Then the patients were divided into two groups, "a stable-dose group" with sufficient efficacy who remained on 0.1 mg of imidafenacin daily, and "a dose-escalation group" with insufficient efficacy in whom the daily dose of imidafenacin was increased to 0.2 mg before sleeping. Lower urinary tract symptoms and postvoid residual volume (PVR) were examined before treatment and after 4 and 8 weeks of imidafenacin therapy. RESULTS: In the stable-dose group, nighttime frequency decreased significantly from 3.4 ± 1.1 to 2.3 ± 1.1 and 2.6 ± 2.0 times after four and eight weeks, respectively. In the dose-escalation group, nighttime frequency did not change significantly (from 3.8 ± 1.5 to 3.6 ± 1.8 times) at four weeks, but decreased significantly to 2.8 ± 1.4 times at eight weeks. Daytime frequency, OAB symptom score, and IPSS-QOL index score were significantly improved in both groups at four and/or eight weeks. There was no increase of PVR and no serious adverse events. CONCLUSION: Administration of imidafenacin at 0.1-0.2 mg once daily before sleeping was safe and effective for the treatment of OAB with the main symptom of nocturia.