托特罗定联合奥昔布宁治疗膀胱过度活动症的疗效及对患者焦虑评分的影响

目的：观察托特罗定联合奥昔布宁治疗膀胱过度活动症的疗效,关注治疗后患者焦虑评分,以期为临床工作提供帮助。方法选取医院收治的144例膀胱过度活动症患者作为研究对象,应用随机区组的原则分为观察组和对照组各72例,对照组应用托特罗定进行治疗,观察组应用托特罗定联合奥昔布宁进行治疗,观察治疗效果。同时应用焦虑自评量表评价治疗后患者的焦虑评分。结果观察组总有效率为98．61％明显高于对照组的90．28％,且治疗后焦虑评分明显低于对照组,差异均有统计学意义（P＜0．05）。结论托特罗定联合奥昔布宁治疗膀胱过度活动症患者的疗效明显,同时能更有效地减少患者的焦虑情绪,临床治疗中可以积极应用。     

酒石酸托特罗定与奥昔布宁双盲双模拟随机对照治疗膀胱过度活动症多中心临床研究

目的评价国产酒石酸托特罗定治疗膀胱过度活动症的有效性和安全性.方法以盐酸奥昔布宁为对照,采用随机双盲双模拟多中心临床试验设计,对237例(托特罗定组114例,奥昔布宁组123例)膀胱过度活动症患者进行研究,服药方法每日2次,每次托特罗定2mg或奥昔布宁5mg.结果治疗6周后,试验组(n=109)和对照组(n=108)24h平均排尿次数减少、尿失禁患者的平均尿失禁次数减少以及平均每次尿量增加比较无统计学差异(P＞0.05).试验组患者不良事件的总发生率48.2%,其中主要不良事件口干发生率为32.5%;而奥昔布宁组不良事件的总发生率为65.0%,口干发生率为55.3%,不良事件总发生率及口干发生率在两组间均有统计学差异(P＜0.05).结论托特罗定是治疗膀胱过度活动症的有效药物,其疗效与奥昔布宁等效,但其药物不良反应明显低于奥昔布宁.     

托特罗定对膀胱活动过度疗效及安全性临床评价

目的评价国产托特罗定治疗膀胱活动过度的疗效和安全性。方法采用多中心、随机、双盲、双模拟平行对照方法,实验组101例,托特罗定2mgbid,共6周;对照组105例,奥昔布宁5mgbid,共6周。于治疗前和治疗后6周测24h平均排尿次数,24h平均排尿量及24h平均尿失禁次数,比较两者的结果及药物不良反应。结果托特罗定治疗后,24h平均排尿次数由12.16±3.44减至7.15±1.78,24h平均每次排尿量从117.97±31.84ml增至213.23±74.72ml,24h平均尿失禁次数从2.98±2.45减至0.06±0.31,与治疗前比较差异非常显著,与奥昔布宁比较无显著性差异。托特罗定药物不良反应发生率32.68%,中度占不良反应的27.27%;奥昔布宁分别为55.24%和39.66%,两者差异非常显著。结论国产托特罗定与奥昔布宁比较,疗效相当,药物不良反应少,是治疗膀胱活动过度的更安全、有效的药物。     

国产盐酸丙哌维林片治疗膀胱过度活动症的临床观察

目的：研究国产盐酸丙哌维林片治疗膀胱过度活动症的疗效和安全性。方法：选择膀胱过度活动症患者42例,分成试验组(22例)和对照组(20例)。试验组早、晚各给予盐酸丙哌维林片20mg 盐酸奥昔布宁模拟片5mg;对照组早、晚各给予盐酸奥昔布宁片5mg 盐酸丙哌维林模拟片20mg。两组疗程为6周。结果：丙哌维林和奥昔布宁治疗膀胱过度活动症疗效相当。前者的不良反应发生率低于后者。结论：盐酸丙哌维林是治疗膀胱过度活动症更为理想的药物。     

治疗膀胱过度活动症的新药托特罗定

托特罗定是新型竞争性毒蕈碱受体拮抗剂，对膀胱的选择性远大于唾液腺的选择性，在临床上用于治疗由膀胱过度活动引起的尿频、尿急和急迫性尿失禁。疗效与奥昔布宁相当，耐受性却明显优于奥昔布宁。主要代谢物为5－羟甲基衍生物，也具有相似的药学活性。     

大视野

新药研发美食品药监局批准奥昔布宁凝用于膀胱过度活动症美FDA已经批准局部外用的3%奥昔布宁凝胶制剂(剂型为84 mg,约为3 ml)用于治疗膀胱过度活动症(OAB),其中涉及尿急、尿频及急迫性尿失禁等症状。奥昔布宁是一种兼     

托特罗定联合氟哌噻吨美利曲辛治疗膀胱过度活动症临床观察

目的 探讨托特罗定联合氟哌噻吨美利曲辛治疗女性膀胱过度活动症（OAB）的临床疗效及安全性.方法 选择确诊为女性膀胱过度活动症患者84例,采用随机数字表法分为观察组和对照组各42例.观察组42例采用托特罗定联合氟哌噻吨美利曲辛治疗,对照组42例单用托特罗定治疗,4周后记录并比较两组临床疗效.结果 观察组总有效率明显优于对照组（95.24％比76.19％,x2=6.291,P＜0.05）;两组平均24h排尿次数、平均24 h尿失禁次数、初始尿意容量及最大膀胱压容量差异均有统计学意义（均P＜0.05）.结论 托特罗定联合氟哌噻吨美利曲辛治疗女性膀胱过度活动症具有疗程短、疗效高、不良反应少等优点.     

托特罗定缓释片治疗膀胱过度活动症的临床研究

目的评价酒石酸托特罗定缓释片治疗膀胱过度活动症的有效性与安全性。方法采用随机、双盲、双模拟平行对照的方法对膀胱过度活动症220例进行托特罗定缓释片剂型组（观察组,110例）和托特罗定原剂型组（对照组,110例）对比研究。托特罗定缓释片,每片4 mg,每日1次,口服;托特罗定片,每片2 mg,每日2次,口服。各连服6周。结果治疗后观察组24 h平均排尿次数由（12.21±3.10）次降至（8.50±2.31）次,24 h平均每次排尿量由（119.80±30.54）ml增至（215.50±68.52）ml、24 h平均尿失禁次数由（2.88±2.5）次减至（0.07±0.38）次。治疗前后比较,有极显著差异（P〈0.01）。两组治疗后相比较,无显著性差异。观察组对药物不良反应发生率为38.0%,中毒发生率为18.5%;对照组分别为40.8%和20.0%,总发生率两者无显著性差异（P〉0.05）。结论托特罗定缓释片与托特罗定片,其疗效与不良反应基本相同。但托特罗定缓释片,用药次数少,服用方便,为膀胱过度活动症治疗药物的最佳选择。     

酒石酸托特罗定缓释片治疗膀胱过度活动症的多中心双盲双模拟随机对照临床研究

目的 评价国产酒石酸托特罗定缓释片（抗膀胱过度活动症药）治疗膀胱过度活动症的有效性和安全性.方法 用随机双盲双模拟多中心临床试验设计,232例（试验组和对照组均为116例）托特罗定缓释片每日1次,每次4 mg;对照组口服托特罗定片每日2次,每次2 mg.均服药6周.结果 试验组（n=111）和对照组（n=112）24 h平均排尿次数减少、平均尿失禁次数均减少;平均每次尿量均增加,2组比较无统计学意义（P＞0.05）.试验组和对照组总药物不良反应发生率分别为39.3%和41.2%,主要表现为口干,发生率分别为35.7%,30.7%,经比较无统计学意义（P＞0.05）.结论 酒石酸托特罗定缓释片治疗膀胱过度活动症的疗效及安全性与其普通片相当.     

曲司氯铵治疗膀胱过度活动症的多中心临床研究

目的：评价曲司氯铵治疗膀胱过度活动症的有效性和安全性。方法：以盐酸奥昔布宁为对照，采用随机双盲双模拟多中心临床试验设计，144例膀胱过度活动症患者随机均分为试验组和对照组，分别服用曲司氨铵20mg或奥昔布宁5mg,bid。结果：治疗6周后，试验组（n=69）和对照组（n=64)24h平均排尿次数头值，尿失禁患者的平均尿失禁次数减少值以及平均每次尿量增加值比较无统计学差异（P＞0．05）。试验组患者不良事件的总发生率为47．2％，其中主要不良事件口干发生率为23．6％，而奥昔布宁组不良事件总发生率为76．4％，口干发生率为68．1％，不良事件总发生率及口干发生率在两组间均有明显统计学差异（P＜0．001）。结论：曲司氨铵治疗膀胱过度活动症与奥昔布宁等效，但不良反应明显低于奥昔布宁。     

Ocular side-effects of tolterodine and oxybutynin, a single-blind prospective randomized trial

AIM: To evaluate the effects of tolterodine and oxybutynin on visual accommodation, pupillary diameter, intraocular pressure and tear secretion in women with overactive bladder. METHODS: One hundred and four eyes from 52 consecutive female patients (age range: 22-60 years) with a urodynamic diagnosis of overactive bladder were prospectively investigated. Patients with a history of ocular disease or surgery were excluded. The subjects were randomly assigned to one of two groups: Group I received 2 mg tolterodine bid and Group II received 5 mg oxybutynin tid. All patients were evaluated at baseline (day 0) and after 1 month of treatment (day 28) by an ophthalmologist who was blinded to the medication. At each time point, a complete ophthalmic examination was performed and accommodation amplitude (AA), and pupillary diameter (PD) in dim and bright light were recorded. As well, tear secretion was assessed based on tear film break-up time and Schirmer I-test results. Statistical comparisons were made using the chi-square test, Student's t-test and Mann-Whitney U-test, as appropriate. RESULTS: Twenty-eight patients (56 eyes) received tolterodine and 24 patients (48 eyes) received oxybutynin. The mean ages of the two groups were similar (P = 0.523). After 4 weeks of treatment, AA was significantly lower in the oxybutynin treated group (P = 0.003, 95% CI 0.15, 0.62) whereas there was no significant change in AA in the tolterodine treated group (P = 0.155, 95% CI -0.042, 0.86). At day 28, PD in dim light was significantly larger in the tolterodine treated group (P = 0.031, 95% CI -0.82, -0.06), whereas no significant change in PD in dim light was noted in the oxybutynin treated group (P = 0.330, 95% CI -0.38, 0.18). Neither group showed a significant change in PD in bright light values on day 28 (P > 0.05 for both). In each group, the differences from day 0 to day 28 for intraocular pressure, and Schirmer-I results were insignificant (P > 0.05 for all). Both groups had significantly shorter tear film break-up time after 1 month of therapy (P = 0.014 (95% CI 0.47, 3.81) and P = 0.02 (95% CI 1.14, 4.61) for the tolterodine and oxybutynin treated groups, respectively). CONCLUSION: Four weeks of standard-dose oxybutynin treatment in women with overactive bladder decreases AA significantly, whereas the same duration of standard-dose tolterodine does not have this effect. However, tolterodine seemed to affect PD in dim light. One month of treatment with either of these anticholinergic drugs shortens tear film break-up time significantly. Concerning ocular side-effects, tolterodine seems to offer an advantage over oxybutynin because it does not affect AA, however, the shorter tear film break-up time with both agents suggests potential problems for patients who already have dry eye.     

Characterization of muscarinic receptor binding and inhibition of salivation after oral administration of tolterodine in mice

The current study was undertaken to characterize the effects of oral administration of tolterodine on muscarinic receptor binding in the bladder and submaxillary gland and on salivation in mice. In the in vitro experiment, tolterodine and its metabolite (5-hydroxymethyl metabolite: 5-HM) competed concentration-dependently with [N-methyl-(3)H]-scopolamine ([(3)H]NMS) in the mouse bladder, submaxillary gland and heart, and the potencies of both agents were greater than that of oxybutynin. After oral administration of tolterodine (6.31, 21.0 micromol/kg) and oxybutynin (76.1 micromol/kg), there was a dose and time-dependent increase in K(d) values for specific [(3)H]NMS binding in the bladder, prostate, submaxillary gland, heart, colon and lung, compared with control values, suggesting significant muscarinic receptor binding in each tissue. The K(d) increase in each tissue by oral oxybutynin reached a maximum value of 0.5 h after oral administration and then rapidly declined, while that by tolterodine was greatest 2 h after the administration and it was maintained for at least 6 or 12 h, depending on the dose and on the tissue. Thus, muscarinic receptor binding of oral tolterodine was slower in onset and of a longer duration than that of oxybutynin. Also, oral oxybutynin showed relatively greater receptor binding in the submaxillary gland as compared with other tissues, but such high selectivity to the exocrine gland muscarinic receptors was not observed by oral tolterodine. Oral administration of tolterodine and oxybutynin reduced significantly the pilocarpine-induced salivary secretion in mice, and the attenuation of oral tolterodine appeared more slowly and it was more persistent than that of oral oxybutynin. The antagonistic effect of oral tolterodine on the dose-response curves to pilocarpine was significantly weaker than that of oxybutynin. These data suggest that oral tolterodine, compared with the case of oral oxybutynin, binds more selectively to muscarinic receptors in the mouse bladder than in the submaxillary gland, which may be advantageous in treating patients with overactive bladder.     

Immediate-release oxybutynin versus tolterodine in detrusor overactivity: a population analysis

We evaluated adherence to treatment with immediate-release (IR) oxybutynin (515 patients) and tolterodine (505 patients) for detrusor overactivity through retrospective analysis of a pharmacy claims database. Outcomes included percentage of patients continuing therapy for 6 months, medication possession ratios, and time to discontinuation of therapy. The proportion of patients continuing therapy for 6 months was statistically superior for tolterodine (32%) compared with IR oxybutynin (22%, p<0.001). Medication possession ratios were also superior for patients in the tolterodine group (medians 0.83 and 0.64, ranges 0.11-1.15 and 0.07-1.13, respectively, p<0.001). Oxybutynin was discontinued significantly earlier (mean 45 days) than tolterodine (mean 59 days, p<0.001) and was switched to another therapy more commonly than tolterodine (19% and 14%, respectively). Tolterodine was favored over oxybutynin for several measurements of patient adherence. However, less than one-third of patients continued therapy with either agent for 6 months. The clinical relevance of these differences is unknown.     

Tolterodine: a review of its use in the treatment of overactive bladder

Tolterodine is a competitive muscarinic receptor antagonist that shows in vivo selectivity for the bladder over the salivary glands compared with oxybutinin. Results of randomised double-blind placebo-controlled studies indicate that tolterodine 4 mg/day (administered as immediate-release tablets 2mg twice daily or extended-release capsules 4mg daily) is superior to placebo in improving micturition diary variables in patients with overactive bladder. Moreover, tolterodine 2mg twice daily is as effective as oxybutynin 5mg 3 times daily. Maximum treatment effects with both drugs occurred after 5 to 8 weeks of treatment and improvements were maintained during long term treatment for up to 24 months. In a pooled analysis of four 12-week studies, equivalent and significant reductions in micturition frequency (-2.3 and -2.0 vs -1.4, p < 0.001) and the incidence of urge incontinence episodes (-1.6 and -1.8 vs -1.1, p < 0.05) were reported for tolterodine 2mg twice daily and oxybutynin 5mg 3 times daily compared with placebo. Functional bladder capacity was also significantly increased. Improvements in patient perceptions of their urgency symptoms and of problems caused by their bladder condition were significantly greater during treatment with tolterodine than with placebo. Tolterodine was generally well tolerated in clinical trials of up to 24 months' duration. Dry mouth was the most frequent adverse event. The incidence (40 vs 78%, p < 0.001) and intensity of this event was lower with tolterodine 2mg twice daily than oxybutynin 5mg 3 times daily. Additionally, a 23% lower incidence of dry mouth was reported with once daily extended-release tolterodine capsules than with twice daily immediate-release tablets (p < 0.02). The incidence of adverse CNS events with tolterodine was low and similar to that of placebo. Tolterodine was well tolerated in elderly patients and no serious tolerability concerns were identified. CONCLUSION: Tolterodine is the first antimuscarinic agent to specifically developed for the treatment of overactive bladder. The functional selectivity of tolterodine for the bladder translates into good efficacy and tolerability in patients, including the elderly, with overactive bladder. Tolterodine is as effective as oxybutynin in improving micturition diary variables but is associated with a significantly lower incidence and intensity of dry mouth. This favourable tolerability profile, together with sustained clinical efficacy during long term treatment, places tolterodine as valuable treatment for the symptoms of overactive bladder.     

Urodynamic effects of oxybutynin and tolterodine in conscious and anesthetized rats under different cystometrographic conditions

Background

Antimuscarinic agents are the most popular treatment for overactive bladder and their efficacy in man is well documented, producing decreased urinary frequency and an increase in bladder capacity. During cystometry in rats, however, the main effect reported after acute treatment with antimuscarinics is a decrease in peak micturition pressure together with little or no effect on bladder capacity. In the present experiments we studied the effects, in rats, of the two most widely used antimuscarinic drugs, namely oxybutynin and tolterodine, utilising several different cystometrographic conditions. The aim was to determine the experimental conditions required to reproduce the clinical pharmacological effects of antimuscarinic agents, as seen in humans, in particular their ability to increase bladder capacity.

Results

Intravenous or oral administration of tolterodine or oxybutynin in conscious rats utilized 1 day after catheter implantation and with saline infusion at constant rate of 0.1 ml/min, gave a dose-dependent decrease of micturition pressure (MP) with no significant change in bladder volume capacity (BVC). When the saline infusion rate into the bladder was decreased to 0.025 ml/min, the effect of oral oxybutynin was similar to that obtained with the higher infusion rate. Also, experiments were performed in rats in which bladders were infused with suramin (3 and 10 μM) in order to block the non-adrenergic, non-cholinergic component of bladder contraction. Under these conditions, oral administration of oxybutynin significantly reduced MP (as observed previously), but again BVC was not significantly changed. In conscious rats with bladders infused with diluted acetic acid, both tolterodine and oxybutynin administered at the same doses as in animals infused with saline, reduced MP, although the reduction appeared less marked, with no effect on BVC. In conscious rats utilized 5 days after catheter implantation, a situation where inflammation due to surgery is reduced, the effect of tolterodine (i.v.) and oxybutynin (p.o.) on MP was smaller and similar, respectively, to that observed in rats utilized 1 day after catheter implantation, but the increase of BVC was not statistically significant. In anesthetized rats, i.v. administration of oxybutynin again induced a significant decrease in MP, although it was of questionable relevance. Both BVC and threshold pressure were not significantly reduced. The number and amplitude of high frequency oscillations in MP were unmodified by treatment. Finally, in conscious obstructed rats, intravenous oxybutynin did not modify frequency and amplitude of non-voiding contractions or bladder capacity and micturition volume.

Conclusion

Despite the different experimental conditions used, the only effect on cystometrographic parameters of oxybutynin and tolterodine in anesthetized and conscious rats was a decrease in MP, whereas BVC was hardly and non-significantly affected. Therefore, it is difficult to reproduce in rats the cystometrographic increase in BVC as observed in humans after chronic administration of antimuscarinic agents, whereas the acute effects seem more similar.     

Transdermal oxybutynin: for overactive bladder

Oxybutynin binds to the M(3) muscarinic receptors on the detrusor muscle of the bladder, preventing acetylcholinergic activation and relaxing the muscle. The transdermal system delivers oxybutynin over a 3- to 4-day period after application to intact skin. Peak plasma concentrations of oxybutynin and the major active metabolite, N-desethyloxybutynin, are reached 24 - 48 hours after a single application and therapeutic concentrations are maintained throughout the dosage interval. In a large, randomised, double-blind trial, transdermal oxybutynin 3.9 mg/day significantly decreased the median number of incontinence episodes per week compared with placebo (-19 vs -15, p = 0.0165) in patients with overactive bladder. In addition, the micturition frequency was reduced and average voided volume was increased by transdermal oxybutynin treatment. Significant reductions in incontinence episodes following transdermal oxybutynin treatment were also observed in two further studies and the clinical efficacy was similar to that of oral tolterodine or oral oxybutynin. Transdermal oxybutynin was well tolerated in clinical trials. Application site reactions were the most common adverse effect; however, the majority were mild to moderate in severity. Adverse events associated with anticholinergic drugs (e.g. dry mouth) were less frequently reported in patients treated with transdermal oxybutynin than in those receiving orally administered oxybutynin or tolterodine.     

Effect of mirabegron, a novel β3-adrenoceptor agonist, on bladder function during storage phase in rats

Mirabegron, a selective β₃-adrenoceptor agonist, facilitates urine storage function by exerting a relaxing effect on bladder smooth muscle. Here, we investigated the effect of mirabegron on bladder function during the storage phase. We assessed the effect of mirabegron on the resting intravesical pressure in anesthetized rats and also tested antimuscarinics (oxybutynin and tolterodine) under the same experimental conditions. Mirabegron dose-dependently decreased the resting intravesical pressure, while oxybutynin and tolterodine showed no statistically significant effects on resting intravesical pressure. We also investigated the effect of mirabegron on bladder function using cystometry technique in conscious rats with bladder outlet obstruction. While mirabegron dose-dependently decreased the frequency of nonvoiding contractions, considered an index of abnormal response in bladder storage, no significant effects were noted on the amplitude of nonvoiding contractions, micturition pressure, threshold pressure, voided volume, residual volume, or bladder capacity. Neither oxybutynin nor tolterodine affected the frequency of nonvoiding contractions; however, oxybutynin increased residual volume and tended to decrease voided volume in a dose-dependent manner, and tolterodine dose-dependently decreased voided volume. Taken together, these results shed light on the suggestion of mirabegron as a therapeutic agent, compared with antimuscarinics, with its most prominent effect being the facilitation of bladder storage.     

Pharmacological effects of imidafenacin (KRP-197/ONO-8025), a new bladder selective anti-cholinergic agent, in rats. Comparison of effects on urinary bladder capacity and contraction, salivary secretion and performance in the Morris water maze task

Imidafenacin (CAS 170105-16-5, KRP-197, ONO-8025) has been developed for the treatment of overactive bladder as a new anti-cholinergic with high affinities for muscarinic acetylcholine M3 and M1 receptors. The pharmacological profiles of imidafenacin on the urinary bladder function by determining carbamylcholine (CCh)-induced decrease in bladder capacity and distention-induced rhythmic bladder contraction in conscious rats were investigated. In addition, effects of imidafenacin on CCh-induced salivary secretion and performance in the Morris water maze task in rats were investigated to evaluate side effects, such as dry mouth and cognitive dysfunction in the central nervous system (CNS). Imidafenacin prevented the CCh-induced decrease in bladder capacity dose-dependently with an ID50 of 0.055 mg/kg. On the distention-induced rhythmic bladder contraction, imidafenacin, propiverine, tolterodine, oxybutynin and darifenacin showed inhibitory effects with ID30's of 0.17, 15, 3.0, 3.2 and 0.85 mg/kg, respectively. The rank order of inhibitory potency was: imidafenacin > darifenacin > tolterodine > or = oxybutynin > propiverine. Imidafenacin, propiverine, tolterodine, oxybutynin and darifenacin showed inhibitory effects on the CCh-stimulated salivary secretion with ID50's of 1.5, 14, 15, 4.4 and 1.2 mg/kg, respectively. The rank order of inhibitory potency was: darifenacin > or = imidafenacin > oxybutynin > propiverine > or = tolterodine. Imidafenacin at the doses of 1 and 10 mg/ kg did not affect the escape latencies in the Morris water maze task compared with those in vehicle controls. Oxybutynin at the dose of 100 mg/kg induced a significant increase in the escape latencies, but propiverine at the dose of 100 mg/kg did not induce significant changes. These results suggest that imidafenacin inhibits urinary bladder contraction to a greater extent than the salivary secretion (compared with the M3 receptor selective antagonist, darifenacin, and the non-selective antagonists, propiverine, tolterodine and oxybutynin) or the CNS functions, such as performance in the Morris water maze task (compared with oxybutynin). In conclusion, imidafenacin has organ selectivity for the bladder over the salivary gland, without influence on the central nervous system such as spatial learning and memory.