托特罗定治疗脊髓损伤所致逼尿肌反射亢进的临床报道

目的观察托特罗定抑制脊髓损伤所致逼尿肌反射亢进,从而建立低压贮留安全膀胱的临床效果。方法36例脊髓损伤的患者经尿动力检查证实存在明确的逼尿肌反射亢进,逼尿肌漏尿点压力均大于40cmH2O,平均82.4cmH2O,并伴有严重的急迫性尿失禁。全部患者均服用舍尼亭治疗,根据清洁间歇导尿记录判断治疗效果。结果4-8周后32例患者最大导尿容量均大于300ml,与治疗前首次无抑制收缩并发生尿失禁时的平均膀胱容量160ml相比明显增加,其中20例完全无尿失禁发生,获得满意效果,12例患者偶发尿失禁治疗有效,4例患者最大导尿容量小于200ml,治疗无效。总有效率89%。结论托特罗定可以有效的抑制脊髓损伤后发生的逼尿肌反射亢进,可以用来建立低压贮留膀胱。     

托特罗定治疗特发性膀胱过度活动症

目的观察新型毒蕈咸受体拮抗药托特罗定治疗特发性膀胱过度活动症的有效性和安全性。方法将托特罗定1mg呼奥昔布宁5mg及安慰剂进行对比,疗程3周。夜间入睡前2h口服。结果与安慰剂相比,托特罗定和奥昔布宁都使入睡前1h夜尿次数(P<0.01)显著减少。两种药物的副作用主要为口干。在口干(发生率和强度)方面,托特罗定要明显优于奥昔布宁(P<0.05)。结论托特罗定治疗特发性膀胱过度活动症效果明确,疗程3周即能达到疗效。尽管奥昔布宁也具有很好的疗效,但不良反应限制了它的应用。     

In vivo evaluation of the potency and bladder-vascular selectivity of the ATP-sensitive potassium channel openers (-)-cromakalim,ZD6169 and WAY-133537 in rats

OBJECTIVE: To compare in vivo the potency and bladder-vascular selectivity of ATP-sensitive potassium channel openers (KCOs) (-)-cromakalim, WAY-133537 and ZD6169 and a muscarinic antagonist, tolterodine in rats. MATERIALS AND METHODS: Bladder and arterial pressures were monitored simultaneously, before and after increasing intravenous doses of compounds, in each of two urethane-anaesthetized rat bladder hyperactivity models: spontaneous non-voiding myogenic contractions secondary to partial outlet obstruction and volume-induced neurogenic contractions. RESULTS: (-)-Cromakalim, WAY-133537 and ZD6169 caused a dose-dependent suppression of spontaneous contractions in the obstructed model, with a 50% inhibition of the contraction area under the curve at doses of 0.06, 0.14 and 2.4 micro mol/kg (intravenous), respectively. Corresponding decreases in mean arterial pressure at these effective doses were 24%, 15% and 15%, respectively. The KCO potency rank order was the same and their relative potency highly comparable in the neurogenic model. There was complete inhibition of spontaneous contractions in obstructed rats at doses corresponding to approximately 50% inhibition of the neurogenic contractions. While tolterodine caused a dose-dependent inhibition of contractions in the neurogenic model, it was ineffective at inhibiting non-voiding contractions in obstructed rats. CONCLUSIONS: All KCOs tested caused significant decreases in arterial pressure at doses effective on the bladder in the model of obstructive instability, suggesting a lack of bladder-vascular selectivity. Similar KCO potency in both assays suggests no appreciable changes in KATP channel function as a result of partial outlet obstruction.     

酒石酸托特罗定渗透泵片的制备及释放度测定

目的制备酒石酸托特罗定渗透泵片,考察其体外释药特性。方法以阿拉伯胶和氯化钠为渗透活性物质制成片芯,以醋酸纤维素、邻苯二甲酸二丁酯和聚乙二醇400为包衣材料,丙酮为包衣溶剂,制备酒石酸托特罗定渗透泵片;采用高效液相色谱法测定其体外释放度。结果以单用阿拉伯胶为促渗剂,当主药与阿拉伯胶用量比为1∶25时,制得的酒石酸托特罗定渗透泵片10h内恒速释药,释药量达85%以上。结论本试验研制的酒石酸托特罗定渗透泵片释药恒速,制备简单,重现性好。     

Efficacy of tolterodine as a first-line treatment for non-neurogenic voiding dysfunction in children

OBJECTIVE: To assess the effect of antimuscarinic treatment with tolterodine combined with behavioural modification as a first-line treatment, before invasive investigation, in children with non-neurogenic voiding dysfunction but no obvious anatomical or neurogenic cause. PATIENTS AND METHODS: The study comprised 44 children presenting with voiding dysfunction (30 girls and 14 boys, mean age 7 years, range 5-14); all had a noninvasive evaluation consisting of a history, urine analysis, renal and bladder ultrasonography and physical examination, with specific emphasis on the voiding pattern. Anticholinergic treatment with tolterodine (1 mg twice daily) was started in all patients; they were also informed about conservative management, including timed voiding, double voiding and relaxation of the pelvic floor during voiding. At the start and after 3 months, the dysfunctional voiding symptom score (DVSS) was completed twice by all patients. RESULTS: For all patients the mean (sd) DVSS was 14.0 (2.67) and 6.68 (3.67) before and after treatment, respectively; the difference was statistically significant (P < 0.001). The mean scores for girls and boys, respectively, were 13.8 (2.79) and 14.5 (2.44) before and 6.43 (3.79) and 7.50 (3.34) after treatment. CONCLUSION: Tolterodine combined with behavioural modification for dysfunctional voiding in children with no neurological or anatomical abnormality can be recommended as a first-line treatment before invasive evaluation. Additionally, the DVSS appears to provide accurate and objective data for monitoring the effect of treatment in such children.     

Solifenacin appears effective and well tolerated in patients with symptomatic idiopathic detrusor overactivity in a placebo- and tolterodine-controlled phase 2 dose-finding study

OBJECTIVES: To evaluate the dose-response relationship and safety/tolerability of solifenacin succinate (YM905) in the treatment of overactive bladder (OAB), and to compare its efficacy and safety/tolerability with tolterodine 2 mg twice daily. PATIENTS AND METHODS: This multicentre study included a 2-week single-blind placebo run-in, a 4-week double-blind placebo-controlled active treatment phase, and a 2-week follow-up. Men and women with an OAB and urodynamic evidence of detrusor overactivity were randomized to placebo or solifenacin 2.5, 5, 10 or 20 mg once daily, or tolterodine 2 mg twice daily. RESULTS: Of 265 patients enrolled, 225 were randomized and 192 completed the study. Solifenacin 5, 10 and 20 mg produced statistically significant (P < 0.05) improvements in voids/24 h vs placebo, whereas tolterodine did not; the mean change with tolterodine was between those with solifenacin 2.5 and 5 mg. The outcome was similar for the mean change from baseline to endpoint in mean volume voided/void. For incontinence and urgency episodes/24 h the solifenacin dose groups showed numerically superior changes vs placebo; the mean effects with tolterodine were generally smaller than with solifenacin. Most of the efficacy effect of solifenacin was evident at 2 weeks. Quality-of-life outcomes supported the efficacy results. Solifenacin 5 and 10 mg were well tolerated; there were no serious treatment-related adverse events. The incidence of dry mouth was 14% for solifenacin 5 and 10 mg, 2.6% for placebo and 24% for tolterodine. CONCLUSION: In this study, the 5- and 10-mg doses of solifenacin appeared to be the most clinically effective for treating OAB, considering the balance between efficacy, quality of life and tolerability. From the results of this study solifenacin 5 and 10 mg were selected for further evaluation in large-scale phase 3 studies.     

Effects of ATP-sensitive K+ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction

AIMS: To compare in vivo the efficacy, potency, and bladder-vascular selectivity of ATP-sensitive potassium channel openers (KCOs), YM934 and (-)-cromakalim to a muscarinic antagonist, tolterodine in a novel partial outlet obstructed pig model. METHODS: Partially obstructed female Landrace pigs were implanted with telemetry transmitters to allow the continuous measurement of intravesical, abdominal and arterial pressures. A subcutaneous port catheter was used to adjust bladder volume. Bladder and arterial pressure were simultaneously monitored under isoflurane anesthesia before and after increasing i.v. doses of test compounds. RESULTS: Under anesthesia, voiding was completely inhibited, but spontaneous, nonvoiding bladder contractions were observed with mean amplitude of 16 +/- 1 cm H(2)O, duration of 35 +/- 2 seconds, and intercontraction interval of 43 +/- 4 seconds (n = 25). YM934 and (-)-cromakalim both caused dose-dependent decreases in bladder contraction area under the curve (AUC) with effective doses to inhibit AUC by 35% of 3.6 and 14.9 nmol/kg, i.v., respectively. However, concomitant reductions in mean arterial pressure of 12 and 13% were also observed. Tolterodine did not inhibit spontaneous bladder contractions at doses up to 100 nmol/kg, i.v. corresponding to plasma concentrations up to 41 ng/mL. CONCLUSIONS: The superior efficacy of KCOs to inhibit spontaneous bladder contractions relative to tolterodine support the hypothesis that KCOs may provide an alternate therapeutic mechanism to treat symptoms of overactive bladder if bladder-vascular selectivity can be sufficiently improved. The minimally invasive model described herein appears useful in the preclinical evaluation of potential therapeutics targeted to treat the overactive bladder.     

The use of tolterodine in children after oxybutynin failure

OBJECTIVE: To assess the safety and efficacy of tolterodine tartrate prescribed to children who previously failed to tolerate oxybutynin chloride. PATIENTS AND METHODS: We reviewed 34 children, followed for>1 year, who were prospectively crossed-over from oxybutynin to tolterodine because of side-effects. The initial diagnosis was dysfunctional voiding in 31 patients. All patients were placed on a behavioural modification protocol. When their symptoms did not improve after 6 months, treatment with an anticholinergic agent was considered. Urodynamic studies were conducted in 20 patients, confirming uninhibited contractions in 19. The remaining 14 patients were empirically started on antimuscarinic or anticholinergic agents. The 34 patients were treated with oxybutynin for a median (range) of 6 (2-84) months. When significant side-effects were reported, they were crossed over to tolterodine. The efficacy of tolterodine was assessed as defined by the International Children's Continence Society, with tolerability assessed and side-effects documented using a questionnaire. RESULTS: The mean age at the first dose of tolterodine was 8.9 years; the dose was 1 mg twice daily for 12 patients and 2 mg twice daily for 22. The median treatment with tolterodine was 11.5 months, with 20 (59%) patients reporting no side-effects; six described the same but tolerable side-effects as with oxybutynin. Eight patients discontinued tolterodine because of side-effects after a median (range) of 5 (1-11) months. The efficacy of tolterodine was comparable with that of oxybutynin, as reported by the questionnaire and voiding diaries. The reduction in wetting episodes at 1 year was> 90% in 23 (68%), more than half in five and less than half (or failure) in six patients. CONCLUSION: Tolterodine is tolerated well in children. In this subgroup of patients who could not tolerate oxybutynin, 77% were able to continue tolterodine treatment with no significant side-effects.     

Fistula Secondary to Unoperated Benign Gastroduodenal Ulcer

The physician must be prepared to recognize bizarre fistulas complicating benign gastroduodenal ulcer and occurring without previous gastric surgery. A benign, often subclinical ulcer crater may suddenly perforate any hollow structure in the upper abdomen or lower chest. The consequences may be remarkably benign or immediately calamitous, depending on the anatomy of the resulting fistula.