盐酸丙哌维林对豚鼠离体膀胱平滑肌条的钙拮抗作用

目的　研究盐酸丙哌维林 (P 4)对豚鼠离体膀胱平滑肌条的钙拮抗作用及作用机制。方法　采用离体平滑肌条浴槽实验方法 ,以维拉帕米为对照 ,测定P 4对CaCl2 和组胺 (His)所致离体膀胱平滑肌条的收缩及对乙酰胆碱 (ACh)所致膀胱平滑肌依赖细胞内钙、外钙收缩的影响。结果　P 41～ 1 0 0 μmol·L- 1 使CaCl2 累积量效曲线非平行右移 ,最大反应降低 ,pD2 ′为 4 73± 0 1 4。P 41 μmol·L- 1 使His量效曲线平行右移 ,最大效应不变 ,pA2 为 5 44± 0 1 4 ;1 0～ 1 0 0μmol·L- 1 使His量效曲线非平行右移 ,最大效应降低 ,pD2 ′为 4 71± 0 1 0。P 41、1 0和 1 0 0 μmol·L- 1 对ACh所致依赖细胞内钙收缩的抑制率分别为 45 77%± 6 54 %、86 2 6 %± 5 59%和 90 55 %± 3 1 1 % ,对依赖细胞外钙收缩的抑制率分别为 7 30 %± 2 89%、49 1 6 %± 6 0 9%和 88 2 5 %±3 70 %。结论　P 4低浓度时竞争性拮抗His所致膀胱平滑肌条的收缩反应 ,明显抑制膀胱平滑肌条依赖细胞内钙释放的收缩反应 ;高浓度时非竞争性拮抗His和CaCl2 所致膀胱平滑肌条的收缩反应 ,明显抑制膀胱平滑肌条依赖细胞内钙释放和外钙经钙通道内流所致收缩反应     

Randomized Controlled Trial to Treat Benign Prostatic Hyperplasia with Overactive Bladder Using an Alpha‐blocker Combined with Anticholinergics

Objectives: TAABO was a randomized, controlled trial to evaluate the efficacy and safety of combination therapy of tamsulosin (TAM) with propiverine (PROP) in men with both benign prostatic hyperplasia and overactive bladder. Methods: It enrolled men 50 years or older who had an international prostate symptom score (IPSS) of 8 or higher, an urgency item score of 1 or higher, and a quality of life (QOL) score of 2 or higher. After 8 weeks of TAM 0.2 mg/day, patients who met the inclusion criteria (8 micturitions per 24 h and 1 urgency per 24 h, evaluated by bladder diary) and were eligible for 12‐weeks of continued Treatment II. Five hundred and fifteen patients were enrolled. Thereafter, 214 patients were assigned randomly to receive either TAM alone (n = 67), TAM plus PROP 10 mg (n = 72), or TAM plus PROP 20 mg (n = 75) in Treatment II. The primary efficacy end point was a change in micturitions per 24 h documented in the bladder diary. The change from baseline in urgency episodes per 24 h, IPSS, IPSS/QOL subscore, urinary flow rate and postvoid residual volume were assessed as secondary efficacy measures. Results: A total of 141 men (47 TAM, 49 TAM plus PROP 10 mg, and 45 TAM plus PROP 20 mg patients) were assessed by week 12. Compared with the TAM, TAM plus PROP 10 mg patients experienced significantly fewer micturitions (P = 0.0261), urgencies (P = 0.0093) per 24 h, lower IPSS storage (P = 0.0465), and IPSS urgency (P = 0.0252) subscores. Conclusions: These results suggest that combining TAM and 10 mg of PROP for 12 weeks provides added benefit for men with both benign prostatic hyperplasia and overactive bladder.     

Failure of monotherapy in primary monosymptomatic enuresis: a combined desmopressin and propiverine treatment regimen improves efficacy outcomes

OBJECTIVE

To evaluate, in a prospective study, the combination of the antimuscarinic propiverine and the antidiuretic hormone‐agonist desmopressin in children and adolescents not responsive to previous monotherapy, as in primary monosymptomatic enuresis (PME), combined treatments are considered a second‐line approach after the failure of monotherapy.

PATIENTS AND METHODS

The study included 122 children and adolescents (mean age 10.8 years, range 5–21) with PME and so far unresponsive to single or multiple monotherapy. Propiverine (body weight <30 kg, 15 mg/day; ≥30 kg, 20 mg/day) and desmopressin (0.4 mg/night) were administered over 3 months, followed by successive structured withdrawal programmes for propiverine and desmopressin, depending on the amount of loss of urine at night before treatment.

RESULTS

The re‐evaluation of unresponsive patients, incorporating video‐urodynamics, showed neurogenic detrusor overactivity, isolated detrusor sphincter dyssynergia and vesicorenal reflux in 12.3% (15/122) of patients, so far falsely treated as enuresis. In 107 of 122 patients the diagnosis of PME was confirmed. The primary efficacy outcome, continence at night, was achieved in 104 of 107 patients (97.2%). During the individual follow‐up periods (3–12 months), 23 of 107 (21.5%) patients relapsed after withdrawal of both medications. Adverse events of moderate intensity were rare (3.7%).

CONCLUSION

Re‐evaluation of patients after monotherapy has failed is justified, because other entities can be discovered in patients so far treated unsuccessfully for enuresis. The combination of propiverine and desmopressin is highly effective in children with PME. Our results support the case for further optimizing the inaugurated treatment algorithm of PME for treatment duration, dose‐titration and structured withdrawal programmes, thus possibly further decreasing relapse rates.     

Comparison of the efficacy, safety, and tolerability of propiverine and oxybutynin for the treatment of overactive bladder syndrome

AIM: To compare the effects of propiverine and oxybutynin on ambulatory urodynamic monitoring (AUM) parameters, safety, and tolerability in patients with overactive bladder. METHODS: This was a randomized, double-blind, placebo-controlled, multicentre, crossover study. Patients (n = 77) received two of the following treatments during two 2-week periods: propiverine 20 mg once daily, propiverine 15 mg three times daily, oxybutynin 5 mg three times daily, and placebo. AUM parameters, salivary flow, visual near point, and heart rate were assessed. RESULTS: A consistent order in the efficacy between active treatment groups was observed for the reduction in mean involuntary detrusor contractions (IDCs; oxybutynin 15 mg propiverine 45 mg propiverine 20 mg). Differences between the oxybutynin and propiverine 20 mg groups were statistically significant for several AUM endpoints. Statistically significant differences between the oxybutynin and both propiverine groups were also noted in salivary flow rate and heart rate (oxybutynin 15 mg < both propiverine regimens) and in heart rate variability (both propiverine regimens < oxybutynin 15 mg). All active treatments lengthened visual near point. The incidence of dry mouth was significantly more pronounced in the oxybutynin group than in either propiverine group. Treatment with propiverine 45 mg resulted in the highest rates of constipation, lengthening of the visual near point, and effects on heart rate. CONCLUSIONS: Oxybutynin 15 mg was more effective than propiverine 20 mg in reducing symptomatic and asymptomatic IDCs in ambulatory patients. The primary differences between the two drugs were the incidence and type of adverse events, which varied with the antimuscarinic receptor specificity of each agent.     

盐酸丙哌维林对膀胱平滑肌收缩的影响(英文)

观察了盐酸丙哌维林 ( Pro)对离体豚鼠膀胱平滑肌自动节律性收缩和 KCl诱导离体豚鼠膀胱平滑肌收缩的影响 ;同时观察了 Pro对家犬在体膀胱自动节律性收缩的影响 .Pro在 1 ,1 0 μmol· L-1浓度时 ,对离体豚鼠膀胱平滑肌自动节律性活动具有兴奋作用 ,可使自动节律性收缩频率增加 ,幅度加大 ;在 1 0 0μmol· L-1浓度时则表现为抑制作用 ,可完全抑制豚鼠膀胱平滑肌的自动节律性收缩 ,同时可使平滑肌松弛 ,基础张力降低 .Pro对 KCl引起的豚鼠离体膀胱平滑肌的收缩具有明显的抑制作用 ,在 1 ,1 0 ,1 0 0 μmol· L-1浓度时对 KCl诱导豚鼠离体膀胱平滑肌收缩的抑制率分别为 ( 7.4±6.5) % ,( 31 .3± 1 2 .8) % ,( 68.4± 7.1 ) % ,其 IC50 为( 2 5.2± 4.7) μmol·L-1.十二指肠给 Pro对在体家犬膀胱自动节律性收缩具有明显的抑制作用 ,60 ,30mg· kg-1可明显降低膀胱自动节律性收缩频率和幅度且具有剂量依赖性 ,与药前比有显著性差异 ,60 mg· kg-1药后 1 0 min即可起效 ,药效可持续 90min,Pro在上述剂量下对血压 ,心率无明显影响 .本实验结果提示 Pro在低剂量时对离体膀胱自动节律性收缩具有一定的兴奋作用 ,在高剂量时则表现为明显的抑制作用 ;Pro对 KCl诱导的豚鼠离体膀胱平滑肌收缩和膀胱扩张诱导的家?     

Efficacy,tolerability and safety of propiverine hydrochloride in comparison to oxybutynin in children with urge incontinence due to overactive bladder: Results of a multicentre observational cohort study

Study Type – Therapy (observational cohort)
Level of Evidence 2b

OBJECTIVE

To compare, in a retrospective observational cohort study, the efficacy, tolerability and safety of propiverine and oxybutynin in children with urge incontinence (UI) due to overactive bladder.

PATIENTS AND METHODS

Medical records were scrutinized for children with UI. As a primary efficacy outcome variable the achievement of continence after treatment with variable doses of propiverine or oxybutynin was assessed. Weekly UI episodes and daily voiding frequency were evaluated as secondary efficacy outcomes. Tolerability was evaluated by the rate of adverse events, adverse drug reactions caused by antimuscarinics and premature treatment termination.

RESULTS

At 16 study centres, 621 children aged 5–14 years with UI due to overactive bladder were enrolled. After anticholinergic treatment (437 propiverine, 184 oxybutynin) continence was achieved in 61.6% and 58.7% of the patients after 186 and 259 days, respectively. There were clinically relevant improvements in voiding frequency across treatment groups. Daily doses of propiverine were markedly below the recommendations (0.54 vs 0.8 mg/kg body weight), daily doses of oxybutynin were according to the recommendations (0.31 vs 0.2–0.4 mg/kg body weight) at treatment initiation. There was a significantly more favourable tolerability to propiverine than oxybutynin for the overall rate of adverse events (3.9% vs 16.3%, odds ratio 4.813), adverse drug reactions caused by propiverine or oxybutynin (2.8% vs 9.2%) and premature treatment termination due to adverse drug reactions (1.6% vs 4.4%).

CONCLUSION

Propiverine and oxybutynin are effective in children with UI due to overactive bladder. Sufficient treatment periods of at least 2, preferably 3–4, months are the crucial factors for a successful treatment. The tolerability profile of propiverine is better than for oxybutynin.     

Urinary urgency outcomes after propiverine treatment for an overactive bladder: the ‘Propiverine study on overactive bladder including urgency data’

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To investigate the effects of a daily regimen of propiverine 20 mg in patients with an overactive bladder (OAB), focused on improving urgency, as the clinical efficacy of treatment for OAB should be measured in terms of urgency, the cornerstone symptom of OAB.

PATIENTS AND METHODS

Eligible patients aged ≥18 years with symptoms of OAB were enrolled in this multicentre, prospective, parallel, double‐blind, placebo‐controlled trial. Of 264 patients (mean age 52.2 years), 221 who had efficacy data available from baseline and at least one on‐treatment visit with >75% compliance with medication were analysed (142 in the propiverine group and 79 in the placebo group). All patients were randomized to receive a placebo or 20 mg propiverine once daily in a 12‐week study. They completed a 3‐day voiding diary before visits during the study period, including the severity of urgency associated with every voiding, using the Indevus Urgency Severity Scale and the Urgency Perception Score. The patients’ overall self‐evaluation of treatment benefits at the end of the study, and safety data, were also collected.

RESULTS

The daily urgency episodes reduced significantly from baseline to 12 weeks on propiverine treatment, compared with placebo (?46.0% vs ?31.3%, P = 0.005). Secondary endpoints, including sum of urgency severity per 24 h, urgency severity per void, and daytime voiding frequency, were also improved significantly in the propiverine group. Overall, of those patients treated with propiverine, 38.7% rated their treatment as providing ‘much benefit’, compared with 15.2% of the placebo group (P = 0.025). Adverse events reported by 32 (22.5%) and 10 (12.7%) patients in the propiverine and placebo group were all tolerable. However, this is a short‐term study using only one fixed regimen.

CONCLUSIONS

Propiverine 20 mg once‐daily could be an effective treatment for patients with OAB, by improving urgency.     

盐酸丙哌维林片稳定性及溶出度研究

 目的:对盐酸丙哌维林片剂的稳定性和溶出度进行系统研究。方法:采用高效液相色语-紫外检测法为测定影响因素试验、加速试验及室温留样条件下的稳定性和溶出度。结果:在各种考察条件下，样品的外观、含量、有关物 质及溶出度均未发生明显变化，45min时溶出度在85%以上。结论:盐酸丙哌维林片剂质量稳定，并具有较好的溶出性能。     

Pharmacological effects of propiverine and its active metabolite, M-1, on isolated human urinary bladder smooth muscle, and on bladder contraction in rats

Objective:   To investigate the effects of M-1, a major active metabolite of propiverine on the bladder.
Methods:   We have evaluated the effects of M-1 on the contractions induced by carbachol, KCl, CaCl₂, and electrical field stimulation (EFS) in human detrusor smooth muscles, and pelvic nerve stimulation-induced bladder contractions in rats. The effects of M-1 were also compared with the effects of propiverine and tolterodine.
Results:   Pretreatment with propiverine and tolterodine caused parallel shifts to the right of the concentration-response curves to carbachol. M-1 caused concentration-dependent reduction in the maximum contractile responses induced by carbachol. Although tolterodine did not inhibit the KCl- and CaCl₂-induced contractions, M-1 and propiverine significantly inhibited these contractions. In the presence of atropine, M-1 and propiverine significantly inhibited the atropine resistant part of the contraction induced by EFS. On the other hand, tolterodine did not have significant inhibitory effects on atropine resistant contractions. Pelvic nerve stimulation induced bimodal phasic and tonic contractions in the rat bladder. M-1 mainly inhibited the phasic contraction. Tolterodine caused a significant inhibition in the tonic contraction, and propiverine had inhibitory effects on both contractions.
Conclusions:   The present results suggest that M-1 has inhibitory effects on the bladder smooth muscles through calcium antagonistic action. It is possible that the clinical effects of propiverine on the human bladder are based not only on the action of propiverine itself but also on one of its active metabolites, M-1.