propiverine-n-oxide and propiverine

Two comprehensively designed mono-centric ECG studies were performed to investigate the influence of propiverine hydrochloride and its main metabolite propiverine-N-oxide on cardiac function with regard to QTc prolongation, QTc dispersion and T-wave shape.. The first study was conducted on 24 healthy females, followed by a second study on 24 male patients with coronary heart disease (CHD) and a pathological Pardee-Q-wave in the ECG. Both studies were placebo-controlled and compared the effects of single (30 mg s.i.d.) and multiple dosing (15 mg t.i.d.) of propiverine hydrochloride in a crossover design over 6 and 13 days, respectively. In CHD patients, the ECG was recorded under standardized exercise stress conditions.. An effect of propiverine on cardiac safety in healthy women and male patients with CHD could not be determined by the evaluation of QTc intervals derived from ECG under the following conditions: (1) single dosage; (2) steady-state and elevated dosage; (3) healthy female volunteers and male CHD patients; (4) resting and stress conditions in CHD patients. Moreover, other ECG parameters like QT dispersion, T-wave shape, and U-wave occurrence were not affected by propiverine compared to placebo after single or repeated dosing to reach steady-state conditions.. These results reflect and confirm preclinical data as well as clinical observations on hundreds of volunteers and numberless patients suffering from overactive bladder syndrome and neurogenic detrusor overactivity who were treated with propiverine hydrochloride over nearly three decades in Europe and Japan.

Topics: Adult; Aged; Benzilates; Cholinergic Antagonists; Coronary Disease; Cross-Over Studies; Cyclic N-Oxides; Double-Blind Method; Electrocardiography; Female; Heart; Humans; Male; Middle Aged; Potassium

Pharmacokinetic studies in children are particularly required for drugs with intensive hepatic and regioselective intestinal elimination and pharmacological effects that may be critical for absorption at therapeutic doses, such as a delay in intestinal transit. One example is the antimuscarinic drug propiverine, the pharmacokinetics of which were evaluated in the present study in children with symptoms of overactive bladder.. The pharmacokinetics of immediate-release propiverine were studied in a dose-escalating, parallel-group study (propiverine 5, 10 and 15 mg twice daily for 14 days) in 25 subjects (11 females and 14 males aged 5-10 years; bodyweight 17-44 kg; body mass index 14-21 kg/m2) with symptoms of overactive bladder during waking hours. Serum concentration-time curves of propiverine and its major metabolite propiverine N-oxide (M-5) were evaluated up to 3 hours and 8 hours after the first and last administration, respectively, using liquid chromatography with tandem mass spectrometry. The voiding frequency, number of incontinence and urgency episodes, single voided volume and urine flow variables were measured before and after treatment.. Significant dose-related increases in the serum exposure (the area under the concentration-time curve, the maximum concentration and the minimum concentration) with propiverine and M-5 in the dose groups < or =0.3 mg/kg and 0.3 to < or =0.45 mg/kg after both single-dose and repeated-dose administration were found. The elimination half-lives of propiverine and M-5 at steady state were no different (mean +/- SD 12.2 +/- 11.2 and 14.5 +/- 9.94 hours, respectively). Higher doses did not result in additional dose-proportional increases in the respective pharmacokinetic parameters, particularly not after repeated-dose treatment. The voiding frequency, voided volume and urge symptoms were beneficially changed from baseline; significant dose-dependent changes were not observed. Most of the adverse events that were probably or possibly drug related were reported for patients in the high-dose group (>0.45 mg/kg).. The disposition of propiverine is dose related after repeated administration of the recommended doses below 0.45 mg/kg (0.3-0.45 mg/kg) twice daily in children aged 5-10 years with symptoms of overactive bladder and urinary incontinence. (. [clinicaltrials.gov] NCT00795925; [EudraCT] 2004-001243-30).

Topics: Age Factors; Benzilates; Child; Child, Preschool; Cyclic N-Oxides; Dose-Response Relationship, Drug; Female; Humans; Male; Muscarinic Antagonists; Urinary Bladder, Overactive

The objective of this study was to evaluate the influence of propiverine-HCl (P4) and propiverine-N-oxide (P4NO), one of the major metabolites of P4, on bladder contraction in a standardized in vivo model. Additionally, salivary flow measurements enabled the evaluation of hyposalivation, one of the most predominant anticholinergic side effects.. Ten male mini pigs were anesthetized. P4 (0.4 mg/kg b.w.) and P4NO (0.422 mg/kg b.w.) were administered intravenously. Bladder contractions were induced through sacral anterior root stimulation and cystometrogram evaluation was performed. For stimulation-induced salivary flow measurements, the lingual nerve was exposed for neurostimulation. The effects of P4 and P4NO on stimulation-induced bladder contraction and salivation were evaluated in 5 mini pigs, respectively.. In all experiments, for each animal reproducible intravesical pressure values (Pves) were elicited during sacral anterior root stimulation before administration of the study drug. After administration of P4, Pves decreased by 64% whereas P4NO decreased Pves by 28%. Inhibition of salivary flow with P4 and P4NO was 71 and 32%, respectively. Directly following intravenous administration of P4, a short-term and reversible period of mild fluctuations in heart rate was observed. Administration of P4NO revealed no changes in either heart rate, or blood pressure.. All of the investigated parameters revealed less anticholinergic effects for P4NO compared to P4. Under the experimental conditions described above, it may be assumed that P4NO behaves as a substance with poor anticholinergic effects with respect to side effects. As expected, P4 showed anticholinergic effects on bladder contraction and salivation.

Topics: Anesthesia; Animals; Benzilates; Blood Pressure; Cholinergic Agents; Cholinergic Antagonists; Cyclic N-Oxides; Heart Rate; Male; Salivation; Swine; Swine, Miniature; Treatment Outcome; Urinary Bladder

The anticholinergic propiverine (1-methyl-4-piperidyl diphenylpropoxyacetate), which is used for the treatment of overactive bladder syndrome, has functionally active metabolites [M-1 (1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide) and M-2 (1-methyl-4-piperidyl benzilate N-oxide)], but the site of actions of these metabolites is uncertain. Propiverine is rapidly absorbed after oral administration and is extensively biotransformed in the liver, giving rise to several active metabolites (M-1 and M-2). This study determines the effect of M-1 and M-2 on voltage-dependent nifedipine-sensitive inward Ca(2+) currents (I(Ca)) using patch-clamp techniques and fluorescent Ca(2+) imaging [after electrical field stimulation (EFS) and acetylcholine (ACh)] in the murine urinary bladder. In conventional whole-cell recording, propiverine and M-1 but not M-2 inhibited the peak amplitude of I(Ca) in a concentration-dependent manner at a holding potential of -60 mV (propiverine, K(i) = 10 microM; M-1, K(i) = 118 microM). M-1 shifted the steady-state inactivation curve of I(Ca) to the left at -90 mV by 7 mV. Carbachol (CCh) reversibly inhibited I(Ca). This inhibition probably occurred through muscarinic type 3 receptors, coupling with G-proteins, because nanomolar concentrations of 4-diphenylacetoxy-N-methyl-piperidine greatly reduced this inhibition, whereas pirenzepine or 11-([2-[(diethylamino)methyl]-1-piperdinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116) at concentrations up to 1 microM was almost ineffective. In the presence of M-2, the CCh-induced inhibition of I(Ca) was blocked. In fluorescent Ca(2+) imaging, M-2 inhibited EFS-induced and ACh-induced Ca(2+) transients. These results suggest that M-1 acts, at least in part, as a Ca(2+) channel antagonist (as it inhibited I(Ca)), whereas M-2 has more direct antimuscarinic actions.

Topics: Animals; Benzilates; Calcium; Calcium Channel Blockers; Calcium Channels, L-Type; Cholinergic Antagonists; Cyclic N-Oxides; Electric Stimulation; Male; Mice; Mice, Inbred BALB C; Myocytes, Smooth Muscle; Patch-Clamp Techniques; Receptor, Muscarinic M3; Urinary Bladder

To investigate the effects of M-1, a major active metabolite of propiverine on the bladder.. We have evaluated the effects of M-1 on the contractions induced by carbachol, KCl, CaCl(2), 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.. 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 CaCl(2)-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.. 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.

Topics: Aged; Animals; Benzhydryl Compounds; Benzilates; Carbachol; Cholinergic Agonists; Cresols; Cyclic N-Oxides; Female; Humans; Models, Animal; Muscarinic Antagonists; Muscle Contraction; Muscle, Smooth; Parasympatholytics; Phenylpropanolamine; Rats; Rats, Wistar; Tolterodine Tartrate; Urinary Bladder

A high-performance liquid chromatographic method has been developed for the determination of propiverine hydrochloride (P4) and its main metabolite, propiverine N-oxide (P4NO) in human serum. P4 has been shown to be efficacious in those patients who have either idiopathic bladder instability, or neurogenic bladder (detrusor hyperflexia) resulting from spinal cord injuries. In the present method, the analytes were extracted from serum (1 ml, pH 8) into methyl tert.-butyl ether. The separation was performed on a reversed-phase C8 (RP-select B) column using phosphate buffer-acetonitrile (30:70, v/v). UV absorption was used for measuring the analytes, with a limit of quantitation of about 10 ng/ml, which is appropriate for pharmacokinetic studies.

Topics: Benzilates; Chromatography, High Pressure Liquid; Cyclic N-Oxides; Humans; Oxides; Reproducibility of Results; Sensitivity and Specificity