Effect of terodiline hydrochloride in isolated rabbit detrusor

Effect of terodiline on isolated rabbit and guinea pig detrusor was investigated in comparison with that of flavoxate and oxybutynin. Terodiline (10(-6) M) parallelly shifted the dose-response curve for carbachol in rabbit detrusor to the right, and high doses of terodiline (3 X 10(-6)-3 X 10(-5) M) inhibited the maximal contraction. Flavoxate (10(-5) M or more) also inhibited the maximal contraction. Oxybutynin (10(-8) M or more) shifted the dose-response curve to the right, but did not affect the maximal contraction. At 3 X 10(-6) M or more, terodiline dose-dependently inhibited the Ca-contraction of rabbit detrusor. While the contraction of rabbit detrusor induced by electrical field stimulation was inhibited by atropine (3 X 10(-7) M) or nifedipine (3 X 10(-6) M) by 35% or 73%, respectively, the combination of atropine (10(-7) M) and nifedipine (10(-6) M) abolished it. Oxybutynin (3 X 10(-7) M) inhibited it by about 30%; terodiline (10(-6) M or more) and flavoxate (10(-5) M or more) dose-dependently inhibited it, and abolished at 10(-4) M and 3 X 10(-4) M, respectively. Terodiline inhibited the 1-quinuclidinyl-[phenyl-4-3H]-benzilate binding to the microsomal fraction of guinea pig urinary bladder, brain, atria and ileum dose-dependently, and it had similar affinity among these fractions. Terodiline (3 X 10(-6) M or more) inhibited the 45Ca uptake to minced guinea pig urinary bladder dose-dependently, but did not influence the 45Ca efflux even at 10(-4) M. Flavoxate (10(-4) M) only slightly inhibited the 45Ca uptake.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of absorption,distribution and elimination of fenfluramine and its main metabolite in man

Previously reported data (Beckett & Brookes, 1967) for the excretion of (±)-fenfluramine and its main metabolite, norfenfluramine, have been examined pharmacokinetically using an analogue computer. A three compartment open model was proposed to simulate the biological processes with one peripheral compartment rapidly equilibrating with the central compartment and the second (tissue) compartment only slowly attaining equilibrium. Good agreement between experimental and computed data was obtained, although marked inter-subject variation was recorded. This was attributed to inter-subject differences in the three body compartments. Differences between the pharmacokinetic parameters obtained after oral and intravenous administration of fenfluramine indicated that the drug was significantly N-dealkylated in the intestine or on a first-pass through the liver.     

Effects of amiodarone and its metabolite, desethylamiodarone, on the electrophysiologic properties of isolated cardiac muscle

The electrophysiologic (EP) effects of chronically administered amiodarone (AM) is known, but the nature of its acute effects are unclear. Whether the delayed onset of AM action is due to its metabolite, desethylamiodarone (DAM), is also uncertain. By standard microelectrode techniques in isolated canine ventricular muscle (VM) and Purkinje fibers (PF) and in rabbit sinoatrial (SA) node and atrium, we therefore studied the comparative effects of AM and DAM, 10(-6) M (0.68 micrograms/ml), 10(-5) M (6.8 micrograms/ml), and 5 X 10(-5) M (34 micrograms/ml), dissolved in ethanol and homologous serum. In VM, PF, and atria stimulated at 1 Hz, AM and DAM had no effect on Vmax, action potential amplitude (APA), or resting membrane potential. At 2-4 Hz, AM exerted a marked use-dependent effect in VM and PF. In atria, 5 X 10(-5) M, AM and DAM increased (p less than 0.01) action potential duration at 90% repolarization (APD90); the effective refractory period (ERP) increased by 10.5% (p less than 0.05 for AM) and 21.6% (p less than 0.01 for DAM). In VM, AM increased APD90 by 9.6% (p less than 0.01) at 10(-6) M, 13.7% (p less than 0.01) at 10(-5) M, and 16.9% (p less than 0.01) at 5 X 10(-5) M. The corresponding values for DAM were 5.6% (NS), and 7.3% (p less than 0.01), respectively. The ERP in VM was increased significantly by AM but not by DAM at all 3 drug concentrations without a change in APD90/ERP ratio. In PF, AM and DAM decreased APD50 and APD90; the effects were greater than those produced by the superfusion medium, but the degree of shortening in ERP induced by AM and DAM was not. AM and DAM (10(-5) and 5 X 10(-5) M) increased spontaneous cycle length of rabbit SA node. AM significantly decreased slope of phase 4 depolarization (10.4% at 10(-6) M, p less than 0.05; 14.5% at 10(-5) M, p less than 0.01; 24.0% at 5 X 10(-5) M, p less than 0.01). At 5 X 10(-5) M, AM significantly decreased APA, maximum diastolic potential and threshold potential with an insignificant effect on APD100.(ABSTRACT TRUNCATED AT 400 WORDS)     

Cardiac electrophysiological actions of NS-21 and its active metabolite, RCC-36, compared with terodiline

Terodiline, an anticholinergic drug with a Ca²⁺ blocking action, is thought to be associated with torsade de pointes, a serious ventricular tachycardia. NS-21 is a newly developed drug for the treatment of urinary frequency and urinary incontinence and it has pharmacological properties similar to those of terodiline. It remains unknown, however, whether NS-21 and its active metabolite, RCC-36, have any proarrhythmic activity. The electrophysiological properties of NS-21 and RCC-36 were examined in guinea pig ventricular myocytes and were compared with those of terodiline using the whole-cell patch-clamp technique. NS-21, RCC-36 and terodiline inhibited L-type Ca²⁺ currents in a concentration-dependent manner with IC₅₀ values of 27.0, 27.0 and 33.5 μM, respectively. At a concentration of 10 μM, terodiline inhibited both the time-dependent current and the tail current of the delayed rectifier K⁺ current, with the latter being significantly inhibited at voltages more positive than +10 mV. In contrast, NS-21 and RCC-36 had almost no effect on either of these currents. Terodiline also inhibited the inward rectifier K⁺ current significantly at voltages more negative than -100 mV, whereas NS-21 and RCC-36 had little effect. If the proarrhythmic activity of terodiline resulted primarily from the combined inhibition of K⁺ and Ca²⁺ currents, one might expect that NS-21 and RCC-36, which inhibit L-type Ca²⁺ currents without affecting either the delayed rectifier K⁺ current or the inward rectifier K⁺ current, would not share the proarrhythmic activities of terodiline. Received: 27 August 1996 / Accepted: 13 February 1997     

多沙唑嗪对映体对兔离体膀胱逼尿肌的作用及机制

目的观察多沙唑嗪(rac-DOX)及其对映体(S-DOX、R-DOX)对兔离体膀胱逼尿肌的作用并分析其机制。方法制备兔背侧和腹侧膀胱逼尿肌标本,记录药物或神经刺激诱发的膀胱平滑肌收缩反应。结果在兔背侧和腹侧膀胱逼尿肌标本,卡巴胆碱产生浓度依赖性收缩反应,两种标本的收缩反应差异无显著性(P>0·05)。在背侧膀胱逼尿肌标本,苯肾上腺素产生浓度依赖性收缩反应;但是,苯肾上腺素对腹侧膀胱逼尿肌无作用。S-DOX、R-DOX和rac-DOX在1μmol·L-1时,均可竞争性拮抗苯肾上腺素诱发的兔背侧膀胱逼尿肌收缩反应,其pKB值分别为7·44±0·19、7·39±0·14和7·38±0·30,三者的pKB值相同。电场刺激诱发兔背侧和腹侧膀胱逼尿肌产生稳定的收缩反应,该收缩反应被0·3μmol·L-1浓度的河豚毒素完全阻断。S-DOX、R-DOX和rac-DOX均抑制电场刺激诱发的背侧膀胱逼尿肌收缩反应(P<0·01),且三者的抑制作用强度差异无显著性(P>0·05);但是,它们对电场刺激诱发的腹侧膀胱逼尿肌收缩反应无影响。结论在兔离体膀胱背侧逼尿肌,S-DOX拮抗苯肾上腺素诱发收缩反应的pKB值与rac-DOX和R-DOX相同,三者尚能抑制电场刺激诱发的神经源性收缩反应。     

Effects of metabolic inhibitors on contraction of rabbit detrusor muscle

1. The contractile responses of rabbit detrusor muscle strips to acetylcholine are reversibly depressed but not abolished by 2,4-dinitrophenol (0.1-1.0 mM) provided that D-glucose or D-mannose is present. L-glucose, D-2-deoxyglucose, D-galactose, D-fructose, D-xylose, maltose, lactose and sucrose are ineffective in this respect.2. The contractile responses are greatly reduced by iodoacetic acid (0.1-1.0 mM) in 30-60 min and eventually abolished. The depressant effect of iodoacetic acid (0.25 mM) can be partially reversed or retarded by pyruvate (20 mM).3. It is concluded that the energy for contraction of the detrusor muscle can be supplied by glycolysis alone. Because both D-glucose and pyruvate can be utilized, it is assumed that the glycolytic route and Krebs cycle are available in the detrusor muscle cells.     

Some effects of disopyramide and its N-dealkylated metabolite on isolated nerve and cardiac muscle

In animals and man the antidysrhythmic agent disopyramide in primarily metabolised by mono-N-dealkylation. The effects of disopyramide and its N-dealkylated metabolite (MIP) have been investigated using isolated cardiac and nervous tissue, and their effects have been compared with the effects of other antidysrhythmic agents. Disopyramide, d,l-propranolol and quinidine all decreased both maximum driving frequency and developed tension in electrically driven guinea pit atria. MIP and procaine amide also decreased maximum driving frequency, but had a positive intropic effect. MIP was only 4 times less active than disopyramide in decreasing maximum driving frequency. There was no evidence that either disopyramide or MIP possessed beta-adrenoceptor antagonist properties. In superfused rat sciatic nerves, it has been shown that neither disopyramide nor MIP possesses significant local anaesthetic properties. Procaine amide and lignocaine were highly active in this test. The possible contribution of MIP to the actions of disopyramide in vivo is discussed.     

The metabolite patterns of eltoprazine in man, dog, rat and rabbit

To compare the metabolism of eltoprazine of dog, rat and rabbit with that in man, urine samples were collected after dosing with 14C-eltoprazine. The 14C-labelled metabolites were separated by chromatography and detected by their radioactivity. This resulted in so-called metabolite patterns. The human metabolite pattern contained peaks that were all found in that obtained from the dog's urine. The dog's metabolite pattern had two peaks that were (almost) absent in all other species. The rat's urine gave a pattern which had only two peaks in common with the human pattern. Unchanged drug was excreted in significant amounts by man, dog, and rat, but not by rabbit. This excretion was even a little more pronounced after intravenous injection of the drug. In man, the ratio between unchanged drug and metabolites was fairly constant with time after dosing, while this ratio decreased in the animal species. The major part of the metabolites were sulphate- or glucuronide conjugates, but hydrolysis of these required extraordinary amounts of enzyme. We do not yet know whether the observed species differences reflect differences in conjugating activity or (and) oxidative metabolism. We could not identify important differences in the metabolite patterns that were due to sex or route of drug administration. Also, the site of the 14C-label in the drug molecule hardly affected the metabolite patterns; the only effect was the excretion by the rat of a very polar but minor component when it was dosed with 14C-piperazine labelled eltoprazine. This component was absent when 14C-phenyl labelled eltoprazine was given.     

Inhibitory effects of NS-21, a novel drug for urinary incontinence, and its active metabolite, RCC-36, on L-type calcium currents in isolated guinea pig detrusor smooth muscle cells

The inhibitory effects of NS-21, a newly developed drug for the treatment of urinary frequency and urinary incontinence, and its active metabolite, RCC-36, on L-type Ca²⁺ currents (I_Ca) in guinea pig detrusor smooth muscle cells have been compared to those of terodiline by a whole-cell patch-clamp technique. Like terodiline (10 μM), both NS-21 (10 μM) and RCC-36 (10 μM) induced a sizeable decrease in I_Ca elicited from a holding potential of -60 mV without changing the current-voltage relationship. The three drugs shifted the inactivation curves for I_Ca in the hyperpolarizing direction by 13 to 20 mV but had no effect on the activation curves for I_Ca, resulting in a decrease in the calcium window current. The inhibitory effects of NS-21 and RCC-36 were greater than those of terodiline. The three drugs inhibited I_Ca in a concentration- and holding-potential-dependent manner. The IC₅₀ values at a holding potential of -60 mV were 7.9 μM for NS-21, 6.4 μM for RCC-36, and 5.9 μM for terodiline, and at -40 mV they were 1.3, 1.2, and 3.5 μM, respectively. The ratio calculated by dividing the IC₅₀ value at -60 mV by the value at -40 mV was 6.1, 5.3 and 1.7, respectively, indicating that the inhibitory effects of NS-21 and RCC-36 on I_Ca were more sensitive to voltage than those of terodiline. These results suggest that NS-21 and RCC-36 could be more effective in the treatment of urinary bladder ailments, such as urinary frequency and urinary incontinence. Received: 27 August 1996 / Accepted: 13 February 1997     

Comparison of tegaserod (HTF 919) and its main human metabolite with cisapride and erythromycin on cardiac repolarization in the isolated rabbit heart.

Tegaserod (HTF 919) is a new drug being developed for gastrointestinal motility disorders. Because other gastrointestinal prokinetic agents, such as cisapride and erythromycin, cause slowing of cardiac repolarization and have been implicated in the development of the potentially fatal ventricular arrhythmia, torsades de pointes, a study was initiated to determine whether tegaserod and its main human metabolite adversely influence cardiac repolarization. By using isolated Langendorff-perfused rabbit hearts, we show that QT intervals remain unchanged at concentrations of tegaserod from 0.5 to 10 microM. It was not until the tegaserod concentration was increased to 50 microM (roughly 500-5,000 times more concentrated than those typically found in human plasma after administration of recommended clinical dosages), that a small, but significant increase in the QT interval (12+/-4%; p < 0.05; n = 4) was observed. No significant changes in QT occurred in the presence of the tegaserod metabolite at any of the concentrations tested (0.5-50 microM). In contrast, cisapride caused QT lengthening at concentrations as low as 0.1 microM, with significant QT increases occurring when 5-50 microM cisapride was used (22+/-4% to >70%, respectively; p < 0.01; n = 4). Erythromycin also caused significant lengthening of QT intervals (11+/-2%; p < 0.001; n = 4), although 100 microM concentrations of this drug were required to achieve this effect. These results demonstrate that both cisapride and erythromycin can slow cardiac repolarization at therapeutic doses and that tegaserod's lack of QT prolongation at therapeutic doses suggests that it has the potential to be a safer alternative to cisapride as a gastrointestinal prokinetic agent.     

Comparison of the effects of pinacidil and its metabolite,pinacidil-N-oxide,in isolated smooth and cardiac muscle

The effects of pinacidil and its major metabolite, pinacidil-N-oxide, were compared in isolated smooth and cardiac muscle preparations. Wide variation occurred in the sensitivity of different smooth muscle preparations to the relaxant effect of pinacidil. Relaxant sensitivity of pinacidil was greatest in the one vascular preparation examined, the rat aorta, where the ED₅₀ for pinacidil was approximately 0.5 μM. Pinacidil was equally potent in relaxing serotonin- or norepinephrine-contracted aortic preparations. Although pinacidil was also a smooth muscle relaxant in the guinea pig trachea, guinea pig ileum, rat vas deferens, and rat stomach funds, the ED₅₀ ranged from 1--25 μM in these smooth muscle preparations. In the trachea, pinacidil was most effective in relaxing histamine-induced contractions as compared to contractions induced by carbamylcholine. Thus, bronchodilatory effects of pinacidil might be most apparent when bronchoconstriction is produced by allergic responses that result from histamine release. Pinacidil was least effective in quiescent rat uterine smooth muscle, where approximately 80% of the maximum contractile response to oxytocin was maintained in the presence of 10^?4 M pinacidil. Although a direct cardiostimulatory effect of hydralazine has been postulated, no direct stimulatory effect on guinea pig cardiac rate or force occurred with pinacidil. Furthermore, an inhibitory effect on rate and force of atrial responses occurred only in higher doses of pinacidil. The major metabolite of pinacidil, pinacidil-N-oxide, also relaxed the rat aorta, although it was approximately eight- to tenfold less potent than pinacidil. These data are consistent with the contention that pinacidil-N-oxide would contribute to the antihypertensive activity seen after pinacidil only when plasma levels were approximately tenfold greater than the parent compound. Furthermore, because of the relative insensitivity of other smooth and cardiac.     

Tramadol inhibits the contractility of isolated caprine detrusor muscle

1 The atypical opioid analgesic tramadol has been shown to provide beneficial clinical and urodynamic effects in patients with detrusor overactivity. The effect of tramadol on isolated detrusor muscle has not been studied. This study investigated the ability of tramadol to inhibit acetylcholine (ACh)‐induced contractility of the isolated caprine (goat) detrusor muscle. The effect of three concentrations (30, 100 and 300 μm ) of tramadol on 10 caprine detrusor strips contracted by the addition of 100, 200 or 400 μm ACh was studied. The sensitivity of tramadol‐induced inhibition of ACh responses to treatment with the β‐adrenoceptor antagonist propranolol (1 μm ) and the opioid receptor antagonist naloxone (100 μμ ) was also studied. 2 Tramadol caused a concentration‐dependent inhibition of ACh‐induced detrusor contraction that was reversed by raising the concentration of ACh. Propranolol, but not naloxone, reversed the tramadol‐induced inhibition of contractions to ACh in the detrusor. 3 These results suggest that tramadol inhibits ACh‐induced contractility of the isolated detrusor. They also suggest that tramadol does so by an indirect anticholinergic mechanism involving the stimulation of β‐adrenoceptors. Tramadol may be useful in managing clinical conditions requiring relaxation of the detrusor muscle. Although the concentrations of tramadol needed to relax the detrusor were relatively high, these could be clinically attained via intravesical administration.     

Pharmacodynamics of propiverine and three of its main metabolites on detrusor contraction

1. Besides its antimuscarinic effects, propiverine may possess an additional mode of action. We compared the effects of propiverine, three of its metabolites (M-5, M-6, M-14) and atropine in human, pig and mouse urinary bladder preparations in order to elucidate the nature of a possible additional mode of action. 2. Like the parent compound, M-5, M-6 and M-14 reduced to variable degrees the contractions elicited by electric field stimulation (EFS) of isolated, urothelium-denuded detrusor strips. In mouse the atropine-resistant and therefore the nonadrenergic, noncholinergic component of contractile response to EFS was reduced by M-5, M-14 and propiverine, but was hardly affected by M-6. 3. Atropine, propiverine and M-6 significantly shifted the cumulative concentration-response curves for carbachol (CCh) to higher concentrations. Atropine and M-6 did not affect the maximum tension induced by CCh. Propiverine, M-5 and M-14 reduced the maximum CCh effect, suggesting at least one additional mode of action. This pattern of response was observed in all the three species, albeit with some differences in sensitivity to the various agents. 4. In freshly isolated human detrusor smooth muscle cells, propiverine and M-14 inhibited the nifedipine-sensitive L-type calcium current (I(Ca)) in a concentration-dependent manner. In contrast, the effects of M-5 and M-6 on I(Ca) were insignificant in the concentration range examined. 5. The investigated responses to propiverine and its metabolites suggest that impairment of maximum CCh-induced contractions is due to strong effect on I(Ca) and that this may be associated with the presence of the aliphatic side chain.     

In vitro characterization of alpha-adrenergic receptor in rabbit detrusor muscle

In the isolated detrusor smooth muscle of the rabbit urinary bladder, acetylcholine, prostaglandin (PG) F2 alpha, histamine and methoxamine produced dose-dependent contractions. The order of efficacy was acetylcholine greater than PGF2 alpha greater than histamine greater than methoxamine. Acetylcholine and oxotremorine increased tension remarkably in the rabbit detrusor muscle; and McN-A-343 also developed tension, but with weaker sensitivity and efficacy. The contractile response to acetylcholine was competitively antagonized by atropine (pA2 9.24) and pirenzepine (pA2 6.96), respectively. Histamine and 2-pyridylethylamine caused dose-dependent contractions. On the other hand, dimaprit caused no response in this tissue. Mepyramine (pA2 8.80) competitively antagonized the contraction induced by histamine, whereas cimetidine failed to antagonize the contraction even at a high concentration of 10(-5) M. Norepinephrine, phenylephrine and methoxamine have greater efficacies in the ability to contract than clonidine. R(-)- and S(+)-YM-12617 and YM-12617 (pA2 10.4, 8.31 and 9.75, respectively) and prazosin (pA2 8.13), phentolamine (pA2 7.55) and yohimbine (pA2 6.44) competitively antagonized the contraction elicited by methoxamine. These results suggest that the contraction of rabbit detrusor muscle can be mediated by alpha 1-adrenergic receptors as well as M2-muscarinic and H1-histaminergic receptors and suggest that the contractile force mediated by alpha 1-adrenergic receptor agonist is smaller than those stimulated by the other receptor agonists.     

Bidirectional placental transfer of Bisphenol A and its main metabolite,Bisphenol A-Glucuronide,in the isolated perfused human placenta

The widespread human exposure to Bisphenol A (BPA), an endocrine disruptor interfering with developmental processes, raises the question of the risk for human health of BPA fetal exposure. In humans, highly variable BPA concentrations have been reported in the feto-placental compartment. However the human fetal exposure to BPA still remains unclear. The aim of the study was to characterize placental exchanges of BPA and its main metabolite, Bisphenol A-Glucuronide (BPA-G) using the non-recirculating dual human placental perfusion. This high placental bidirectional permeability to the lipid soluble BPA strongly suggests a transport by passive diffusion in both materno-to-fetal and feto-to-maternal direction, leading to a calculated ratio between fetal and maternal free BPA concentrations of about 1. In contrast, BPA-G has limited placental permeability, particularly in the materno-to-fetal direction. Thus the fetal exposure to BPA conjugates could be explained mainly by its limited capacity to extrude BPA-G.     

多沙唑嗪及其光学异构体对兔离体肠肌收缩活动的影响

指肠收缩力分别为(0.75±0.44)、(0.71±0.22)和(0.87±0.58)g,与用药前收缩力[(3.81±0.66)、(4.12±0.66)和(3.96±0.74)g]或蒸馏水的收缩力[(3.87±0.70)g]相比,差异均有统计学意义(均P<0.01).结论:多沙唑嗪及其光学异构体对回肠和回肠纵肌收缩频率及十二指肠收缩频率和幅度有显著抑制作用,其中左旋多沙唑嗪的抑制作用相对较弱.     

Influence of food on tianeptine and its main metabolite kinetics

The influence of a test meal on the absorption and disposition of tianeptine (Stablon), a new antidepressant, was investigated in 12 healthy subjects in a two-way, randomized, open cross-over study. Single 12.5-mg oral doses of tianeptine were administered following a night of fasting or immediately after a standardized breakfast. When subjects received tianeptine under fasting conditions the lag time before absorption onset, and the time of the maximum plasma concentration were 0.55 +/- 0.26 hours and 1.29 +/- 0.29 hours, respectively. The maximum plasma concentration was 322 +/- 44 ng/mL, and the total area under the curve 994 +/- 248 ng/hr/mL. When tianeptine was given at the end of the meal, several significant changes were found for tianeptine kinetic parameters; the lag time increased by 0.3 hour and the maximum plasma concentration was lowered (decreased by 25%) and occurred later (tmax increased by 0.5 hour). However, no significant change was found in the area under the plasma concentration-time curve. The trend and extent of changes in the MC5 metabolite parameters were similar to those observed for the parent drug. Absorption of tianeptine is slightly delayed and slowed down without modification of its extent when tianeptine is given at the end of a meal. These slight changes are not clinically relevant for an antidepressant administered three times a day. Despite the changes observed, tianeptine may be given at meal times to improve compliance with treatment.     

Pharmacokinetics of triamterene and its metabolite in man

The pharmacokinetic profiles of triamterene and hydroxytriamterene sulfuric acid ester, the major metabolite of triamterene, were studied in six normal male volunteers using a newly developed specific HPLC analytical method. Following a 100 mg oral dose of triamterene, the plasma concentration time course of the sulfate conjugate parallels that of triamterene in all subjects, but concentrations of the metabolite were more than 10 times higher than unchanged triamterene concentrations at identical sampling times. Interestingly, the renal clearance of the sulfate conjugate was less than that of triamterene. These characteristic features of triamterene disposition were fitted to a compartment model incorporating a first-pass metabolic process. Unbound fractions of triamterene and metabolite in plasma were 0.39 and 0.10 (mean of 6 subjects), respectively. The low unbound fraction of the metabolite in plasma most probably accounts for the low renal clearance of the sulfate conjugate as compared with triamterene.Supported in part by NIH Grant AM20884 and funds from Mylan Pharmaceuticals.