[Trospium chloride once daily for overactive bladder syndrome: results of a multicenter observational study]. / Trospiumchlorid als Einmalgabe bei überaktiver Blase: Ergebnisse einer multizentrischen Beobachtungsstudie.

BACKGROUND: An extended release form of trospium chloride (Urivesc 60 mg® slow release capsules) was recently approved for the treatment of overactive bladder syndrome (OAB). A multicentric, prospective observational study was conducted under routine private practice conditions to assess the safety and efficacy of this treatment in this indication, as well as the effect on quality of life parameters. PATIENTS AND METHODS: A total of 305 patients with OAB syndrome (mean age 60 years, 79% females) were evaluated in this prospective, non-interventional observation study. All patients received trospium chloride once daily (Urivesc® 60 mg extended release capsules) in accordance with the approved prescribing instructions. At the start of therapy and after a treatment period of 4 and 13 weeks (median) the patient urological endpoints and quality of life parameters were assessed. Safety and tolerability were evaluated from the documentation of all adverse events occurring during the entire observation period. RESULTS: Mean daily frequency of micturition decreased over the treatment period with once daily trospium chloride from 11.7 ± 4.3 to 7.7 ± 2.9 per 24 h (p<0.0001). In parallel the mean individual urine volume voided increased from 169.3 ± 79.8 ml to 238.4 ± 122.0 ml (p<0.0001). The proportion of patients with incontinence fell from 36.7% at the initiation of therapy to 20.3% at the end of therapy. Furthermore, the mean number of incontinence pads used declined from 3 per day to 1 per day. More than one third of initially incontinent patients (39.3%) needed no incontinence pads at the end of the treatment period. Quality of life parameters improved significantly in all five subsections recorded (i.e. daily life, family life, sleep quality, self esteem and ability to travel). The safety and tolerability of Urivesc 60 mg extended release was good, with a particularly low incidence of mouth dryness (1% of patients) reported. No central nervous system (CNS) associated adverse events and no serious adverse events occurred. CONCLUSION: As a once daily formulation prescribed under normal private practice conditions, the new trospium chloride extended-release formulation consistently demonstrated efficacy and tolerability for treatment of OBS. Treatment with once daily trospium chloride 60 mg extended release capsules significantly improved the frequency of micturition and nocturia, as well as incontinence episodes and use of absorptive pads in this patient population, accompanied by an improvement in quality of life. The reason for the good tolerability, in particular the relatively low incidence of mouth dryness, is probably due to the lower peak plasma concentration of trospium (cmax) enabled by the modified-release galenical form employed by the 60 mg extended release formulation. Once daily administration enabled enhanced compliance for the modified release formulation and associated improved tolerability. The limited access of trospium to the CNS afforded by the intact blood-brain barrier and absence of metabolic interaction potential via cytochrome P450 are established characteristics of trospium chloride. This infers a lower potential to impair cognitive function and a lower potential for metabolic interactions with concomitant medications. In the context of elderly patients and multimorbid and polypharmacy scenarios, the sum of these characteristics may afford distinct advantages in treating OAB patients.

Responses of isolated normal human detrusor muscle to various spasmolytic drugs commonly used in the treatment of the overactive bladder.

The spasmolytic activity of flavoxate (CAS 15301-69-6) and the anticholinergic agents oxybutynin (CAS 5633-20-5), tolterodine (CAS 124937-51-5) and trospium chloride (CAS 10405-02-4), all of which are commonly utilized in the treatment of urinary incontinence, on muscarinic tension and electrically evoked contractions of isolated human detrusor smooth muscle strips was studied using the organ bath technique. Within the concentration ranges tested (trospium chloride 10(-11)-10(-6) mol/l, flavoxate and oxybutynin 10(-9)-10(-5) mol/l, tolterodine 10(-10)-10(-5) mol/l), each drug caused a concentration-dependent relaxation of the tension elicited by muscarinic stimulation and dose-dependently attenuated the contractions induced by electrical field stimulation (EFS). The effects of trospium chloride and tolterodine on carbachol-induced muscarinic tension were more pronounced than those of oxybutynin, while trospium chloride and oxybutynin were most effective in inhibiting the contractions induced by EFS. Flavoxate was significantly less effective than all other drugs tested. Regardless the individual drug concentrations needed for maximal efficacy, the potency of oxybutynin and flavoxate to reverse muscarinic tension and attenuate EFS-evoked contractions was almost comparable while tolterodine and trospium chloride were more effective in relaxing the muscarinic tension of the detrusor strip preparations than causing inhibition of EFS-induced contractions. Our results again underline the ratio for the use of nortropane analogues (trospium chloride) and phenylpropylamine cresols (tolterodine) in the treatment of frequency, urgency and urge incontinence secondary to an overactive bladder.

Comparison of the effects of various spasmolytic drugs on isolated human and porcine detrusor smooth muscle.

The spasmolytic activity of flavoxate (CAS 15301-69-6), anticholinergic agents oxybutynin (CAS 5633-20-5), and trospium chloride (CAS 10405-02-4), drugs commonly utilized in the therapy of hyperactive bladder, and phosphodiesterase (PDE) inhibitors papaverine (CAS 58-74-2) and vinpocetine (CAS 42971-09-5) on muscarinic contractions of detrusor smooth muscle strips isolated from human and porcine urinary bladder was studied in vitro using the organ bath technique. Trospium chloride was most effective in relaxing contractions elicited by muscarinic stimulation, while flavoxate was significantly less effective than all other drugs tested. The relaxing potency of oxybutynin was greater than those of PDE-inhibitors papaverine and vinpocetine but 3,000 fold less significant than those of trospium chloride. The effects of the individual drugs on muscarinic tension of both human and porcine detrusor muscle strips were nearly equal. The present results suggest that the pig might be an appropriate animal model for the study of effects of spasmolytic substances on the contractility of urinary bladder smooth muscle in vitro.

Effects of long-term treatment with anthranoids and sodium picosulphate on the contents of vasoactive intestinal polypeptide, somatostatin and substance P in the rat colon.

OBJECTIVE: To examine the effects of chronic treatment and a single high-dose application of anthranoids and sodium picosulphate on the neuropeptide content of the rat colon. DESIGN AND METHODS: Over a 6-month period, eight groups of rats were each given one of the following: sennosides or sodium picosulphate in low daily doses (10 and 2.5 mg/kg/day, respectively), in high daily doses (40 and 10 mg/kg/day, respectively), and in high twice-weekly doses (30 and 7.5 mg/kg/day, respectively); high daily doses of danthron (500 mg/kg/day); and vehicle (tragacanth 0.5%) only. Four further groups of rats each received a single dose of vehicle or a high dose of one of the three laxatives. All rats were killed 48 h after the last dose. The ascending and descending colon were removed and separated into mucosa, submucosa, and muscularis externa. Vasoactive intestinal polypeptide (VIP), somatostatin, and substance P were extracted by boiling and homogenizing the tissue in acetic acid, and their levels were determined using validated radioimmunoassays. RESULTS: After long-term treatment with high doses of sennosides and danthron, but not after a single high-dose administration, there was a significant reduction in mucosal levels of VIP and somatostatin and in submucosal levels of somatostatin of both colonic segments, as well as in the level of VIP in the muscularis externa of the descending colon. Substance P levels remained unaffected. Sodium picosulphate had no effect. CONCLUSIONS: Chronic treatment with anthranoids in high doses, but not with sodium picosulphate, reduces VIP and somatostatin levels in the rat colon. This may represent damage to the enteric nervous tissue or a pharmacological effect of the anthranoids, causing decreased synthesis or increased breakdown of these peptides.

The involvement of a Ca2+ channel blocking mode of action in the pharmacology of Ammi visnaga fruits.

Based on a screening program of medicinal plants for their possible calcium antagonistic mode of action, the most active lipophilic extract of Ammi visnaga fruits (DAB 10) was fractionated by CC and investigated pharmacologically at K+ (60 mM)-depolarized guinea-pig aortic strips. Visnadin, khellin, and visnagin were identified and determined as the effective principles in this testing model with the dihydropyranocoumarin visnadin being the most active. Further selectivity tests against norepinephrine (100 microM)-induced contractions evaluated a possible pharmacological differentiation between these compounds as the furanochromones khellin and visnagin inhibited both spasms to a similar extent while visnadin's activity was significantly higher against K(+)-spasms, suggesting an involvement of a calcium channel blocking mode of action for visnadin.

Effects of long-term sennoside treatment on in vitro motility of rat colon.

Colonic motility of rats chronically pretreated with either 10 or 40 mg sennosides/kg body weight daily, 30 mg sennosides/kg twice a week or 500 mg danthron/kg daily for 6 months has been evaluated in ex vivo preparations. Registration of colonic contractions 48 h after the last application of drugs or placebo revealed striking differences between the ascending, transverse and descending parts of the colon as well as between corresponding circularly or longitudinally orientated segments. Treatment did not influence motility in the various parts of the colon except some reduction in spontaneous motility in the descending colon. Response to electrical stimulation and acetylcholine was independent of treatment in most segments, but a decrease in maximal contraction was observed by the high daily sennoside dose and by danthron in the ascending colon and descending colon, respectively. Sensitivity to rhein, an active metabolite of sennosides, was similar in all groups. Thus, chronic treatment with anthranoids reveals no abnormal motility pattern but a residual pharmacological activity 48 h after the last administration of high doses.

Chronic sennoside treatment does not cause habituation and secondary hyperaldosteronism in rats.

Rats were treated with sennosides (6 x 10, 6 x 40 or 2 x 30 mg/kg weekly) or with danthron (6 x 500 mg/kg weekly) for 6 months. The laxative effect as measured by faecal wet weight during the first 10 h after treatment increased 3- to 4-fold by the higher sennoside doses (daily or intermittently) and 1- to 3-fold by danthron. The low sennoside dose had no measurable effect except on the 1st day (2 fold) compared with the control group. Mean faecal water content increased from 53% (controls) to 66-79% in rats treated with high sennoside doses and to 57 (1st day) -69% in danthron-treated rats. Serum aldosterone levels and mucosal Na(+)-K(+)-ATPase activities in the small intestine and colon did not change with treatment. There were no signs of habituation or secondary hyperaldosteronism due to sennosides or danthron in spite of chronic diarrhoea over 6 months.

A new method for determining bronchospasmolytic drug effects in vagotomized guinea pigs.

Airways resistance to electrical field stimulation of the vagus nerves was applied to study the efficacies of atropine and trospium chloride in anesthetized guinea pigs. Stimulation induced an airways resistance that was reproducible, thereby significantly lowering blood pressure and reducing heart rate (p less than 0.05). The induced airways resistance was antagonized using 5 micrograms/kg of either atropine or trospium, but was unaffected by physiological sodium chloride solution. At the dose 10 micrograms/kg, trospium chloride was significantly more potent than atropine which showed only slight augmentation in activity. The present results demonstrate that this procedure can be utilized to investigate, both qualitatively and quantitatively, the actions of anticholinergic and bronchospasmolytic agents in laboratory set-ups.

Influence of ganglioside treatment on acrylamide neuropathy in mice. A morphometric study.

Female CBA/J mice were given oral doses of 40 mg/kg acrylamide 3 times weekly for 7 or 11 weeks in order to induce peripheral neuropathy. Half the animals were concurrently treated with 20 mg/kg, subcutaneously, of a ganglioside mixture (Cronassial). The other half received physiological saline and served as control. At the end of 7 or 11 weeks, the tibial nerves were removed and examined histomorphometrically. Every animal had developed a neuropathy. However, the mice treated with the ganglioside mixture showed on both the examination dates a substantially larger proportion of small sprouting nerve fibres than the control. It was concluded from this that treatment with gangliosides stimulated the regenerative potential of the damaged nerves.

In vitro effects of anthraquinones on rat intestine and uterus.

Isolated uterus and colon segments were taken from sennoside-pretreated female rats. They indicate a possible decrease in spontaneous contractility of both organ segments. Addition of rhein-Na, as one of the probable active metabolites of sennosides, into the bath medium of isolated colon and ileum segments of untreated rats showed a reduction in contractility at concentrations of more than 10(-5) and 10(-4) mol/l, respectively. Though rhein-Na in concentrations of more than 10(-4) mol/l impaired acetylcholine-mediated contractures of isolated colon, the antagonism was obviously partial and noncompetitive. Isolated uteri from previously estrogen-treated rats did not show a change in the contractile behaviour up to concentrations of 10(-4) mol/l rhein-Na, whereas higher concentrations induced an increase in contractions. The importance of this finding is not clear.

Spasmolytische wirkung des isoasaronfreien kalmus1.

ACORUS CALAMUS yields different drug types with varying content of beta-asarone, a substance which proved to be carcinogetic in rats. We tested essential oils with different beta-asarone content for their activity against histatnine-spasms in the isolated guinea pig ileum. At a dose level of 10 microg/cm (3), the beta-asarone-free oil (type I) had a pronounced, spasmolytic activity which was comparable to that of the antihistaminic drug pyrilaminemaleate used as a standard antagonist (4 microg/cm (3). Each of these drugs changed the EC (50) for histamine from 29 microg/cm (3) to 118 microg/cm (3) approximately. At a dose level of 10 microg/cm (3) the beta-asarone-rich oil (type IV) showed no spasmolytic activity at all. The essential oil of the european calamus with low content of beta-asarone (type II) had also a good spasmolytic effect, however inferior to that of the beta-asarone-free oil, so that the above cited decrease of the EC (50) value of histamine could be seen in a concentration of 32 microg/cm (3). For this reasons and for better drug-safety, only the rhizomas of the beta-asarone-free diploid or of the triploid calamus with low content of beta-asarone should be used.

[Pharmacodynamics of carteolol]. / Zur Pharmakodynamik von Carteolol.

The compound known as 5-(3-tert-butylamino-2-hydroxy-propoxy)-3,4-dihydro-2 (1H)-quinolinone hydrochloride (carteolol hydrochloride, Endak, Endak mite) has been tested in extensive experimental pharmacological investigations both in vivo in various animal species and in appropriate in vitro systems. From the results it is clear that carteolol is a beta-adrenolytic agent with the following characteristics: 1. Carteolol exerts potent and long lasting blockade of adrenergic receptors, by oral or intravenous administration alike. 2. The effect comprises beta 1- and beta 2-receptors to an equal extent, and for this reason the drug produces haemodynamic changes and metabolic shifts in addition to cardiac effects. Carteolol can therefore be classified as a nonspecific beta-adrenergic blocker. 3. The drug displays a striking feeble local anaesthetic or nonspecific membrane-stabilizing action, probably owing to its pronounced hydrophilia. 4. There is evidence that carteolol has a relatively strong intrinsic sympathomimetic activity (ISA). This has been shown by appropriately planned investigations, and is also apparent after exceeding the doses or concentrations required for adrenolysis. 5. Carteolol causes dose-dependent changes in the electrophysiological parameters of cardiac function. In low doses or concentrations it slows heart rate and in higher doses it sometimes accelerates it. 6. Carteolol is converted - with species-specific differences - almost exclusively and to a relatively small extent into 8-hydroxycarteolol. This metabolite closely resembles the original substance and exceeds it only in ISA.

Damage in vitro to various organs and tissues by rubescenslysin from the edible mushroom Amanita rubescens.

Rubescenslysin, a haemolytic protein from Amanita rubescens, disrupted the cytoplasmic membrane of human leucocytes which were more sensitive than erythrocytes. In the isolated hearts of rats and guinea pigs it caused systolic contracture, which was preceded by potassium outflow and sometimes by a transient positive inotropic effect. On the electrically stimulated guinea-pig left atrium it showed at first a positive, followed by a negative inotropic effect; on the spontaneously beating right atrium it produced transient positive followed by negative inotropic and chronotropic effects. Atria were less sensitive than intact hearts. In the isolated rat phrenic nerve-diaphragm preparation it produced a contracture, which was associated with reduction of indirect and direct contractility. In the isolated guinea-pig ileum it produced a slow contraction followed by tachyphylaxis. As excitability declined due to rubescenslysin, so did excitability by acetylcholine and potassium. Atropine and pheniramine had only feeble antagonistic effects, but papaverine was more powerful. In isolated rat hepatocytes, rubescenslysin caused a rapid outflow of potassium and coarse cell protrusions while later the cells became stainable with trypan blue. In the isolated perfused rat liver it produced a rapid outflow of potassium and of cytoplasmic and mitochondrial enzymes, and a somewhat slower outflow of lysosomal beta-glucuronidase, accompanied by a rise in the lactate/pyruvate ratio and a decrease in bile production. In the isolated perfused rat kidney it caused an outflow of cytoplasmic and mitochondrial enzymes, together with massive proteinuria and serious restriction of sodium and potassium reabsorption and of urine output. In all the tissues investigated the effects of rubescenslysin began within a few min, were dose-dependent and practically irreversible. There were only minor differences in sensitivity between various organs and species. The observations indicate that the toxin is relatively nonspecific in its attack on components of cell membranes.

Toxic effects of phallolysin from amanita phalloides.

Phallolysin, a protein from Amanita phalloides with cytolytic effects in vitro, was highly toxic when given intravenously to rats, mice, rabbits and guinea pigs: i.v. LD50 in rats was 85 Haemolytic Units (HU)/kg, corresponding to 0.05 mg protein/kg b.w. Death ensued from intravascular haemolysis. In rats large doses (600 HU/kg b.w.) caused cardiac death within a few minutes due to liberation of potassium from lysed cells. The serum contained lethal concentrations of potassium. There was also histological evidence of severe renal damage as a result of the haemolysis. In addition, phallolysin directly damaged the isolated guinea pig heart and the isolated rat liver, probably by its action on membranes. Given by mouth, phallolysin was not poisonous to rats.