Importance of pharmacological and physicochemical properties for tolerance of antimuscarinic drugs in the treatment of detrusor instability and detrusor hyperreflexia--chances for improvement of therapy.

BACKGROUND: Antimuscarinic side-effects are relatively frequent problems in oral pharmacotherapy of detrusor instability and neurogenic dysfunction of the urinary bladder. Results of recent clinical trials demonstrate differences in tolerance between antimuscarinic drugs. It is the purpose of this paper to relate the available clinical data to the pharmacological and physicochemical properties of the different antimuscarinic drugs, in order to discuss the reasons for this enhanced tolerance and to make possible modes for improvement of antimuscarinic therapy plainly visible. METHODS: Therefore, we reviewed the available literature using among others the computerized library systems Medline (National Library of Medicine, Bethesda, Maryland, USA) and Embase (Excerpta Medica, Amsterdam, the Netherlands). Differences in tolerance of oral antimuscarinic drugs may result from muscarine-receptor selectivity, organ selectivity, and pharmacokinetic as well as physicochemical properties. While the roles of m-receptor and organ selectivity need more detailed clarification, influences of differences in bioavailability and physicochemical properties on the tolerance of antimuscarinic drugs are more sufficiently investigated. RESULTS: Generally, tolerance as well as efficacy of antimuscarinic drugs seem to be a complex result of a combination of various pharmacological properties distinguishing the individual substances. The enhancement of tolerance of propiverine hydrochloride, tolterodine tartrate and trospium chloride compared to oxybutynin chloride seems to be reached by different modes, from which the molecular structure -- propiverine and tolterodine are tertiary amines, trospium chloride possesses a quarternary ammonium structure -- may be of great importance. First investigations with alternative transdermal and intravesical application routes show interesting possibilities for further improvement of antimuscarinic therapy in urological indications. CONCLUSION: In conclusion, from pharmacological and clinical data it becomes obvious that there are significant differences between antimuscarinic drugs, which are of clinical relevance and include possible starting points for the development of new drugs and application forms.

Effect of Trospium Chloride on Duodenal Motility during Upper Gastrointestinal Endoscopy: A Randomised, Double-Blind, Placebo-Controlled Trial.

In a placebo-controlled, double-blind study the effects of depressing duodenal motility by administration of intravenous trospium chloride during gastroduodenoscopy were studied in 72 patients randomised to receive trospium chloride or saline (controls). Intravenous trospium chloride 1.2mg stopped the visible contractile activity of the duodenum as assessed by 3 independent observers during videoendoscopy within 76 seconds (median). During a 4-minute observation period of duodenal peristalsis, duodenal motor activity was found to stop in 18 of 36 patients after trospium chloride but in only 5 of 36 patients in the placebo group (p = 0.002). Adverse effects were dry mouth, micturition difficulties, sweat retention, accommodation disturbance and tachycardia. Trospium chloride was effective in reducing contractile activity in the duodenum. Its potent action and minor adverse effect profile appear to be promising for gastroduodenoscopy and especially for sphincter of Oddi motility in patients during routine endoscopic retrograde cholangiopancreatography.

Influences of trospium chloride and oxybutynin on quantitative EEG in healthy volunteers.

Trospium chloride and oxybutynin are two antimuscarinergic agents used in the treatment of unstable bladder, urge incontinence, combined stress urge incontinence and detrusor hyperreflexia. The possibility that these two drugs produce changes in central nervous electrical activity was examined in an open, prospective, phase I study involving 12 volunteers. Quantitative evaluation of the multichannel electroencephalogram obtained from young healthy volunteers showed statistically significant decreases in alpha and beta 1 activity after oxybutynin, but not after intravenous or oral administration of trospium chloride. The biological activity of both drugs was ascertained by continuous simultaneous recording of the heart rate. A decrease in heart rate was detected after oral administration of oxybutynin, and an increase was seen after i.v. administration of trospium chloride. The results suggest that trospium chloride is less likely to produce central nervous adverse effects than to oxybutynin.

Ulcer relapse rates following initial treatment with bismuth subnitrate as compared with cimetidine respectively.

As part of an open clinical trial, 18 out of 23 (78%) patients were treated with bismuth subnitrate (3 x 700 mg/d) and 15 out of 25 (60%) patients were treated with cimetidine (1 x 800 mg/d) to cure peptic ulcers linked with H. pylori, as ascertained following an endoscopic examination. All patients underwent continued observation after complete healing on completion of four weeks of acute treatment. In order to determine the effect of the initial treatment on the rate of relapse, all patients were asked to return for a check-up to establish any relapse, 6 and 12 months following completion of treatment. Gastroduodenoscopy was performed where a recurrent ulcer was suspected. An immediate control examination was carried out if acute symptoms occurred between the controls. In cases of suspected ulcer recurrence, and endoscopic examination was carried out and biopsy specimens were taken in order to detect H. pylori by biochemical and histological tests. In the bismuth group, three relapses (17%) were endoscopically verified 19 to 34 weeks after completion of treatment; 2 patients showed H. pylori positive results. Of the cimetidine group, 6 patients (35%) suffered a recurrent ulcer from the 9th to the 34th week following completion of the acute therapy. Five out of the six patients were H. pylori-positive. A comparison of relapse rates between the two groups was of no statistical significance. Compared with the initial H2 receptor antagonist treatment, there was a distinctly lower relapse rate in patients who were initially treated with bismuth subnitrate.

A study relating to bioavailability and renal elimination of bismuth after oral administration of basic bismuth nitrate.

The extent to which bismuth is absorbed following single and multiple oral administration of basic bismuth nitrate was investigated in healthy male subjects. The blood concentration of bismuth and the amounts excreted in urine and feces were determined. The results show that only a small fraction of the administered bismuth dose given in this form is absorbed. Existing differences in the absorption kinetics between this relatively insoluble bismuth salt and colloidal bismuth citrate are discussed.