Efficacy and tolerability of propiverine hydrochloride extended-release compared with immediate-release in patients with neurogenic detrusor overactivity.

STUDY DESIGN: Double-blind, randomised, multicentre study. OBJECTIVES: Efficacy and tolerability of propiverine extended-release (ER) compared with immediate-release (IR) were evaluated in patients with proven neurogenic detrusor overactivity (NDO). SETTING: Six Spinal Cord Injury Units located in Austria, Germany and Romania. METHODS: Propiverine ER 45 mg s.i.d. or IR 15 mg t.i.d. were administered in patients with proven NDO. Outcomes were assessed at baseline (V1), and after 21 days of treatment (V2): Reflex volume served as primary, leak point volume and maximum detrusor pressure as secondary efficacy outcomes, treatment-related adverse events as tolerability outcomes. RESULTS: Sixty-six patients with proven NDO were enrolled. Reflex volume (ml) increased significantly in the IR (V1: 100.9, V2: 202.9) and in the ER (V1: 89.8, V2: 180.3) group, no significant intergroup difference. Leak point volume increased, and maximum detrusor pressure decreased significantly in both groups, no significant intergroup differences. The percentage of patients presenting with incontinence was reduced by 14% in the IR and by 39% in the ER group, the difference is significant. Treatment-related adverse events manifested in 42 and 36% following propiverine IR and ER, respectively. CONCLUSION: The urodynamic efficacy outcomes demonstrated both galenic formulations to be equieffective. However, following propiverine ER 45 mg s.i.d. higher continence rates compared with propiverine IR 15 mg t.i.d. were achieved, possibly indicative of more balanced plasma-levels. A slight tendency for superior tolerability outcomes of propiverine ER compared with IR was demonstrated.

Desmopressin treatment regimens in monosymptomatic and nonmonosymptomatic enuresis: A review from a clinical perspective.

OBJECTIVE: To evaluate outcomes of desmopressin treatment in monosymptomatic enuresis (ME) and nonmonosymptomatic enuresis (NME). MATERIALS AND METHODS: PubMed was searched for all studies investigating enuresis, up to July 2009, in which desmopressin was administered alone or combined with other treatments. Each study was graded according to its respective level of evidence. RESULTS: Altogether, 99 studies enrolling 7422 patients were identified as fulfilling the inclusion criteria. In 76 studies, desmopressin was administered as monotherapy; in 29 it was combined with other treatments such as antimuscarinics and enuresis alarm. CONCLUSION: Studies incorporating a minor invasive versus a non-invasive diagnostic approach seem to achieve superior long-term success rates. Primary efficacy outcomes following desmopressin treatment are more favourable in ME than NME. Desmopressin administered with adjunct measures achieves superior outcomes compared to monotherapy, especially in NME. Compared to sudden withdrawal, the structured withdrawal programs show better long-term success and lower relapse rates. So far, no superiority has been shown for either time- or dose-dependent structured withdrawal programs. Most studies incorporated only small case series; only 25 studies with level of evidence 1 or 2 have been conducted. The broad range of mono- and adjunct treatments were evaluated according to the evidence based criteria recommended by the European Association of Urology.

Active transport inhibition in rat small intestine by amphiphilic amines: an in vitro study with various local anaesthetics.

In the present investigation with rings of everted rat small intestine, amphiphilic amines such as local anaesthetics (e.g. lidocaine, procaine, tolycaine) were employed to study their effects on intestinal absorption of methyl alpha-D-glucoside, L-leucine, D-fructose, and 2-deoxy-D-glucose. All the amphiphilic amines tested, except for benzocaine, significantly inhibited Na(+)-dependent active uptake of methyl alpha-D-glucoside and L-leucine while leaving uptake of D-fructose (facilitated diffusion) and 2-deoxy-D-glucose (passive diffusion) unaffected. Increasing concentrations of lidocaine in the incubation medium inhibited the uptake of methyl alpha-D-glucoside (IC(50) approximately 3.5 mmol/L) and L-leucine (IC(50) approximately 6 mmol/L) in a dose-dependent manner. Complete reversibility of the inhibitory effect could only be achieved at short-term incubations (

Longitudinal pattern of enzymatic and absorptive functions in the small intestine of rats after short-term exposure to dietary cadmium chloride.

In vitro and in situ findings suggest an impairment of digestive and absorptive functions in the small intestine by enteral cadmium salts. In the rat, diets with up to 1 mmol Cd/kg are well tolerated, however, so that the impairment might not be this drastic or compensated by adaptive changes. To elucidate whether small intestinal functions are altered, we studied the effect of dietary cadmium on the longitudinal pattern of mucosal enzymes and the in vitro uptake of methyl alpha-D-glucoside in the small intestine of female rats. Three groups of rats were employed, a control group and two groups receiving dietary CdCl2 either at 0.3 or 1.0 mmol Cd/kg of diet. Rats were killed after 1 week of feeding. The entire small intestine was removed, rinsed with ice-cold saline and divided into 12 segments of equal length. Mucosal scrapings from each segment were used to measure mucosal cadmium levels, sucrase, lactase, alkaline phosphatase, glycylleucine-hydrolase, and diamine oxidase activities. Sugar uptake was determined in vitro in all segments using everted rings tissue accumulation method. Although cadmium levels in the mucosa were high (>100 ng Cd/mg protein or >100 micromol Cd/kg WW) most enzyme activities were only slightly changed. When significant decreases in activity were detected, they were only observed in the proximal small intestine. Sugar uptake was also impaired only in proximal segments, the maximal transport capacity was reduced by approximately 20%. These findings suggest that cadmium even at dietary levels of 1 mmol/kg do not lead to a drastic impairment of digestive and absorptive functions in the small intestine and that in the rat presently observed, mostly proximal impairments are easily compensated by unaltered distal functions. Certainly, absorption of micronutrients, for which an impaired proximal function cannot be compensated, e.g. iron, might be critical in this respect.

Small-intestinal absorption of cadmium and the significance of mucosal metallothionein.

1 Although food intake is among the most important routes of Cd exposure, not many details are known about the intestinal absorption mechanisms of Cd. In this respect Cd is representative of most other nonessential, merely toxic metals. 2 Based on a concept of two distinguishable steps, intestinal absorption of Cd is characterized by high accumulation within the intestinal mucosa and a low rate of diffusive transfer into the organism. 3 After uptake into the mammalian organism, Cd is sequestered into hepatic metallothionein (MT). It is assumed that hepatic Cd-MT then gradually redistributes Cd to the kidney, which is the main target organ for chronic Cd toxicity. 4 When feeding low levels of dietary CdCl2, however, Cd accumulates preferentially in the kidney and to a lesser degree in the liver, a distribution pattern also found after intravenous and peroral administration of the Cd-MT complex itself. As dietary Cd induces intestinal MT, intestinal Cd-MT complexes could be at least partly responsible for the renal accumulation of dietary Cd. 5 For this mechanism, however, serosal release of mucosal Cd-MT is required. In fact, in vitro findings in rats reveal a concentration-dependent release of intestinal MT to the serosal side of the small intestine. These results indicate that endogenous intestinal MT may deliver Cd-MT to other inner organs, thus contributing to the preferential renal accumulation of ingested Cd.

Small-intestinal transfer mechanism of prunasin, the primary metabolite of the cyanogenic glycoside amygdalin.

1. The small-intestinal transfer of prunasin (D-mandelo-nitrile-beta-D-glucoside), the primary metabolite of amygdalin which is not absorbed in the small intestine as such, was studied in rat jejunum and ileum in vitro. 2. As shown by high pressure liquid chromatography, prunasin is transferred essentially intact across the intestinal wall, without cleavage of the glycosidic bond and thus no formation of benzaldehyde or cyanide during the mucosal passage. 3. Only the jejunal transfer of prunasin followed saturation kinetics (vmax = 1.6 mumol cm-1 min-1; KT = 460 mumol l-1) and exhibited a clearsodium-ion dependence. As indicated by the temperature dependence, only the jejunal mucosa-to-serosa transfer and the corresponding tissue uptake of prunasin required apparently high activation energies. Transfer in the terminal ileum showed diffusion characteristics. 4. Jejunal methyl alpha-D-glucoside transfer was inhibited by the presence of prunasin. Furthermore, the tissue uptake of methyl alpha-D-glucoside in rat jejunum was competitively inhibited by prunasin. 5. The results indicate that prunasin is absorbed unmetabolised in the jejunum of the rat via the transport system of glucose.

Influence of hydroxycarboxylic acids on the water solubility of various bismuth compounds.

In an equilibrium dialysis assay (bismuth being determined by atomic absorption spectrometry) a constant amount of bismuth (Bi, CAS 7440-69-9) (final maximum conc. 50 mumol Bi/l) was dialyzed against solutions with increasing concentrations of the chelators (0-25 mmol/l). At pH 5, 50% of Bi(III) nitrate was soluble in solutions with 0.3, 6.3, 13.4 and 14.6 mmol/l of edetic acid (EDTA), citric, tartaric and malic acid, respectively. At the highest concentration applied, lactic acid kept 7% of bismuth in solution. Without any chelator, bismuth was found to be essentially insoluble (limit of detection: approx. 4 nmol Bi/l). A concentration-dependent increase in solubility was found also for the other bismuth compounds; the sequence of the solubilizing capacity of the chelators was the same as for Bi(III) nitrate. Lowering the pH to 3 generally increased and raising the pH to 7, decreased the solubility of bismuth.

Influence of low luminal cadmium-concentrations on transfer of water and cadmium in the rat small intestine in vitro.

The sensitivity of the small intestinal water transfer for cadmium (Cd) exposure and its longitudinal gradient were investigated in luminally perfused intestinal segments in vitro and in vivo. Proximal segments accumulated Cd to a higher extent and, in addition, were more sensitive to Cd exposure than distal segments. In the proximal small intestine Cd impairs the intestinal water transfer at concentrations between 0.1 and 1.0 mumol/l in vitro and 4 mumol Cd/l in vivo. In vitro the Cd transfer from the intestinal tissue into the serosal absorbate declined in parallel to the reduction of the water transfer. In proximal but not in distal segments the declining water transfer corresponded to the decreases in glucose transfer in response to Cd exposure. According to literature the Cd effect on intestinal water transfer may be mediated by interaction of Cd with the Na-glucose co-carrier or by inhibition of the oxidative phosphorylation. The involvement of both mechanisms may differ along the small intestine.

Influence of subchronic exposure to low dietary deoxynivalenol, a trichothecene mycotoxin, on intestinal absorption of nutrients in mice.

During a 6-wk feeding trial, effects of low dietary deoxynivalenol (DON; 0, 0.1, 1 and 10 ppm) on food consumption and weight gain were investigated in male mice. Food intake was similar in all four dietary groups. Weight gain in the group receiving 10 ppm DON was significantly (P less than 0.01) reduced. At the end of the feeding period, test animals were sacrificed and absorption of water, D-glucose, L-leucine, L-tryptophan, 5-methyltetrahydrofolic acid and iron was measured in isolated perfused jejunal segments in vitro. No effects were observed on absorption of water, leucine, tryptophan and iron. However, at a dietary DON concentration of 10 ppm, a slightly but significantly (P less than 0.05) reduced transfer of glucose was measured. Furthermore, transfer as well as tissue accumulation of 5-methyltetrahydrofolic acid in the jejunal segment were both significantly decreased up to 50%. Heavy metal and trace element content was determined in liver, kidney and small intestine. Manganese and molybdenum content in liver tissue was reduced with a DON concentration of 10 ppm in the diet. The findings indicate that subchronic ingestion of DON, in concentrations occurring in contaminated food and feed, results in an impairment of intestinal transfer and uptake of nutrients such as glucose and 5-methyltetrahydrofolic acid.

Increase of the intestinal iron absorption in growing rats and mice after 8 days of iron-deficient feeding.

In investigations of intestinal iron absorption the combination of repetitive bleeding and iron-deficient feeding is frequently used. It induces iron deficiency which, in turn, stimulates iron absorption. When this combined procedure was compared with the effect of an 8 d iron-deficient feeding schedule in growing rats, no significant differences were found regarding the stimulating effect on intestinal iron transfer. Body iron stores, however, as represented by the hepatic ferritin and iron content are remarkably less depleted. Contrary to the effect of the combined procedure the animals growth was only marginally retarded and anaemia did not develop. This was also demonstrated in mice. The stimulation of intestinal iron absorption by iron-deficient feeding of growing animals thus seems preferable, as this procedure largely avoids the disturbing side effects observed with repetitive blood sampling.

Intestinal first pass metabolism of amygdalin in the rat in vitro.

The intestinal first pass metabolism of amygdalin has been investigated in rat small intestine in vitro. The results show that amygdalin is hydrolyzed to prunasin, essentially in the wall of the proximal jejunum. This specific beta(1-6)hydrolytic cleavage of the terminal glucose residue is pH-dependent and can be inhibited by glucono-delta-lactone, a potent inhibitor of the lysosomal beta-glucosidase of the rat intestine. No substrate competition between phloridzin and lactose vs amygdalin was noted. None of the more common soluble beta- or alpha-enzymatic activities of mammalian intestine (alpha-glucosidase, alpha-amylase) or mammalian liver (beta-galactosidase, beta-glucuronidase) were capable of catalyzing the hydrolysis of the terminal glucose from amygdalin at pH's 5.0, 7.0 or 9.0. Furthermore, no metabolic activity of isolated rat livers toward amygdalin and prunasin was observed within two hours of recirculating perfusion. However, cecal contents of conventional rats, exhibited both amygdalin- and prunasin-hydrolyzing activities. The resulting mandelonitrile dissociates spontaneously into cyanide and benzaldehyde. Therefore, our findings indicate that metabolism of amygdalin to prunasin occurring in the proximal part of jejunum is apparently mediated by enzymatic beta(1-6)glucosidase activity of the gut wall. In contrast, the toxicity of amygdalin due to the release of cyanide obviously requires microbiological activities of the gut flora.

An all-glass perfusator for investigation of the intestinal transport and metabolism of foreign compounds in vitro.

The in vitro perfusion technique of surviving intestinal segments as described by Fisher and Parsons (1949) and modified by Rummel and Stupp (1960) was further improved by the introduction of an all-glass perfusator for studying the intestinal transport and metabolism of lipophilic xenobiotics.

Dexamethasone decreases lethality of rats in acute poisoning with T-2 toxin.

T-2 toxin, a major trichothecene mycotoxin, was administered intravenously to rats. At a dose of 0.75 mg/kg two thirds of the animals died. In animals that received dexamethasone (1.6 mg/kg IV) either 30 min before or 1 h after the toxin, there was a more than fourfold reduction in lethality rate. Dexamethasone injected 3 h after the toxin was less effective. At a lethal dose of T-2 toxin (1 mg/kg IV) pretreatment with dexamethasone only delayed death, whereas lethality rate was barely affected (9/10 vs 10/10 in controls). Dexamethasone markedly reduced the incidence of lung edema and diarrhea. The incidence of hemorrhages, however, was not reduced by dexamethasone. Gastrointestinal bleeding was even more frequent in treated rats than in controls.

Bidirectional transfer and tissue accumulation of folic acid by rat intestine in vitro.

The transfer and tissue content of 3H-pteroylmonoglutamate (PteGlu) from the mucosal to the serosal side (Jms, TCm) and in the reverse direction (Jsm, TCs) was studied using the everted sac technique. In the entire intestine, except for the colon, 3H-PteGlu was transferred preferentially into the serosal solution. When 3H-PteGlu was applied to the serosal side the final tissue concentration in either jejunal, duodenal, ileal or colonic segments was not significantly different from each other and about two-fold the serosal concentration. Apparently there exists a specific transfer process from the mucosal to the serosal side in the jejunum. The transfer of 3H-PteGlu shows saturation kinetics (S0.5 = 4.9 X 10(-5) mol/l). At low concentration (2 nmol/l) 3H-PteGlu was accumulated within the mucosal epithelium (tissue/mucosal fluid ratio = 3.8). Transfer and accumulation in the mucosal tissue of 3H-PteGlu apparently need high activation energy as indicated by the temperature dependency of these processes. Finally, transfer and accumulation in the tissue of 3H-PteGlu could be inhibited by salazosulfapyridine and phenobarbital.

Effect of lidocaine on in vitro absorption of glucose in jejunal and ileal segments of the rat.

The influence of lidocaine on the intestinal glucose absorption was investigated on Tyrode-perfused isolated intestinal segments of the rat. In ileal segments the transmural transfer of glucose decreased with increasing lidocaine concentration (5 X 10(-9) -2 X 10(-4) mol/l), whereas the water movement was unaffected. No inhibitory effect on glucose and water absorption was observed in the proximal jejunum.

Absorption of 14C-clanobutin-Na isolated perfused intestinal segments in vitro of rats.

1. The absorption of 14C-labelled 4-[4-chloro-N-(4-methoxyphenyl)-benzamido]-butyric acid (clanobutin) was investigated on isolated perfused jejunal segments of rats in vitro according to the method of Fisher and Parsons and using everted (Wilson and Wiseman) and non-everted sac preparations. 2. Transfer to and content of the mucosal tissue of 14C-clanobutin in isolated perfused jejunal segments is proportional to the concentration administered on the mucosal side in the range of 1-100 mumol/l. 3. The concentration of 14C-clanobutin in the absorbate is 1.5 times higher than in the perfusion fluid. As compared on the basis nmol/ml perfusion fluid versus nmol/g wet weight the concentration of 14C-clanobutin in the tissue is twice that in the perfusion fluid. 4. No detectable metabolic alteration of 14C-clanobutin could be demonstrated during the passage across the jejunal epithelium. 5. The transfer of 14C-clanobutin in everted sac preparations from the mucosal to the serosal side (M leads to S) is about 3.7 times higher than in the reverse direction (S leads to M). 6. In the intestinal tissue the concentration of 14C-clanobutin is 1.7 times higher than that in the incubation medium; this calculation was made on the basis nmol/ml fluid versus nmol/g tissue wet weight. 7. When having administered 14C-clanobutin on both sides, on the serosal side the 14C-clanobutin concentration increases slightly whereas on the mucosal side due to uptake into the intestinal a slight decrease of the 14C-clanobutin concentration was observed.

Absorption of 14C-clanobutin-Na in blood-perfused tied-off jejunal segments in vivo of rats.

1. Absorption, elimination and retention of 14C-clanobutin was investigated on tied-off jejunal segments in situ of rats. 2. 14C-clanobutin completely disappeared from the intestinal lumen within 15-90 min depending on the dose administered (28.8-230.5 micromol/kg). 3. The amount absorbed of 14 C-clanobutin is proportional to the amount administered (28.8-230.5 micromol/kg). 4. The maximum of the accumulation of 14 C-clanobutin in the jejunal tissue is reached within the first 2 min. 5. Within 120 min 40-70% of the 14 C-clanobutin administered are excreted into bile. A concentration gradient bile/blood of nearly up to 300 is established. About 80% of the 14C-clanobutin was converted into (a) metabolite(s). 6. The highest dose of 14C-clanobutin, 230,5 micromol/kg, inhibited the absorption of glucose statistically significantly by about 60% within the first 5 min after administration. After 40 min, however, the amount of glucose adsorbed is not further reduced. The residual fluid as well as the amount of Na+-ions in the jejunal lumen is slightly increased with increasing doses of 14C-clanobutin ( dose: 57.6 and 230.5 micromol/kg), whereas the amount of K+-ions excreted into the intestinal lumen is decreased.