Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial.

Importance: A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia. Objective: To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia. Design, Setting, and Participants: EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023. Interventions: Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks. Main Outcomes and Measures: The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated. Results: A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups. Conclusions and Relevance: Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity. Trial Registration: ClinicalTrials.gov Identifier: NCT04738123.

Sensory satellite glial Gq-GPCR activation alleviates inflammatory pain via peripheral adenosine 1 receptor activation.

Glial fibrillary acidic protein expressing (GFAP+) glia modulate nociceptive neuronal activity in both the peripheral nervous system (PNS) and the central nervous system (CNS). Resident GFAP+ glia in dorsal root ganglia (DRG) known as satellite glial cells (SGCs) potentiate neuronal activity by releasing pro-inflammatory cytokines and neuroactive compounds. In this study, we tested the hypothesis that SGC Gq-coupled receptor (Gq-GPCR) signaling modulates pain sensitivity in vivo using Gfap-hM3Dq mice. Complete Freund's adjuvant (CFA) was used to induce inflammatory pain, and mechanical sensitivity and thermal sensitivity were used to assess the neuromodulatory effect of glial Gq-GPCR activation in awake mice. Pharmacogenetic activation of Gq-GPCR signaling in sensory SGCs decreased heat-induced nociceptive responses and reversed inflammation-induced mechanical allodynia via peripheral adenosine A1 receptor activation. These data reveal a previously unexplored role of sensory SGCs in decreasing afferent excitability. The identified molecular mechanism underlying the analgesic role of SGCs offers new approaches for reversing peripheral nociceptive sensitization.

Mechanisms underlying the effects of propiverine on bladder activity in rats with pelvic venous congestion and urinary frequency.

We investigated the mechanisms by which propiverine hydrochloride influenced bladder activity in rats with pelvic venous congestion (PC) and urinary frequency. To create PC rats, female rats were anesthetized with isoflurane and the bilateral common iliac veins and bilateral uterine veins were ligated. At 4 weeks after ligation, we assessed voiding behaviour, locomotor activity, and urinary 8-hydroxydeoxyguanosine (8-OHdG) and nitric oxide metabolites (NOx). We also performed cystometry and measured mRNAs for nitric oxide synthase (NOS) and several receptors in the bladder wall. PC rats showed a decrease in locomotor activity and an increased frequency of urination. There was a decrease in endothelial NOS (eNOS), M3, and TRPV1 mRNA expression in the bladder wall, as well as an increase in inducible NOS (iNOS) mRNA. Administration of propiverine to PC rats increased locomotor activity to the level in sham rats, improved bladder function, decreased urinary 8-OHdG excretion, and increased urinary NOx excretion. In addition, propiverine increased neuronal NOS (nNOS) mRNA expression, and decreased expression of iNOS, M3 and TRPV1 mRNA in the bladder wall. Therefore, propiverine not only improved bladder dysfunction through its previously reported actions (anti-muscarinic effect, Ca antagonist effect, and inhibition of noradrenaline re-uptake), but also by reducing inflammation.

Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity.

The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(-)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(-)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(-)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(-)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.

Influence of denaverine hydrochloride on calving ease in Holstein-Friesian heifers.

Calving is assumed to be an exhausting and painful event. A drug that eases the calving procedure and alleviates pain would help cows, especially those suffering from dystocia. In a randomized, controlled, and blinded trial, we measured the effect of denaverine hydrochloride on physical and physiological calving parameters. Eighty-three Holstein-Friesian heifers were included in the analysis. Pulling force was measured using a digital force gauge interposed between the calf and a mechanical calf puller. The concentration of cortisol was measured in serum before and after parturition. There was no effect of treatment group on calving modality (i.e., spontaneous vs. assisted calving), duration of calving, and cortisol concentration. The area under the curve of pulling force × time (n = 44), however, was significantly smaller in the treatment group compared with the placebo group. Also, duration of calving assistance was numerically shorter in the treatment group compared with the placebo group. The results provide evidence that calving ease can be influenced by denaverine hydrochloride during calving assistance.

Which antimuscarinic agents used in the treatment of overactive bladder increase heart rate? a prospective randomized clinical trial.

PURPOSE: To compare the heart rate increase side effect of different antimuscarinic drugs used in overactive bladder (OAB). METHODS: Overall 341 patients were consecutively randomized to take seven different antimuscarinic drugs between January 2014 and June 2016 at three institutions, and 250 patients who completed the follow-up visits were accepted into this study. Ninety-one patients who never came to visits were excluded. Drugs were classified into two groups as selective (darifenacin hydrobromide, solifenacin succinate and oxybutynin hydrochloride) and non-selective (fesoterodine fumarate, tolterodine tartrate, trospium chloride and propiverine hydrochloride) antimuscarinic drugs. The cardiac pulse rates and the blood pressures were recorded during the baseline, first visit (1 week) and second visit (1 month). Data were compared for drugs and two groups (selective versus non-selective) by using ANOVA test. RESULTS: Baseline characteristics were similar among the patients using different antimuscarinic drugs. Statistically significant increase in heart rate occurred in patients treated with non-selective antimuscarinic drugs compared to those treated with selective drugs (p < 0.001), and this increase was especially evident in patients treated with trospium chloride, tolterodine tartrate, fesoterodine fumarate and propiverine hydrochloride (p < 0.001, 0.003, 0.011 and 0.37, respectively). There was no statistical difference for the other side effects. CONCLUSIONS: Our results showed that heart rate significantly increased in OAB patients treated with non-selective antimuscarinic drugs. Trospium chloride, tolterodine tartrate, fesoterodine fumarate and propiverine hydrochloride seem to have the most unfavorable properties with regard to increased heart rate side effect when compared to the other antimuscarinic drugs (darifenacin hydrobromide, solifenacin succinate and oxybutynin hydrochloride).

Pelvic venous congestion induces lower urinary tract dysfunction in rats.

Pelvic venous congestion (PC) is thought to be related to several diseases of the lower urinary tract (LUT). We examined the characteristics of the LUT in rats with PC. To create PC, female rats were anesthetized with isoflurane, and the bilateral common iliac veins and bilateral uterine veins were ligated. At 1-8 weeks after either ligation or sham surgery, we performed cystometry with or without administration of carbazochrome sodium sulfonate hydrate or propiverine hydrochloride, histologic examination of the bladder, blood flow imaging, assessment of locomotor activity, measurement of urinary 8-hydroxydeoxyguanosine (8-OHdG) and nitric oxide metabolites (NOx), and the Evans blue dye extravasation test. PC elevated frequency of urination after 2-6 weeks, and caused a decrease of spontaneous locomotor activity. In addition, there was a decrease of bladder blood flow, an increase of bladder vascular permeability, an increase of urinary 8-OHdG, a decrease of urinary NOx, and mild inflammatory changes of the bladder. In rats with PC, frequency of urination was normalized by administration of propiverine or carbazochrome. Rats with PC may be used as a model of PC associated with high frequency of urination, and this model may be useful when developing treatment for LUT symptoms associated with PC.

Evaluating the effect of three newly approved overactive bladder syndrome treating agents on parotid and submandibular salivary glands: Modulation of CXCL10 expression.

BACKGROUND: Despite enormous progresses in understanding pathophysiology of the lower urinary tract, antimuscarinics remain the chief clinically well-established approach for improving symptoms of overactive bladder (OAB). Dry mouth on the other hand remains one of the most untolerated systemic side effects of these drugs that limits their uses and results in high discontinuation rate. Three novel drugs have been recently approved by US Food and Drug Administration for treatment of OAB: trospium, darifenacin, and solifenacin. AIMS: This study has been conducted to provide clear head to head comparative studying of histological and ultrastructural effect of those newly emerging drugs on parotid and submandibular salivary glands and to demonstrate the differential expression of CXCL10 to make a cogent structural and molecular assessment of the relative tolerability of these drugs and the potential mechanisms of occurrence of dry mouth. METHODS: Fifty male Sprague Dawley rats were equally divided into five groups: Group I (control), Group II (oxybutynin-treated), Group III (trospium-treated), Group IV (darifenacin-treated) and Group V (solifenacin-treated). Histological and ultrastructural studies were performed on parotid and submandibular glands. Measurement of salivary flow, PCR analysis and immunohistochemical assessment of CXCL10 expression have been carried-out. RESULTS: Muscarinic receptor antagonists led to various histological, morphometric and ultrastructural changes together with diminished salivary secretion and up-regulation of CXCL10 expression with the mildest alterations observed with solifenacin. CONCLUSIONS: Solifenacin has shown the least adverse effects to salivary glands. CXCL10 is involved in degenerative changes of salivary glands induced by muscarinic antagonists.

Histopathologic and Urodynamic Effects of the Anticholinergic Drugs Oxybutynin, Tolterodine, and Trospium on the Bladder.

OBJECTIVES: This study aimed to evaluate the effects of intravesical instillation of the anticholinergic drugs oxybutynin, tolterodine, and trospium on bladder capacity and histopathological changes in the bladder mucosa. METHODS: The study included 20 male New Zealand white rabbits that were randomly allocated to four groups of five. In the oxybutynin, tolterodine, and trospium groups, the drugs used were 1 mg/kg of crushed tablet mixed with 5 mL of saline, instilled intravesically once per day for 4 weeks. The control group was administered only 5 mL of saline once per day for 4 weeks. Urodynamic measurement of the bladder was made before and after treatment. At the end of the treatment the animals were killed and the bladders were evaluated histopathologically. RESULTS: There were no significant differences between pre- and post-treatment bladder capacity in any of the groups (P > 0.05). Histopathological evaluation showed that the mucosal epithelium was intact and there was minor inflammation in the control group and oxybutynin group (P > 0.05), whereas there was destruction of the mucosal epithelium and findings of diffuse inflammation in the tolterodine (P = 0.014) and trospium (P = 0.014) groups. CONCLUSION: Intravesical oxybutynin treatment was observed to be safe; however, a single daily dose of oxybutynin may not be sufficient to increase bladder capacity. Intravesical use of trospium and tolterodine at high doses caused epithelial destruction and diffuse inflammation in the bladder mucosa. The irritation associated with epithelial destruction and inflammation prevented an increase in bladder capacity.

Muscarinic Receptor Binding in Rat Bladder Urothelium and Detrusor Muscle by Intravesical Solifenacin.

Solifenacin is an antimuscarinic agent used to treat symptoms of overactive bladder. Pharmacologically significant amounts of solifenacin were excreted in the urine of humans taking a clinical dose of this drug. The aim of this study is to measure muscarinic receptor binding in the bladder urothelium and detrusor muscles of rats following the intravesical instillation of solifenacin. Muscarinic receptors were measured by radioreceptor assay using [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS), a selective radioligand of muscarinic receptors. Solifenacin showed concentration-dependent inhibition of specific [(3)H]NMS binding in the bladder urothelium and detrusor muscle of rats, with no significant difference in Ki values or Hill coefficients between these tissues. Following the intravesical instillation of solifenacin, there was significant muscarinic receptor binding (increase in Kd for specific [(3)H]NMS binding) in the bladder urothelium and detrusor muscle of rats. Similar bladder muscarinic receptor binding was observed by the intravesical instillation of oxybutynin, but not with trospium. In conclusion, the present study has demonstrated that solifenacin binds muscarinic receptors not only in the detrusor muscle but also in the bladder urothelium with high affinity. These bladder muscarinic receptors may be significantly affected by solifenacin excreted in the urine.

Propiverine increases urethral wall catecholamine levels and bladder leak point pressure in rats.

OBJECTIVE: To investigate whether propiverine has a noradrenaline re-uptake inhibitor and whether it acts on the lumbosacral cord or the urethral wall. In addition, we aimed to examine the effect of propiverine on leak point pressure in rats. METHODS: A total of 72 female and 30 male rats were used to examine the following: (i) the change of leak point pressure caused by intravenous agents in rats with vaginal distention; (ii) the change of leak point pressure caused by intrathecal agents in rats with vaginal distention; (iii) the noradrenaline re-uptake inhibitor action of propiverine; and (iv) catecholamine levels in the bladder wall, urethral wall, cerebrospinal fluid and plasma after oral administration of propiverine. RESULTS: Intravenous injection of propiverine, imipramine and duloxetine increased the leak point pressure in rats with vaginal distention. Intrathecal naftopidil decreased the leak point pressure, whereas subsequent intravenous propiverine restored the leak point pressure to the level before intrathecal naftopidil in rats with vaginal distention. Propiverine acted like a noradrenaline re-uptake inhibitor, increasing noradrenaline and/or dopamine levels in the plasma, cerebrospinal fluid, and urethral wall perfusion fluid. CONCLUSION: Propiverine inhibits noradrenaline re-uptake, as well as having antimuscarinic and Ca-antagonist actions. The inhibition of noradrenaline re-uptake by propiverine mainly occurs at the urethral level and partially in the central nervous system, and might stimulate the smooth muscle of the bladder neck and proximal urethra through α1-adrenergic receptors, as well as stimulating the striated muscle of the urethra and pelvic floor by activation of spinal motoneurons. Therefore, propiverine might be effective for both stress and urge incontinence.

Comparative functional selectivity of imidafenacin and propiverine, antimuscarinic agents, for the urinary bladder over colon in conscious rats.

Antimuscarinics are the first-line choice of treatment for overactive bladder (OAB). Imidafenacin distributes in the bladder more selectively than in the submaxillary gland and colon, and hence, this drug is considered more useful for OAB than other antimuscarinics. However, the examination of imidafenacin selectivity to bladder over colon using in vivo models is limited. Thus, the author examined whether imidafenacin could induce more selective blockade of the bladder over colon in conscious rats using two pharmacological indices (colonic transit and neostigmine-induced fecal pellet output) and compared its bladder selectivity with propiverine. In the bladder study, the inhibitory doses of antimuscarinics were calculated using the area under the curve of the distension-induced rhythmic contraction in conscious rats. The relative bladder selectivity of imidafenacin to propiverine was 50-fold and 61-fold, respectively, in a dye marker colonic transit model and in a neostigmine-induced fecal pellet output model. This comparative study shows that the functional bladder selectivity of imidafenacin is higher than that of propiverine tested under the present conditions in conscious rats.

Influence of antimuscarinic therapy on cognitive functions and quality of life in geriatric patients treated for overactive bladder.

OBJECTIVES: Incidences of overactive bladder (OAB) and cognitive dysfunction increase with aging. Treatment of OAB with antimuscarinic agents may result in cognitive decline, especially in patients with Alzheimer's disease (AD). The aim of this study is to evaluate the effect of antimuscarinic treatment on cognitive functions, depression, and quality of life (QOL) of patients with OAB. METHODS: This non-interventional prospective observational study was conducted in a geriatric medicine outpatient clinic. Overall, 168 OAB patients were enrolled. Patients were followed up in five groups: oxybutynin, darifenacin, tolterodine, trospium, and control groups. Follow-up visits were done at second, third, and sixth months. Comprehensive geriatric assessment, cognitive and mood assessment, QOL scales (IIQ-7, UDI-6) were performed. RESULTS: Mean age of the patients was 73.5 ± 6.1. Of the 168 patients, 92.3% were female, 83.3% benefited from the treatment, and 37.1% discontinued the medication. Discontinuation rate and frequency of side effects were more frequent in the oxybutynin group. Mini Mental State Examination scores did not decline after treatment, even in AD patients. Geriatric Depression Scale scores, Activities of Daily Living scores, and QOL scores significantly improved after treatment. CONCLUSION: Antimuscarinic agents are effective in OAB treatment. They have a positive impact on daily life activities, depression, and QOL indices. Furthermore, they do not have a negative effect on cognitive function in older adults with or without AD.

Effect of propiverine hydrochloride on stress urinary incontinence.

OBJECTIVES: To investigate whether the anticholinergic agent, propiverine hydrochloride, is clinically effective for stress urinary incontinence. METHODS: The participants were adult female patients with the chief complaint of stress incontinence. Propiverine (20 mg once daily) was given for 8 weeks. If the response was inadequate after 4 weeks of treatment, the dose was increased to 40 mg/day. Before and after 4 and 8 weeks of treatment, lower urinary tract symptoms were assessed. The urethral pressure and blood catecholamine levels were also measured. RESULTS: A total of 37 patients (mean age 69 ± 11 years) were enrolled, including 15 patients with stress incontinence and 22 with mixed incontinence. The number of episodes of stress incontinence decreased significantly from 2.6 ± 2.3 times per day to 1.3 ± 2.2 times per day after 4 weeks, and 0.4 ± 0.6 times per day after 8 weeks. The daytime and night-time frequency of urination, and quality of life score showed significant improvement. The maximum urethral closing pressure and the functional urethral length increased significantly after treatment, but blood catecholamine levels, blood pressure and pulse rate at 8 weeks were not significantly different from those at baseline. CONCLUSIONS: Propiverine could be an effective drug for stress urinary incontinence by increasing urethral closing pressure without increasing blood catecholamine levels.

Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities.

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist mepenzolate bromide (mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-mepenzolate) and to examine their biochemical and pharmacological activities. (R)- or (S)-mepenzolate was synthesized by condensation of benzilic acid with (R)- or (S)-alcohol, respectively, followed by quaternization of the tertiary amine. As predicted by computational simulation, a filter-binding assay in vitro revealed that (R)-mepenzolate showed a higher affinity for the muscarinic M3 receptor than (S)-mepenzolate. In vivo, the bronchodilatory activity of (R)-mepenzolate was superior to that of (S)-mepenzolate, whereas anti-inflammatory activity was indistinguishable between the two enantiomers. We confirmed that each mepenzolate maintained its original stereochemistry in the lung when administered intratracheally. These results suggest that (R)-mepenzolate may have superior properties to (S)-mepenzolate as a drug to treat COPD patients given that the former has more potent bronchodilatory activity than the latter.

Ameliorative effect of mepenzolate bromide against pulmonary fibrosis.

Idiopathic pulmonary fibrosis is thought to involve lung injury caused by reactive oxygen species (ROS), which in turn is followed by abnormal fibrosis. A transforming growth factor (TGF)-ß1-induced increase in myofibroblast number plays an important role in this abnormal fibrosis. We recently found that mepenzolate bromide (mepenzolate), which has been used clinically to treat gastrointestinal disorders, has ROS-reducing properties. In the present study, we examined the effect of mepenzolate on bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. The severity of pulmonary fibrosis was assessed by histopathologic evaluation and determination of hydroxyproline levels. Lung mechanics (elastance) and respiratory function [forced vital capacity (FVC)] were assessed using a computer-controlled ventilator. Respiratory function was also evaluated by monitoring percutaneous arterial oxygen saturation (SpO2). Intratracheal administration of mepenzolate prior to bleomycin treatment reduced the extent of pulmonary fibrosis and changes in lung mechanics and led to a significant recovery of both FVC and SpO2 compared with control. Furthermore, mepenzolate produced a therapeutic effect even when it was administered after the development of fibrosis. Administration of mepenzolate also prevented bleomycin-induced pulmonary cell death and inflammatory responses and increased myofibroblast number. Mepenzolate also decreased NADPH oxidase activity and active TGF-ß1 level or increased glutathione S-transferase (GST) activity in the presence of bleomycin treatment. These results show that the intratracheal administration of mepenzolate reduced bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. These effects may be due to this drug's inhibitory effect on NADPH oxidase and TGF-ß1 activities and its stimulatory effect on GST.

Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease.

The clinical treatment of chronic obstructive pulmonary disease (COPD) requires not only an improvement of airflow by bronchodilation but also the suppression of emphysema by controlling inflammation. Here we screen a compound library consisting of clinically used drugs for their ability to prevent elastase-induced airspace enlargement in mice. We show that intratracheal administration or inhalation of mepenzolate bromide, a muscarinic antagonist used to treat gastrointestinal disorders, decreases the severity of elastase-induced airspace enlargement and respiratory dysfunction. Although mepenzolate bromide shows bronchodilatory activity, most other muscarinic antagonists do not improve elastase-induced pulmonary disorders. Apart from suppressing elastase-induced pulmonary inflammatory responses and the production of superoxide anions, mepenzolate bromide reduces the level of cigarette smoke-induced airspace enlargement and respiratory dysfunction. Based on these results, we propose that mepenzolate bromide may be an effective therapeutic for the treatment of COPD due to its anti-inflammatory and bronchodilatory activities.

Effect of concomitant administration of trospium chloride extended release on the steady-state pharmacokinetics of metformin in healthy adults.

BACKGROUND: Overactive bladder (OAB) is often associated with a number of co-morbid medical conditions, including diabetes mellitus. This may necessitate several concomitant treatments, thus creating the potential for drug-drug interactions (DDIs). Trospium is renally eliminated, not metabolized via cytochrome P450; therefore, cytochrome P450 DDIs are unlikely. However, coadministration with another renally eliminated drug (e.g., metformin) may theoretically result in a DDI. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics (plasma and urine) and safety/tolerability of the coadministration of trospium chloride extended release (XR) and metformin under steady-state conditions in healthy male and female subjects. METHODS: In a single-centre, randomized, open-label, two-group, two-period study in healthy males and females aged 18-45 years, 44 subjects received oral metformin 500 mg twice daily for 3.5 days during one period, and oral trospium chloride XR 60 mg once daily for 10 days, followed by trospium chloride XR 60 mg once daily for 4 days plus metformin 500 mg twice daily for 3.5 days during the other period. The two periods occurred in a crossover fashion, separated by a 3-day washout period. RESULTS: Trospium chloride XR coadministration did not alter metformin steady-state pharmacokinetics. Metformin coadministration reduced trospium steady-state maximum plasma concentration (by 34 %) and area under the concentration-time curve from 0-24 hours (by 29 %). Neither drug's renal clearance was affected. No safety/tolerability issues of concern were observed with coadministration. CONCLUSION: No dosage adjustment is necessary for metformin when coadministered with trospium chloride XR.

Effects of propiverine hydrochloride, an anticholinergic agent, on urethral continence mechanisms and plasma catecholamine concentration in rats.

INTRODUCTION AND HYPOTHESIS: Anticholinergics are used to treat overactive bladder. Anticholinergic agents such as propiverine hydrochloride reportedly increase plasma catecholamine levels in rats. It is also known that active urethral closure mechanisms prevents stress urinary incontinence (SUI), which is enhanced by central and peripheral noradrenergic system activation. Therefore, we examined the influence of propiverine hydrochloride on urethral anti-incontinence function in rats. METHODS: Adult female rats were divided into propiverine and vehicle-treated groups. The propiverine group was given propiverine orally once a day for 2 weeks, after which urethral function and plasma concentrations of catecholamine (dopamine, norepinephrine, epinephrine) were tested. RESULTS: Urethral baseline pressure measured by a microtransducer-tipped urethral catheter and leak-point pressure during passive intravesical pressure elevation were significantly increased in the propiverine group compared with the vehicle group. Plasma norepinephrine and epinephrine levels in the propiverine group were also significantly increased. CONCLUSIONS: Propiverine treatment that increases plasma catecholamine levels could contribute to improvement of SUI conditions by increasing urethral resistance.

Taste masking of propiverine hydrochloride by conversion to its free base.

The aim of the present study was to mask the bitterness of propiverine hydrochloride (P-4) by converting it to propiverine free base. Fine granules comprising the free base, which was converted from P-4 by desalination, were prepared. By using Fourier transform infrared spectroscopy, thermogravimetry-differential thermal analysis, and powder X-ray diffraction spectra, we confirmed that P-4 had been converted into propiverine free base by desalination during the manufacturing process. Furthermore, the conversion into free base appeared to result in decreased solubility, and both the taste testing sensor and tasting volunteers determined that it masked the bitterness of P-4. On using the gustatory sensation test, the bitterness of the P-4 fine granules was confirmed to be weakened. The dissolution rate and bioavailability of fine granules of the free base were compared with tablets of P-4. The dissolution rate and bioavailability of the fine granules and tablets were almost the same. We successfully masked the taste of P-4 by converting it into free base using a manufacturing process that was suitable for commercial manufacturing.