Competitive Muscarinic Receptor Antagonist Research Articles

Long-Term Stability of Glycopyrrolate Oral Solution Galenic Compound at Different Storage Conditions.

Glycopyrrolate is a competitive muscarinic receptor antagonist used in the treatment of sialorrhea, especially in pediatrics. Degradation research was conducted to better understand the stability of the active pharmaceutical ingredient (API). Using an HPLC-UV method, we evaluated the chemical stability of the oral solution of the galenic compound glycopyrrolate 0.5 mg/mL under different storage conditions. Method validation was performed according to the International Council for Harmonization (ICH) Q2(R2) guidelines. The results of the stability study of the galenic compound in different storage conditions, with the exception of those stored in glass containers at 45 °C for more than 3 months, were stable (100 ± 10% of the nominal concentration). The aim of this work was to study the stability of the galenic compound glycopyrrolate in two different types of containers and at three different storage temperatures. Glycopyrrolate showed degradation beyond the limits only in glass at 45 °C and after 2 months of storage. The results indicate that oral liquid dosage forms of glycopyrrolate are stable for at least 210 days when stored at room temperature or at 4 °C, in glass or PET, for at least 7 months, maintaining product quality according to the standards established by the European Pharmacopoeia, ensuring long-term coverage for pediatric patient therapies.

Influence of regulatory peptides on neurogenic lower urinary tract dysfunction in multiple sclerosis. Data of one center

Objective: Cclinical evaluation of the effectiveness and safety of the effect of the regulatory polypeptide drug on neurogenic overactive bladder (OAB) in patients with multiple sclerosis (MS).Materials and methods: 41 patients with MS and urodynamically confirmed detrusor overactivity were included in a prospective, single-center, simple comparative clinical trial with sequential drug changes. The initial function of the lower urinary tract and its dynamic changes during therapy were studied by filling out a voiding diary and questionnaires using the EDSS, NBSS, SF-Qualiveen, I-QOL questionnaires. The control drug Solifenacin (patient group 1) is a specific competitive antagonist of muscarinic receptors of the M3 subtype, which causes detrusor contraction. The Study Drug (patient group 2) is a complex of regulatory polypeptides that have an organotropic effect on the bladder. Drug administration: control drug for 4 weeks, then an observation period of 4 weeks, after which - taking the Study Drug for 30 days. The results were monitored immediately after the end of taking the Study Drugs, after which they were compared with the initial data. Statistical analysis was carried out by the program “Statistica 10” (StatSoft Inc., USA), using non-parametric data analysis with median analysis, Wilcoxon test and Mann-Whitney U-test search. The results of differences were considered statistically significant if the probability of error was <5% (p<0.05).Results: Vvoiding diary: 14.6% and 24.4% of patients in groups 1 and 2, respectively, were freed from urinary incontinence; from nocturia —- 31.7% and 56.1% of patients for groups 1 and 2, respectively, the frequency of daily urination was normalized in 53.6% and 70.7% of patients in groups 1 and 2, respectively. NBSS questionnaire: decrease in the total questionnaire score by 29.2% and 47.4% for groups 1 and 2, respectively. SF-Qualiveen questionnaire: an increase in the overall assessment score by 42.3% for group 1 versus +66.5% for group 2. I-QOL questionnaire: improvement in quality of life by 56.0% and 80.4% for groups 1 and 2, respectively. The Study Drug has a higher safety profile compared to Solifenacin.Conclusion: Tthe effectiveness of the Study Drug in the correction of neurogenic OAB is higher in comparison with Solifenacin, which is reflected in a decrease in urgency, pollakiuria, the number of episodes of urinary incontinence and a significant improvement in the quality of life of these patients. The Study Drug demonstrates a high safety profile in the study.

Cajanus cajan (L) Millsp. seed extract ameliorates scopolamine-induced amnesia through increase in antioxidant defense mechanisms and cholinergic neurotransmission.

Decline in cholinergic function and oxidative/nitrosative stress play a central role in Alzheimer's disease (AD). Previous quantitative HPLC profiling analysis has revealed the presence of Pinostrobin, formononetin, vitexin and other neuroprotective flavonoids in Cajanus cajan seed extract. This study was designed to investigate the protective action of Cajanus cajan ethanol seed extract (CC) on learning and memory functions using scopolamine mouse model of amnesia. Materials and methods: Adult mice were pretreated with CC (50, 100, or 200mg/kg, p.o) or vehicle (10ml/kg, p.o) for 16 days consecutively. Scopolamine, a competitive muscarinic cholinergic receptor antagonist (1mg/kg, i.p.) was given an hour after CC pretreatment from days 3 to 16. The mice were subjected to behavioural tests from day 11 (open field test (OFT)/ Y-maze test (YMT) and Morris water maze task (MWM) from days 12-16. Animals were euthanized 1h after behavioral test on day 16 and discrete brain regions isolated for markers of oxidative stress and cholinergic signaling. Molecular docking analysis was undertaken to predict the possible mechanism(s) of CC-induced anti-amnesic action. pre-administration of CC significantly reversed working memory and learning deficits caused by scopolamine in YMT and MWM tests, respectively. Moreover, CC prevented scopolamine-induced oxidative and nitrosative stress radicals in the hippocampus evidenced in significant increase in glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities with a marked decrease in malondialdehyde (MDA) production, as well as significant inhibition of hippocampal scopolamine-induced increase in acetylcholinesterase activity by CC. The molecular docking analysis showed that out of the 19 compounds, the following had the highest binding affinity; Pinostrobin (-8.7 Kcal/mol), friedeline (-7.5kCal/mol), and lupeol (-8.2 Kcal/mol), respectively, to neuronal muscarinic M1 acetylcholine receptor, α7 nicotinic acetylcholine receptor and amyloid beta peptide binding pockets, which further supports the ability of CC to enhance neuronal cholinergic signaling and possible inhibition of amyloid beta aggregation. This study showed that Cajanus cajan seeds extract improved working memory and learning through enhancement of cholinergic signaling, antioxidant capacity and reduction in amyloidogenesis.

A Review on Analytical Method Development for the Estimation of a Potent Muscarinic Receptor Antagonist Tolterodine Tartrate

Background: A pharmaceutical will be clinically accepted if it is impurity-free and its dose is accurately maintained. For this, the contribution of analytical techniques for developing and validating a new pharmaceutical dosage form cannot be overlooked. Introduction: Tolterodine tartrate is a potent competitive muscarinic receptor antagonist. It binds to the muscarinic M3 receptors in the bladder selectively and competitively. It is used to treat urinary incontinence and overactive bladder syndrome. The 5-hydroxymethyl derivative is the pharmacologically active metabolite of Tolterodine tartrate, which is as potent as the main drug. It is available with α-adrenergic blocker Tamsulosin in combined pharmaceutical formulations, treating benign prostatic hyperplasia in men. This review article presents several analytical methods, including HPLC, HPTLC, UV-Visible spectrophotometry, spectrofluorimetry, electroanalytical, and various hyphenated techniques like GC-MS, LC-MS, LC-MS-MS, etc., for estimation of Tolterodine tartrate is present as a single material or in combined form in bulk materials, different pharmaceutical formulations, and biological matrices. Conclusion: HPLC and spectrophotometry are the most widely used methods for determining the drug in the bulk and pharmaceutical dosage form among all these methods. LC-MS and LC-MSMS are widely used for the estimation of Tolterodine tartrate from plasma and other biological fluids. All the methods included in this article are accurate, sensitive, and cost-effective.

Scopolamine and MK-801 impair recognition memory in a new spontaneous object exploration task in monkeys

The spontaneous object recognition (SOR) task is one of the most widely used behavioral protocols to assess visual memory in animals. However, only recently was it shown that nonhuman primates also perform well on this task. Here we further characterized this new monkey recognition memory test by assessing the performance of adult marmosets after an acute systemic administration of two putative amnesic agents: the competitive muscarinic acetylcholine receptor antagonist scopolamine (SCP; 0.05 mg/kg) and the noncompetitive N-methyl-d-aspartate glutamate receptor antagonist MK-801 (0.015 mg/kg). We also determined whether the acetylcholinesterase inhibitor donepezil (DNP; 0.50 mg/kg), a clinically-used cognitive enhancer, reverses memory deficits caused by either drug. The subjects had an initial 10 min sample trial where two identical neutral objects could be explored. After a 6 h retention interval, recognition was based on an exploratory preference for a new rather than familiar object during a 10 min test trial. Both SCP and MK-801 impaired the marmosets' performance on the SOR task, as both objects were explored equivalently. Co-administration of 0.50 mg/kg of DNP reversed the SCP- but not the MK-801-induced memory deficit. These results indicate that cholinergic and glutamatergic pathways mediate object recognition memory in the monkey SOR task.

The arrhythmogenic potential of nerve agents and a cardiac safety profile of antidotes - A proof-of-concept study using human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CM)

The global use of organophosphorus compounds (OP) for pest control and nerve agents being used in military conflicts and for assassinations renders intoxications by these agents a public health concern. OP-poisoned patients often suffer from dysrhythmias which may ultimately result in death. In this study, human-induced pluripotent stem cells derived cardiomyocytes were exposed to OP compounds in a microelectrode array system (MEA). The MEA system is widely accepted to assess the proarrhythmic properties of (candidate) drugs. The directly acting cholinergic compounds acetylcholine and carbachol and the irreversible acetylcholinesterase inhibitor cyclosarin - a highly toxic nerve agent - were assessed. All three compounds induced a dose-dependent (up to 600 nmol/L) corrected field potential duration (FPDc) prolongation of 9.7 ± 0.6% for carbachol, for 9.7 ± 1.2% acetylcholine and 9.4 ± 0.5% for cyclosarin. Additionally, the electrophysiological alterations of the clinically approved oxime reactivators obidoxime, pralidoxime and the oximes in development HI-6 and MMB-4 were investigated in the absence of OP. Neither of these oximes (up to a concentration of 300 μmol/L) caused dysrhythmia nor beat arrest. The competitive muscarinic receptor antagonist atropine as a cornerstone in the treatment of OP poisoning was also analyzed. Interestingly, atropine caused a drop in the beat rate which might result from a non-receptor action of this substance in the absence of OP. Atropine in combination with the OP nerve agent cyclosarin and the direct cholinergics acetylcholine or carabachol completely reversed the induced FPDc prolongation. However, the oxime HI-6 as potent reactivator of cyclosarin-inhibited AChE was not able to prevent the FPDc prolongation in this model. In conclusion, the current model allows the assessment of FPDc prolongation by the nerve agent cyclosarin, the cholinergic compounds carbachol, acetylcholine and the block of this effect by atropine.

Counteracting desensitization of human α7-nicotinic acetylcholine receptors with bispyridinium compounds as an approach against organophosphorus poisoning

Irreversible inhibition of acetylcholinesterase (AChE) resulting in accumulation of acetylcholine and overstimulation of muscarinic and nicotinic receptors accounts for the acute toxicity of organophosphorus compounds (OP). Accordingly, the mainstay pharmacotherapy against poisoning by OP comprises the competitive muscarinic acetylcholine receptor antagonist atropine to treat muscarinic effects and, in addition, oximes to reactivate inhibited AChE. A therapeutic gap still remains in the treatment of desensitized nicotinic acetylcholine receptors following OP exposure. Hereby, nicotinic effects result in paralysis of the central and peripheral respiratory system if untreated. Thus, these receptors pose an essential target for therapeutic indication to address these life-threatening nicotinic symptoms of the cholinergic crisis. Identification of ligands regulating dynamic transitions between functional states by binding to modulatory sites appears to be a promising strategy for therapeutic intervention. In this patch clamp study, the ability of differently substituted bispyridinium non-oximes to “resensitize” i.e. to recover the activity of desensitized human homomeric α7-type nAChRs stably transfected in CHO cells was investigated and compared to the already described α7-specific positive allosteric modulator PNU-120596. The structures of these bispyridinium analogues were based on the lead structure of the tert-butyl-substituted bispyridinium propane MB327, which has been shown to have a positive therapeutic effect due to a non-competitive antagonistic action at muscle-type nAChRs in vivo and has been found to have a positive allosteric activity at neuronal receptors in vitro. Prior to test compounds, desensitization of hα7-nAChRs was verified by applying an excess of nicotine revealing activation at low, and desensitization at high concentrations. Thereby, desensitization could be reduced by modulation with PNU-120596. Desensitization was further verified by dose-response profiles of agonists, carbamoylcholine and epibatidine in the absence and presence of PNU-120596. Although less pronounced than PNU-120596 and the lead structure MB327, bispyridinium compounds, particularly those substituted at position 3 and 4, resensitized the nicotine desensitized hα7-nAChRs in a concentration-dependent manner and prolonged the mean channel open time. In summary, identification of more potent compounds able to restore nAChR function in OP intoxication is needed for development of a putative efficient antidote.

The Beneficial Effect of Fesoterodine, a Competitive Muscarinic Receptor Antagonist on Erectile Dysfunction in Streptozotocin-induced Diabetic Rats

To investigate the possible role of fesoterodine (a competitive muscarinic receptor antagonist) on erectile dysfunction in streptozotocin-induced diabetic rats. A total of 16 adult male Sprague-Dawley rats were equally divided into control and diabetic groups. Diabetes was induced by a single intravenous injection of streptozotocin (25-35 mg/kg). In vivo erectile responses were evaluated by the stimulation of cavernosal nerves, and measurements were repeated after the intracavernosal injection of fesoterodine (1 µM) in rats. The relaxation responses to fesoterodine were examined via incubation with various inhibitors. The relaxant responses of corpus cavernosum (CC) strips were observed in the presence or the absence of fesoterodine (10 µM). Intracavernous administration of fesoterodine restored in vivo erectile response at 5.0- and 7.5-V levels, except for 2.5 V in diabetic rats. Basal intracavernosal pressure (5.4 ± 0.9 mm Hg) in diabetic rats was markedly increased after injection of fesoterodine (33.9 ± 7.9 mm Hg, P <.001). In bath studies, fesoterodine resulted in a relaxation of CC in a concentration-dependent manner, which was reduced in diabetic rats. Nifedipine (l-type Ca2+ channel blocker) inhibited maximum fesoterodine-induced relaxation by 58%. The nonselective K+ channel blocker tetraethylammonium and glibenclamide incubation did not change the relaxant response to fesoterodine. The relaxant responses to acetylcholine (10 µM), electrical field stimulation (10 Hz), and sodium nitroprusside (0.01 µM) in diabetic rats were increased after incubation with fesoterodine (10 µM). Fesoterodine improved erectile function and relaxation of isolated strips of rat CC. The underlying mechanism of fesoterodine is likely due to the blocking of l-type calcium channels independent of the nitric oxide-cyclic guanosine monophosphate pathway. Further investigations are warranted to fully elucidate the restorative effects of fesoterodine on overactive bladder-induced diabetic erectile dysfunction.

Nerve-induced responses of mouse vaginal smooth muscle.

Neural and agonist-induced contractions of proximal (i.e. upper half adjacent to the cervix) and distal mouse vaginal smooth muscle strips were investigated. We hypothesised that nerve-mediated vaginal contractions arise through activity of cholinergic nerves. Nerve activation by bursts of electrical field stimulation (EFS) caused a primary transient contraction often accompanied by a secondary transient contraction, both larger in proximal than distal tissues (i.e. primary: 7-fold larger; secondary: 3-fold larger). Our hypothesis was supported as we found that cholinergic nerves mediated the primary transient contraction in both proximal and distal vaginal strips, as EFS responses were enhanced by neostigmine an anticholinesterase, massively inhibited by the competitive muscarinic receptor antagonist atropine and not affected by the non-selective α-adrenergic receptor antagonist phentolamine. Primary transient contractions were halved in amplitude by the L-type Ca2+ channel blocker nifedipine and markedly inhibited by the sarco-endoplasmic reticulum calcium ATPase (SERCA) inhibitor cyclopiazonic acid (CPA). Resultant secondary transient contractions were abolished by nifedipine. Notably, the selective α1-adrenergic receptor agonist phenylephrine caused tonic contracture in distal but not proximal strips. Low-frequency EFS often initiated recurrent transient contractions similar to those elicited by CCh. Immunohistochemical studies demonstrated innervation of the smooth muscle. Findings of enhanced proximal cholinergic nerve-induced transient contractions, evidence that maintained nerve stimulation could cause recurrent contractions and the finding of distal phenylephrine-mediated tonic contraction have implications on insemination.

Tolterodine reduces veratridine-augmented late INa, reverse-INCX and early afterdepolarizations in isolated rabbit ventricular myocytes.

The augmentation of late sodium current (INa.L) not only causes intracellular Na+ accumulation, which results in intracellular Ca2+ overload via the reverse mode of the Na+/Ca2+ exchange current (reverse-INCX), but also prolongs APD and induces early afterdepolarizations (EAD), which can lead to arrhythmia and cardiac dysfunction. Thus, the inhibition of INa.L is considered to be a potential way for therapeutic intervention in ischemia and heart failure. In this study we investigated the effects of tolterodine (Tol), a competitive muscarinic receptor antagonist, on normal and veratridine (Ver)-augmented INa.L, reverse-INCX and APD in isolated rabbit ventricular myocytes, which might contribute to its cardioprotective activity. Rabbit ventricular myocytes were prepared. The INa.L and reverse-INCX were recorded in voltage clamp mode, whereas action potentials and Ver-induced early afterdepolarizations (EADs) were recorded in current clamp mode. Drugs were applied via superfusion. Tol (3-120 nmol/L) concentration-dependently inhibited the normal and Ver-augmented INa.L with IC50 values of 32.08 nmol/L and 42.47 nmol/L, respectively. Atropine (100 μmol/L) did not affect the inhibitory effects of Tol (30 nmol/L) on Ver-augmented INa.L. In contrast, much high concentrations of Tol was needed to inhibit the transient sodium current (INa.T) with an IC50 value of 183.03 μmol/L. In addition, Tol (30 nmol/L) significantly shifted the inactivation curve of INa.T toward a more depolarizing membrane potential without affecting its activation characteristics. Moreover, Tol (30 nmol/L) significantly decreased Ver-augmented reverse-INCX. Tol (30 nmol/L) increased the action potential duration (APD) by 16% under the basal conditions. Ver (20 μmol/L) considerably extended the APD and evoked EADs in 18/24 cells (75%). In the presence of Ver, Tol (30 nmol/L) markedly decreased the APD and eliminated EADs (0/24 cells). Tol inhibits normal and Ver-augmented INaL and decreases Ver-augmented reverse-INCX. In addition, Tol reverses the prolongation of the APD and eliminates the EADs induced by Ver, thus prevents Ver-induced arrhythmia.

Formal Synthesis of Fesoterodine by Acid‐Facilitated Aromatic Alkylation

The competitive muscarinic receptor antagonist fesoterodine is a congener of tolterodine and has better efficiency compared to tolterodine. In this study, we present an efficient synthesis of the fesoterodine intermediate 3‐(3‐diisopropylamino‐1‐phenylpropyl)‐4‐hydroxybenzaldehyde from ethyl benzoylacetate by Friedel–Crafts alkylation in the presence of an acid as a key reaction step. The synthesis is carried out by the reduction of the ketoester to a 1,3‐diol, diisopropylamine substitution, and Friedel–Crafts alkylation, followed by reduction and chiral resolution.

Bioanalytical method for quantification of Solifenacin in rat plasma by LC-MS/MS and its application to pharmacokinetic study

Abstract Background Solifenacin succinate is a competitive muscarinic acetylcholine receptor antagonist used in the treatment of overactive bladder with or without urge incontinence. Methods Liquid chromatography–tandem mass spectrometry method was used for quantification of Solifenacin (SF) in rat plasma. Solifenacin-d5 (SFD5) used as an internal standard. Chromatographic separation was performed Gemini-NX C18, 50 × 4.6 mm, 5 µm, 110 Å column. Mobile phase composed of 5 mM Ammonium formate, pH 3.0: methanol (20:80 v/v), with 0.4 mL/min flow-rate. Drug and IS were extracted by Liquid- liquid extraction method. SF and SFD5 were detected with proton adducts at m/z 363.2®193.2 and 368.2®198.2 in multiple reaction monitoring (MRM) positive mode respectively. The method was validated with the correlation coefficients of (r2) ≥ 0.9975 over a linear concentration range of 0.1-100.0 ng/mL. Results This method demonstrated intra and inter-day precision within 1.09 to 4.84 and 1.75 to 7.68 % and accuracy within 101.21 to 106.67 and 97.94 to 104.79 % for SF. Conclusions This method is successfully applied in the Pharmacokinetic study of rat plasma.

Molecular mechanisms of methoctramine binding and selectivity at muscarinic acetylcholine receptors.

Methoctramine (N,N'-bis[6-[[(2-methoxyphenyl)-methyl]hexyl]-1,8-octane] diamine) is an M(2)-selective competitive antagonist of muscarinic acetylcholine receptors and exhibits allosteric properties at high concentrations. To reveal the molecular mechanisms of methoctramine binding and selectivity we took advantage of reciprocal mutations of the M(2) and M(3) receptors in the second and third extracellular loops that are involved in the binding of allosteric ligands. To this end we performed measurements of kinetics of the radiolabeled antagonists N-methylscopolamine (NMS) in the presence of methoctramine and its precursors, fluorescence energy transfer between green fluorescent protein-fused receptors and an Alexa-555-conjugated precursor of methoctramine, and simulation of molecular dynamics of methoctramine association with the receptor. We confirm the hypothesis that methoctramine high-affinity binding to the M(2) receptors involves simultaneous interaction with both the orthosteric binding site and the allosteric binding site located between the second and third extracellular loops. Methoctramine can bind solely with low affinity to the allosteric binding site on the extracellular domain of NMS-occupied M(2) receptors by interacting primarily with glutamate 175 in the second extracellular loop. In this mode, methoctramine physically prevents dissociation of NMS from the orthosteric binding site. Our results also demonstrate that lysine 523 in the third extracellular loop of the M(3) receptors forms a hydrogen bond with glutamate 219 of the second extracellular loop that hinders methoctramine binding to the allosteric site at this receptor subtype. Impaired interaction with the allosteric binding site manifests as low-affinity binding of methoctramine at the M(3) receptor.

MP47-06 EFFECTS OF FESOTERODINE (COMPETITIVE MUSCARINIC RECEPTOR ANTAGONIST) ON FUNCTIONAL RESPONSES OF RAT CORPUS CAVERNOSUM

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research II1 Apr 2014MP47-06 EFFECTS OF FESOTERODINE (COMPETITIVE MUSCARINIC RECEPTOR ANTAGONIST) ON FUNCTIONAL RESPONSES OF RAT CORPUS CAVERNOSUM Didem Yilmaz, Tamila Akyeva, Sahika Guner, Salih Erpulat Ozis, Ecem Kaya, and Serap Gur Didem YilmazDidem Yilmaz More articles by this author , Tamila AkyevaTamila Akyeva More articles by this author , Sahika GunerSahika Guner More articles by this author , Salih Erpulat OzisSalih Erpulat Ozis More articles by this author , Ecem KayaEcem Kaya More articles by this author , and Serap GurSerap Gur More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1459AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Erectile dysfunction (ED) is strongly associated with overactive bladder (OAB) symptoms. Fesoterodine (Toviaz®, New York, NY: Pfizer, Inc) is competitive muscarinic receptor antagonist which is used for treatment of OAB symptoms. We determined the effects of fesoterodine on functional response of rat corpus cavernosum smooth muscle (CCSM). Methods Adult Sprague-Dawley male rats were used in experiments. In vitro contractile and relaxation responses in the absence and presence of fesoterodine were evaluated using isolated strips of CCSM. Results We provided as a first evidence that fesoterodine induced the marked relaxation (87.2%) after precontraction with phenylephrine (Phe, 10μM) in rat CCSM. N(G)-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase [NOS] inhibitor, 100μM) (88.7%), 1H-[1,2,4] oxadiazole [4,3-a] quinoxalin-1-one (ODQ, soluble guanosyl cyclase blocker, 10μM) (66.5%) and both (62.7%) did not suppress the relaxation response of fesoterodine. The relaxation response to acetylcholine (100μM) after preincubation with fesoterodine was increased in CCSM of rats. Preincubation with fesoterodine did not alter electrical field stimulation (nitrergic) induced relaxation. Fesoterodine enhanced remarkably sodium nitroprusside (SNP)-induced relaxation (at 0.01 nM concentration) in CCSM (before 0.5%; after 22.5%, p<0,05). Contractile response to Phe after preincubation with fesoterodine was decreased in CCSM (before 69.2%; after 12.1%, p<0,001). The contractile response to EFS after preincubation with fesoterodine (10μM) in penile tissue was not altered. Conclusions We conclude that the inhibitory action of fesoterodine on isolated rat CCSM is independent upon the endogenous nitric oxide, soluble guanylate cyclase and cyclic guanosine monophosphate system and dependent on corporal smooth muscle components. To the best of our knowledge, this is the first antagonist able to inhibit two different system (cholinergic and adrenergic) in the penile tissue. Thus, inhibition of muscarinic receptors improves OAB in men, either with BPH and ED. Future studies are warranted to investigate effect of fesoterodine on ED. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e520 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Didem Yilmaz More articles by this author Tamila Akyeva More articles by this author Sahika Guner More articles by this author Salih Erpulat Ozis More articles by this author Ecem Kaya More articles by this author Serap Gur More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Neuromodulatory propensity of Bacopa monniera against scopolamine-induced cytotoxicity in PC12 cells via down-regulation of AChE and up-regulation of BDNF and muscarnic-1 receptor expression.

Scopolamine is a competitive antagonist of muscarinic acetylcholine receptors, and thus classified as an anti-muscarinic and anti-cholinergic drug. PC12 cell lines possess muscarinic receptors and mimic the neuronal cells. These cells were treated with different concentrations of scopolamine for 24 h and were protected from the cellular damage by pretreatment with Bacopa monniera extract (BME). In current study, we have explored the molecular mechanism of neuromodulatory and antioxidant propensity of (BME) to attenuate scopolamine-induced cytotoxicity using PC12 cells. Our results elucidate that pretreatment of PC12 cells with BME ameliorates the mitochondrial and plasma membrane damage induced by 3 μg/ml scopolamine to 54.83 and 30.30 % as evidenced by MTT and lactate dehydrogenase assays respectively. BME (100 μg/ml) ameliorated scopolamine effect by down-regulating acetylcholine esterase and up-regulating brain-derived neurotropic factor and muscarinic muscarinic-1 receptor expression. BME pretreated cells also showed significant protection against scopolamine-induced toxicity by restoring the levels of antioxidant enzymes and lipid peroxidation. This result indicates that the scopolamine-induced cytotoxicity and neuromodulatory changes were restored with the pretreatment of BME.

Inhibition of Cholinergic Contractions of Rat Ileum by Tropane-Type Alkaloids Present in Schizanthus hookeri

The relative lack of specificity of atropine as a competitive antagonist of muscarinic receptors is a frequent cause of undesirable parasympathetic side effects. Consequently, new tropane alkaloids with potentially greater selectivity are usually seen with real interest. The cholinergic antagonistic effects of a purified mixture of tropane alkaloids extracted from Schizanthus hookeri were evaluated in rat ileum. For this purpose, ileal segments were obtained from randomly selected male Sprague-Dawley rats, and the effect of 1 x 10(-4), 1 x 10(-3), and 1 x 10(-2) mg/mL of the purified mixture of alkaloids on the contractile response of the ileum induced with increasing doses of carbachol (5 x 10(-8) - 10(-4) M) was determined. The results were compared with those obtained in the presence of 3.46 x 10(-7), 3.46 x 10(-6), and 3.46 x 10(-5) mg/mL atropine as an agonist. Tropane alkaloids extracted from Schizanthus hookeri competitively antagonized acetylcholine muscarinic receptors.

Dopamine enhances gastric motility through D1 dopaminergic receptors on cholinergic neurons in the myenteric plexus of rats

ObjectivesInvestigate the effect of dopamine on the gastric motility and the underlying mechanism.MethodsImmunofluorescence and gastric motility recording by organ bath study.ResultThe immunoreactivities of D1 and D2 were distributed in the choline acetyltransferase (ChAT)‐immunoreactive neurons in the myenteric plexus of rats. The gastric motility in vitro was enhanced from 8.2 to 10.8£g¡Ámin£©by DA in the concentrations of 1¡Á10–8mol/L (n=10, p&lt;0.05). However, DA manifested inhibitory role at the higher concentrations of 3¡Á10–6mol/L. The excitatory effect of DA was mimicked by SKF‐38393, a selective agonist of D1‐like receptors in dose‐dependent manner, and blocked by neuronal sodium channel blocker, tetrodotoxin (TTX) in 1¡Á10–5mol/L and atropine (competitive nonselective antagonist of muscarinic acetylcholine receptors) in 1¡Á10–5mol/L (n=8, p&lt;0.05). The selective D2‐like receptor antagonist sulpride and selective D2‐like agonist Quipirole did not affect both the excitatory and inhibitory effect of DA.ConclusionsThe present study demonstrates that dopamine is able to enhance gastric motility in lower concentration through D1 dopaminergic receptors activating acetylcholine release from myenteric nerve plexus. The higher dose of DA can inhibit gastric motility, but the mechanism needs to be further investigated.

RAISING THE ‘DEAD’ – REPERFUSION FROM TORPOR

> Kelly Drew discusses Paul Chatfield and Charles Lyman's classic paper ‘Circulatory changes during the process of arousal in the hibernating hamster’, published in the American Journal of Physiology in 1950. Over 60 years ago, Paul Chatfield and Charles Lyman described fundamental

Aclidinium bromide for the treatment of chronic obstructive pulmonary disease

Inhaled aclidinium bromide has recently been approved by the European Medicines Agency and the U.S. Food and Drug Administration for the maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD). Aclidinium bromide is a competitive muscarinic receptor antagonist with kinetic selectivity for the muscarinic M(3) receptor and with a long duration of action. It is rapidly hydrolyzed in human plasma, and its metabolites have no activity on muscarinic receptors. Initial phase I and II studies in patients with COPD indicated that aclidinium bromide 200 μg o.d. had a bronchodilator activity up to 24 hours. However, in subsequent phase III studies, the bronchodilator effect at 24 hours was found to be suboptimal. Phase III trials using 200 and 400 μg b.i.d. have subsequently reported both clinical significant bronchodilator activities and improved patient-reported outcomes such as quality of life and dyspnea. Aclidinium bromide was also found to be safe and the anticholinergic side effects were reported to be low.

Treatment of Overactive Bladder Symptoms with Extended Release Fesoterodine Fumarate

Fesoterodine extended-release (brand name Toviaz) is a new competitive muscarinic receptor antagonist labeled for the treatment of overactive bladder (OAB). Here we have undertaken a substantial update to a systematic review evaluating the effects of fesoterodine in the treatment of OAB. Our results indicate that fesoterodine was found to have significant improvements in the management of OAB symptoms compared with placebo. Post hoc analysis of these trials demonstrated significant improvements in health-related quality of life in patients with overactive bladder. Only one study included tolterodine, and direct comparisons between fesoterodine and tolterodine were not conducted. The most common treatment-emergent adverse effects associated with fesoterodine included dry mouth and constipation. In summary, fesoterodine appears to be effective and generally safe for the treatment of overactive bladder. Nonetheless, additional comparative trials are required to evaluate whether fesoterodine provides a substantial advantage over extended-release tolterodine.