piperidines and Urinary-Bladder--Overactive

Clinically, both overactive bladder (OAB) and dysuria are known to occur in patients with cerebral infarction (CI). A few anticholinergic drugs are used to treat OAB in such patients, although the effect is not satisfactory. On the other hand, little or no therapeutic drug is available for dysuria after CI. We previously reported that dextromethorphan (DM) and cloperastine (CP), centrally acting antitussives, reduce the frequency of micturition reflex and increase the threshold pressure in anesthetized rats. In this article, we describe the effects of DM and CP on urinary disturbances at 24 h after CI, induced by occlusion of the left middle cerebral artery in conscious rats. We also briefly review the structure, function, and distribution of G-protein-coupled inwardly rectifying K(+) (GIRK) channels in the brain, since both drugs have potent inhibitory effect on GIRK channel-activated currents in brain neurons. Of the two drugs, CP at antitussive-effective doses ameliorated both OAB and dysuria 24 h after CI in rats. On the other hand, DM aggravated the dysuria, although it significantly ameliorated the OAB. These results suggest that CP may have some therapeutic value for the treatment of OAB and dysuria after CI. At the present time, mechanisms of the effect of CP are unknown. However, several lines of evidence including pharmacological findings support the idea that the effects of CP may be produced at least partly by an increase in the level of 5-HT in the brain through an inhibitory effect on GIRK channel-activating currents.

Topics: Animals; Antitussive Agents; Brain; Cerebral Infarction; Dextromethorphan; Drug Design; Dysuria; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Humans; Molecular Targeted Therapy; Piperidines; Rats; Serotonin; Urinary Bladder, Overactive

Casopitant, an inhibitor of the neurokinin-1 receptor, and its mesylate salt, are being developed by GlaxoSmithKline plc for the potential treatment of chemotherapy-induced nausea and vomiting (CINV), post-operative nausea and vomiting (PONV), as well as for anxiety, depression and insomnia. Phase II trials are ongoing for anxiety, depression and insomnia, and further results are awaited from phase III trials of CINV and PONV. At the time of publication, it was expected that applications to the FDA for regulatory approval for CINV and PONV would be filed in 2008. Casopitant was previously being developed for the treatment of overactive bladder; however, in September 2007, this indication was no longer listed on the company's product pipeline.

Topics: Animals; Antiemetics; Anxiety Disorders; Clinical Trials as Topic; Contraindications; Depressive Disorder, Major; Drug Evaluation, Preclinical; Female; Fibromyalgia; Humans; Nausea; Neurokinin-1 Receptor Antagonists; Patents as Topic; Piperazines; Piperidines; Postoperative Nausea and Vomiting; Structure-Activity Relationship; Urinary Bladder, Overactive; Vomiting

Spinal cord injury (SCI) above the lumbosacral level results in lower urinary tract dysfunction, including (1) detrusor hyperreflexia, wherein bladder compliance is low, and (2) a lack of external urethral sphincter (EUS) control, leading to detrusor-sphincter dyssynergia (DSD) with poor voiding efficiency. Experimental studies in animals have shown a dense innervation of serotonergic (5-HT) fibers and multiple 5-HT receptors in the spinal reflex circuits that control voiding function. Here, we investigated the efficacy of NLX-112 (a.k.a. befiradol or F13640), in regulating lower urinary tract function after T8 contusive SCI in rats. NLX-112 is a very potent, highly-selective, and fully efficacious 5-HT

Topics: Animals; Dose-Response Relationship, Drug; Electromyography; Female; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Spinal Cord Injuries; Urethra; Urinary Bladder Diseases; Urinary Bladder, Neurogenic; Urinary Bladder, Overactive; Urinary Tract; Urination; Urodynamics

This study was designed to evaluate the effects of CP55,940 on normal bladder function in vivo and examine whether it suppresses urinary frequency induced by nociceptive stimuli in the bladder. Cannabinoid receptor (CBR) activity may be involved in the regulation of bladder function. However, the role of CBR subtypes in micturition has yet to be established. CP55,940 is a synthetic analogue of tetrahydrocannabidiol, which is a psychoactive ingredient of the Cannabis plant.. Cystometry under urethane anaesthesia was performed to evaluate the effect of intravesical delivery of CP55,940 with or without administration of CB1 antagonist AM251 or CB2 antagonist AM630 on bladder function in female rats. The effects of CP55,940 were also examined in rats with urinary irritation induced by intravesical infusion of acetic acid.. Infusion of CP55,940 significantly (p < 0.05) increased micturition interval (MI) and bladder capacity (BC) by 52 % and decreased maximal voiding pressure (MP) by 25 %. Pretreatment with AM251 or AM630 before CP55,940 administration prevented CP55,940-induced increases in MI, BC and reduced MP. Acetic acid induced urinary frequency as evidenced by a reduction in MI and was suppressed by CP55,940.. CP55,940 decreases bladder activity and urinary frequency induced by nociceptive stimuli, probably by suppression of bladder afferent activity. Effects of CP55,940 were abolished by both CBR antagonists. This data implicates a role for the endocannabinoid system in bladder mechanoafferent function in rats. In addition, our results show that CP55,940 reverses urinary frequency exemplified in an overactive bladder model, suggesting it could be an effective treatment for patients with lower urinary tract symptoms.

Topics: Acetic Acid; Administration, Intravesical; Animals; Cannabinoid Receptor Agonists; Cyclohexanols; Disease Models, Animal; Female; Indoles; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Treatment Outcome; Urinary Bladder; Urinary Bladder, Overactive; Urination; Urodynamics

Serotonin 1A (5-HT1A) receptors have been mechanistically implicated in micturition control, and there has been a need for an appropriate biomarker surrogating the potency of a provisional drug acting on this receptor system for developing a new therapeutic approach to overactive bladder (OAB). Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET) imaging, and assessed the utility of a receptor occupancy (RO) assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50) estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%). Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. These findings support the utility of PET RO and plasma pharmacokinetic assays with the aid of adequate mathematical models in determining the in vivo characteristics of a drug acting on 5-HT1A receptors and thereby counteracting OAB.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Administration, Oral; Animals; Computer Simulation; Hippocampus; Microsomes; Piperidines; Positron-Emission Tomography; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Reflex; Superior Colliculi; Time Factors; Urinary Bladder, Overactive; Urination

Existing antimuscarinic drugs for overactive bladder have high affinity for M(3)/M(1) muscarinic receptors and consequently produce M(3)/M(1)-mediated adverse effects including dry mouth, constipation, mydriasis and somnolence. TD-6301 is a M(2/4) muscarinic receptor-selective antagonist developed for the treatment of overactive bladder. The present studies characterize the in vitro and in vivo pharmacological properties of this molecule in comparison to other marketed antimuscarinics agents. In radioligand binding studies, TD-6301 was found to possess high affinity for human M(2) muscarinic receptor (K(i)=0.36 nM) and was 31, 36, 2 and 128-fold selective for the human M(2) muscarinic receptor compared to the M(1), M(3), M(4) and M(5) muscarinic receptors, respectively. The in vivo bladder selectivity of TD-6301 in rats was determined to be 26, 28, >100, 16 and 0.4-fold, respectively, assessed by comparing its potency for inhibition of volume-induced bladder contractions to that for inhibition of oxotremorine-induced salivation, inhibition of small-intestinal transit, decreases in locomotor activity, increases in pupil diameter and increases in heart rate. TD-6301 was more potent in inhibiting volume-induced bladder contractions (ID(50)=0.075 mg/kg) compared to oxotremorine-induced salivation (ID(50)=1.0 mg/kg) resulting in a bladder/salivary gland selectivity ratio greater than that observed for tolterodine, oxybutynin, darifenacin and solifenacin. The preclinical properties of TD-6301 suggest that this molecule is likely to be efficacious in overactive bladder patients with a lower propensity to cause M(3) muscarinic receptor mediated adverse effects.

Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Female; Humans; Inhibitory Concentration 50; Male; Muscarinic Antagonists; Muscle Contraction; Piperidines; Pyridines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M2; Receptor, Muscarinic M4; Salivary Glands; Salivation; Urinary Bladder; Urinary Bladder, Overactive

Topics: Aged; Aged, 80 and over; Benzilates; Chi-Square Distribution; Cholinergic Antagonists; Cholinesterase Inhibitors; Dementia; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Piperidines; Prospective Studies; Surveys and Questionnaires; Treatment Outcome; Urinary Bladder, Overactive

We investigated the effects of the centrally acting antitussives dextromethorphan and cloperastine on urinary bladder dysfunction 24 h after cerebral infarction in rats using the cystometry technique. First, cystometrography was performed in conscious male Sprague-Dawley rats. Cerebral infarction was then induced by occlusion of the left middle cerebral artery. Twenty-four hours after cerebral infarction, the effect of each drug on micturition disorder was estimated for 5 parameters: bladder capacity, maximum voiding pressure, micturition latency, flow rate, and urethral resistance. Cerebral infarction markedly reduced bladder capacity, micturition latency, and flow rate and increased urethral resistance. After cerebral infarction, intravenous dosing of saline had no effect on these parameters. Dextromethorphan (20 mg/kg) and cloperastine (2.5 and 5.0 mg/kg) at antitussive effective doses significantly increased bladder capacity and micturition latency. Unlike dextromethorphan, cloperastine ameliorated decreases in flow rate and increases in urethral resistance caused by cerebral infarction. These results suggest that cloperastine may have therapeutic value for the treatment of disorders of the micturition reflex associated with cerebral infarction, and that the drug may become a base compound from which to develop more active drugs for such disorders.

Topics: Animals; Antitussive Agents; Ataxia; Dextromethorphan; Diagnostic Techniques, Urological; Infarction, Middle Cerebral Artery; Male; Piperidines; Rats; Rats, Sprague-Dawley; Urinary Bladder; Urinary Bladder, Overactive; Urination

Recently, growing clinical evidence has suggested that sexual dysfunction is more prevalent in women with overactive bladder (OAB). Aims. However, there has been no basic research to clarify the relationship between OAB and female sexual dysfunction. Therefore, we investigated this issue using a rabbit model of OAB.. Twenty-seven New Zealand white female rabbits were randomly divided into the OAB and control groups.. The contractile responses of clitoral cavernous strips to K(+), phenylephrine (PE), Bay K 8644, and endothelin (ET)-1, and the relaxation responses of acetylcholine (ACh), sodium nitroprusside (SNP), and Y-27632 to PE-induced contraction by measuring isometric tension. Results. The contractile responses to K(+), PE, Bay K 8644, and ET-1 were significantly more increased in the OAB group in a dose-dependant manner than in the control group (P < 0.05), and the responses to ET-1 were more prominent than those to the remaining substances (P < 0.01). The increased contractile responses to ET-1 were blocked by BQ123 (ET(A) receptor antagonist) but not by BQ788 (ET(B) receptor antagonist). Clitoral cavernosal strips from the OAB group were more difficult to relax than those from the control group in terms of ACh- and SNP-induced relaxation (P < 0.05). The Y-27632-induced relaxant responses to PE- and ET-1-induced contraction were less prominent in the OAB group than in the control group. CONCLUSIONS; The results of this study provide evidence that female OAB may deteriorate clitoral engorgement, which is associated with a greater force generation by increased calcium sensitization and subsequently decreased of relaxation. The activation of ET and Rho-kinase system may be crucial to negatively effect the clitoral smooth muscle relaxation in experimentally induced OAB animal model. But whether these vasomotor effects are revived in human clitoris is still debatable.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Acetylcholine; Adrenergic alpha-Agonists; Amides; Animals; Antihypertensive Agents; Calcium Channel Agonists; Clitoris; Dose-Response Relationship, Drug; Endothelin-1; Female; Isometric Contraction; Models, Animal; Muscle Relaxants, Central; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Oligopeptides; Peptides, Cyclic; Phenylephrine; Piperidines; Potassium; Pyridines; Rabbits; Urinary Bladder, Overactive; Vasodilator Agents

This study examines whether M(2) receptors contribute to direct contraction of the detrusor in human neurogenic and idiopathic overactive bladders.. Control detrusor muscle was obtained from patients undergoing cystectomy for bladder cancer, whilst overactive detrusor muscle was obtained from patients undergoing clam cystoplasty for idiopathic or neurogenic detrusor overactivity. The affinities of a range of subtype selective antagonists (DAMP, darifenacin, methoctramine R0-320-6206, and pirenzepine) were obtained in tissue bath experiments by using carbachol as the agonist. These affinity values were then compared with the known affinities for these antagonists at the muscarinic receptor subtypes.. An increased sensitivity to carbachol was observed in both the neurogenic and idiopathic overactive detrusors compared with the control human detrusor. The M(2)-selective antagonists (methoctramine, R0-320-6206) and M(1)-selective antagonist (pirenzepine) had low affinities, whilst the M(3)-selective antagonists (4-DAMP and darifenacin) had high affinities for the human detrusor muscarinic receptor in all three groups of tissues. The affinities (pK(B) values) for the five antagonists were consistent with antagonisms at the M(3) receptor in all three groups; Schild plot analysis indicated an action at this single receptor subtype.. Contraction mediated by muscarinic receptors is enhanced in idiopathic and neurogenic overactive detrusors compared with control detrusor. The direct contractile response to carbachol is mediated by the M(3) receptor in both human normal and overactive bladders, indicating no change in receptor subtype contribution to contraction in the disease state.

Topics: Adult; Aged; Benzofurans; Carbachol; Diamines; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Male; Middle Aged; Muscle Contraction; Muscle, Smooth; Piperidines; Pirenzepine; Pyrrolidines; Receptors, Muscarinic; Urinary Bladder; Urinary Bladder, Neurogenic; Urinary Bladder, Overactive

The functional contribution of the cholinergic pathway in the frontal cortex to micturition was evaluated following cerebral ischemia. Furthermore, it was examined whether reactivation of this regulatory system using acetylcholinesterase inhibitor could improve detrusor overactivity.. Left middle cerebral artery occlusion (MCAO) was performed in female Sprague-Dawley rats. Choline acetyltransferase (ChAT) activities after MCAO were assayed to assess the damage to cholinergic neurons. ChAT activities in the bilateral cortex, hippocampus, and pons were calculated by measuring the conversion of 1-[14C] acetyl-coenzyme A to [14C] acetylcholine. Effects on cystometrography of i.v. or i.c.v. donepezil hydrochloride (DON), a centrally acting acetylcholinesterase inhibitor, were investigated in conscious sham-operated (SO) and cerebral infarcted (CI) rats. To investigate whether DON in the forebrain was affected, we decerebrated rats after CI or SO, and investigated the effects on cystometrography of i.v. DON.. Bladder capacity was markedly decreased after MCAO, and remained below half of the pre-occlusion capacity. The greatest increase in bladder capacity was attained at 1.2 x 10(-2) nM/kg of DON given i.v., with a change of 52.8% (P < 0.05). In cases of i.c.v. DON, the greatest increase in bladder capacity was at the dose of 6 x 10(-2) pmol with the change of 95.8% (P < 0.01). The activity of ChAT was decreased in the left cortex and hippocampus 24 h after MCAO (P < 0.05). In decerebrated rats, low dose of DON did not change micturition parameters.. These results suggest that by upregulation of the forebrain muscarinic inhibitory mechanism, acetylcholinesterase inhibitor improves detrusor overactivity by cerebral infarction.

Topics: Analysis of Variance; Animals; Brain; Choline O-Acetyltransferase; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Female; Indans; Infarction, Middle Cerebral Artery; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors; Urinary Bladder; Urinary Bladder, Overactive