Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0043352 (xerostomia)
4,250 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the course of continuing efforts to develop potent and bladder-selective muscarinic M3 receptor antagonists, quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives and related compounds were designed as conformationally restricted analogues of quinuclidin-3-yl benzhydrylcarbamate (8). Binding assays with rat muscarinic receptor subtypes revealed that the quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives showed high affinities for the M3 receptor, and selectivity for the M3 receptor over the M2 receptor. Of these derivatives, (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monohydrochloride (9b) exhibited almost the same inhibitory activity against bladder contraction to that of oxybutynin (1), and more than 10-fold selectivity for bladder contraction versus salivary secretion, demonstrating that 9b may be useful for the treatment of symptoms associated with overactive bladder without having side effects such as dry mouth.
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PMID:Synthesis and antimuscarinic properties of quinuclidin-3-yl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives as novel muscarinic receptor antagonists. 1622 Sep 76

Antimuscarinic side-effects, which include dry mouth, tachycardia, thickening of mucus possibly sedation, of the antihistamines limited the usefulness of these drugs. The advent of newer agents has reduced the sedative effect of the antihistamine. The data presented here show that one of the newest antihistamines, desloratadine, and a first generation drug, diphenhydramine, are both competitive inhibitors of muscarinic receptor mediated slowing of the heart as measured using a Langendorff preparation. Both agents have apparent sub-micromolar affinities for the muscarinic receptor. Two other agents, cetirizine and fexofenadine, do not interact with muscarinic receptors in the heart at the concentrations used in this study. Structural similarities of the drugs suggest that substitution of a group with a high dipole moment or charge on the side chain nitrogen decreases the binding with muscarinic receptors. We conclude that of the compounds tested fexofenadine and cetirizine have little or no interaction with muscarinic receptors.
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PMID:Antimuscarinic actions of antihistamines on the heart. 1645 79

The primary pharmacological therapy for overactive bladder syndrome is muscarinic receptor antagonists. Muscarinic receptor blockade is effective in decreasing the symptoms of urinary urgency and urgency incontinence, but can be associated with troublesome complications, such as dry mouth, blurred vision, constipation and CNS side effects. Trospium chloride, an antimuscarinic medication, has been available in Europe for > 20 years and has recently been approved by the FDA for the treatment of overactive bladder. Trospium chloride is a quaternary amine that is minimally metabolised, not highly protein bound and, importantly, has not been demonstrated to cross the unaltered blood-brain barrier in healthy volunteers. Some characteristics of this unique antimuscarinic agent and the European experience with trospium chloride are reviewed in this article.
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PMID:Trospium chloride: the European experience. 1680 22

Anticholinergic agents such as oxybutynin are clinically useful in the treatment of overactive bladder. However, oral administration of oxybutynin is frequently accompanied by side effects such as dry mouth, and novel bladder-selective anticholinergic agents such as solifenacin and tolterodine are now under development. The aim of the present study was to characterize the suppression of cholinergic salivation and exocrine muscarinic receptor binding of solifenacin on oral administration to mice in comparison with those of oxybutynin. Results showed that both drugs produced a significant increase in K(d) values for specific [N-Methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS) binding in the mouse submaxillary gland, compared with control values. However, this enhancement in K(d) values was significantly smaller with solifenacin than with oxybutynin. Moreover, the inhibitory effect of solifenacin on pilocarpine-induced salivary secretion was significantly weaker than that of oxybutynin. Solifenacin dissociated more readily from muscarinic receptors in the mouse submaxillary gland than oxybutynin. In conclusion, the present study indicates that the weak suppression of cholinergic salivation by solifenacin compared with oxybutynin may be partially attributed to its relatively fast dissociation kinetics from exocrine muscarinic receptors.
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PMID:Comparative evaluation of exocrine muscarinic receptor binding characteristics and inhibition of salivation of solifenacin in mice. 1681 76

Muscarinic acetylcholine receptors mediate diverse physiological functions. At present, five receptor subtypes (M(1) - M(5)) have been identified. The odd-numbered receptors (M(1), M(3), and M(5)) are preferentially coupled to G(q/11) and activate phospholipase C, which initiates the phosphatidylinositol trisphosphate cascade leading to intracellular Ca(2+) mobilization and activation of protein kinase C. On the other hand, the even-numbered receptors (M(2) and M(4)) are coupled to G(i/o), and inhibit adenylyl cyclase activity. They also activate G protein-gated potassium channels, which leads to hyperpolarization of the plasma membrane in different excitable cells. Individual members of the family are expressed in an overlapping fashion in various tissues and cell types. Recent gene targeting approaches have unraveled the specific function of these muscarinic receptor subtypes, which were not able to be fully elucidated with pharmacological approaches because of the non-selective effects of the available ligands. Based on these findings, muscarinic receptors have been emerging as an important therapeutic target for various diseases, including dry mouth, incontinence and chronic obstructive pulmonary disease. Here we review the latest advances in the structural and functional characterization of muscarinic acetylcholine receptors and the pharmaceutical development of muscarinic receptor ligands.
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PMID:Muscarinic acetylcholine receptors. 1707 60

Studies on salivary secretion are usually focused on parotid and submandibular glands. However, the film of mucin, that protects the oral structures and is responsible for the feeling of oral comfort, is produced by the submucosal glands. The submucosal zygomatic and molar glands are particularly large in carnivores such as the ferret. Comparisons between the mucous sublingual, zygomatic and molar glands, serous parotid and sero-mucous submandibular glands showed the acetylcholine synthesis, in terms of concentration, to be three to four times higher in the mucous glands than in the parotid and submandibular glands. Bromoacetylcholine inhibited 95-99% of the synthesis of acetylcholine in the incubates of the five types of glands, showing the acetylcholine synthesis to depend on the activity of choline acetyltransferase. The high acetylcholine synthesis in the zygomatic gland was of nervous origin, since cutting the buccal nerve, aiming at parasympathetic denervation, and allowing time for nerve degeneration, reduced the acetylcholine synthesising capacity of the gland by 95%. A similar reduction (96%) in the parotid gland followed upon the avulsion of the parasympathetic auriculo-temporal nerve. Zygomatic saliva was very viscous. The salivary flow rate in response to electrical stimulation (20 Hz) of the buccal nerve (zygomatic gland), expressed per gland weight, was one-third of that to stimulation of the auriculo-temporal nerve (parotid gland) or the chorda-lingual nerve (submandibular gland). As previously shown for the parotid and submandibular gland, a certain fraction (25%) of the parasympathetic secretory response of the zygomatic gland depended on non-adrenergic, non-cholinergic transmission mechanisms, probably involving substance P and vasoactive intestinal peptide and possibly calcitonin gene-related peptide. Particularly, high concentrations of vasoactive intestinal peptide were found in the sublingual and molar glands, and of substance P in the submandibular, zygomatic and molar glands; notably, the concentration of calcitonin gene-related peptide of the sublingual gland was not detectable. All five muscarinic receptor subtypes were detected in the five glands. The receptor protein profile, as judged by immunoblotting and semi-quantitative estimations, was about the same in the glands: high level of M3, low level of M2 and levels roughly in the same range of M1, M4 and M5. Compared to the parotid and submandibular glands, the M5 receptor level was particularly low in the mucin-secreting glands. The present study points out both similarities and dissimilarities between the five types of glands investigated. The zygomatic gland, in particular, appears to be a suitable model for future studies aiming at causing relief of dry mouth by local pharmacological treatment.
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PMID:Acetylcholine synthesis, muscarinic receptor subtypes, neuropeptides and secretion of ferret salivary glands with special reference to the zygomatic gland. 1712 59

Anticholinergic agents are used for treatment of overactive bladder syndrome (OAB) by competitive blockade of acetylcholine at the muscarinic receptor. At present five different subtypes of M-receptors can be differentiated. Primary detrusor effects are mediated by M3-receptors as are side effects like dry mouth and constipation. Cardiac and central nervous system side effects appear to be M2 or M1 related. OAB symptom relief by the unselective drugs tolterodine, oxybutynin or trospium chloride and by M3-selective agents like darifenacin or solifenacin seems to be rather similar. Central side effects are different depending on gastrointestinal reabsorption, serum metabolism and penetration of the blood-brain barrier. Slow release formulations may be better tolerated. Anticholinergics that penetrate the blood-brain barrier may cause cognitive imbalance in older patients, as recent studies have shown for oxybutynin. Here M3-selective agents may offer an advantage.
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PMID:[How do medications used to treat urinary incontinence affect the cerebral function of the elderly?]. 1737 63

Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence, usually with frequency and nocturia. OAB symptoms are often associated with detrusor overactivity (DO). Like OAB symptoms, the prevalence of DO increases with age and can have a neurogenic and/or myogenic aetiology. Bladder outlet obstruction can be a contributing factor in DO, possibly through cholinergic denervation of the detrusor and supersensitivity of muscarinic receptors to acetylcholine, although the prevalence of OAB is similar in men and women across age groups. Acetylcholine is the primary contractile neurotransmitter in the human detrusor, and antimuscarinics exert their effects on OAB/DO by inhibiting the binding of acetylcholine at muscarinic receptors M(2) and M(3) on detrusor smooth muscle cells and other structures within the bladder wall. Worldwide, there are six antimuscarinic drugs currently marketed for the treatment of OAB: oxybutynin, tolterodine, propiverine, trospium, darifenacin, and solifenacin. Each has demonstrated efficacy for the treatment of OAB symptoms, but their pharmacokinetic and adverse event profiles differ somewhat due to structural differences (tertiary vs quaternary amines), muscarinic receptor subtype selectivities, and organ selectivities. Antimuscarinics are generally well tolerated, even in special populations (e.g. men with bladder outlet obstruction, elderly patients, children). The most frequently reported adverse events in clinical studies of antimuscarinics are dry mouth, constipation, headache, and blurred vision; few patients withdraw from clinical trials because of adverse events. Development of an antimuscarinic with functional selectivity for the bladder would reduce the occurrence of antimuscarinic adverse events. The therapeutic potential of several other agents, such as alpha(3)-adrenoceptor agonists, purinergic receptor antagonists, phosphodiesterase inhibitors, neurokinin-1 receptor antagonists, opioids, and Rho-kinase inhibitors, is also under investigation for the treatment of OAB.
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PMID:Muscarinic receptor antagonists for overactive bladder. 1792 84

The aim of this study was to clarify the effects of the muscarinic receptor agonist, cevimeline, on saliva flow and expression of aquaporin5 (AQP5) in submandibular gland after X-ray irradiation. Using a previously established radiation-induced xerostomia model mouse, saliva flow from at 7 days before irradiation to at 28 days after irradiation was investigated in mice that were treated with cevimeline before or after irradiation. Radiation caused a significant decrease in saliva flow compared with nonirradiated salivary glands. Cevimeline post-treatment also caused a significant decrease in saliva flow. In contrast, cevimeline pre-treatment did not significantly decrease saliva flow. Expression of AQP5 fluorescent intensity and mRNA were also analyzed. Irradiation significantly decreased expression of AQP5 in submandibular gland. However, pre-treatment with cevimeline prevented this decrease in AQP5 expression. These data suggest that pretreatment with cevimeline prevents radiation-induced xerostomia and radiation-induced decrease in expression of AQP5 in submandibular gland.
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PMID:Effect of cevimeline on radiation-induced salivary gland dysfunction and AQP5 in submandibular gland in mice. 1797 45

Solifenacin succinate is a novel muscarinic receptor antagonist used for the treatment of overactive bladder (OAB). We investigated the effects of solifenacin by oral and intravenous administration on carbachol (CCh)-induced intravesical pressure (IVP) elevation and compared its efficacy with that on CCh-induced salivary secretion in anesthetized mice. Additionally, we also investigated the change in effects between single and repeated oral administration of solifenacin on CCh-induced IVP elevation. Results showed that intravenous administration of solifenacin dose-dependently inhibited the IVP elevation and salivary secretion. The ratio of bladder response to salivary response (ratio of ID(50) values) was 2.1. Oral administration of solifenacin (0.3-30 mg/kg) also inhibited CCh-induced IVP elevation and salivary secretion. Although inhibition of these responses by solifenacin (10, 30 mg/kg) was comparable at early time points (0.5 and 1 h after administration at 10 mg/kg and 0.5 to 2 h after administration at 30 mg/kg), inhibition of CCh-induced IVP elevation was stronger at later time points (2 to 8 h after administration at 10 mg/kg and 4 to 24 h after administration at 30 mg/kg). No significant difference in ID(50) values for IVP elevation was observed between single and repeated (11 d) oral administration of solifenacin (1-30 mg/kg), suggesting no change in efficacy on chronic administration. In conclusion, intravenous and oral solifenacin inhibits CCh-induced IVP elevation more potently than salivary secretion. These results provide further evidence for the clinical use of solifenacin as a promising therapeutic drug for OAB with a low incidence of dry mouth.
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PMID:Effects of intravenously and orally administered solifenacin succinate (YM905) on carbachol-induced intravesical pressure elevation and salivary secretion in mice. 1805 20


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