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)

The major side effects of racemic oxybutynin (OXY), which is used in the treatment of urinary incontinence are dry mouth (xerostomia) and blurred vision (mydriasis). Highly purified enantiomers of OXY [(R)OXY, (S)OXY] were compared with the racemate both in vitro in functional studies and in vivo in guinea pigs to evaluate their pharmacological action relative to their adverse effects. The affinity of (R)OXY and (S)OXY for different muscarinic receptor subtypes was determined using field stimulated rabbit vas deferens (M1) and guinea pig atria (M2) or bladder (M3) strips. Stereoselective antimuscarinic effects [(R)OXY greater than or equal to (R/S) OXY much greater than (S)OXY] were evident at all three receptor subtypes; the isomeric ratio [(S)OXY/(R)OXY] ranged from 12 to 88. Both (R)OXY and (R/S)OXY were slightly more selective (2-4-fold, P less than .01) for M1 and M3 relative to M2 muscarinic receptors. Stereoselectivity was also evident in vivo for volume-induced urinary bladder contractions as measured by cystometrogram parameters [(S)OXY/(R)OXY approximately 21], mydriasis [(S)OXY/(R)OXY approximately 136] and salivary gland secretory responses [(S)OXY/(R)OXY approximately 30]. The absolute potencies of (R)OXY or (R/S)OXY for mydriasis and salivation were similar to those for inhibition of intravesical bladder pressure. Also, (R)OXY and (R/S)OXY equipotently antagonized cholinergic-mediated CNS effects in mice. Collectively, the data suggest that the activity of (R/S)OXY resides predominantly in the (R)-enantiomer. However, it appears that (R)OXY may offer no significant pharmacological advantage over (R/S)OXY in terms of its principal therapeutic and side effect profile.
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PMID:Enantiomers of oxybutynin: in vitro pharmacological characterization at M1, M2 and M3 muscarinic receptors and in vivo effects on urinary bladder contraction, mydriasis and salivary secretion in guinea pigs. 199 95

Choice of an antidepressant medication is, in part, based on the side effects produced by a drug and the desire to avoid certain reactions in a particular patient. The clinician needs a reliable method of predicting which medications are most likely to produce specific untoward effects. Understanding the synaptic pharmacology of the most commonly used agents could serve as a tool for predicting possible side effects and drug-drug interactions. Antidepressant drugs alter neurotransmitter effects at nerve synapses, probably by blocking norepinephrine and serotonin reuptake, and blockade of neurotransmitter receptor sites - primarily the histamine H1 receptor, the muscarinic receptor, and the alpha-1-adrenoceptor. Possible clinical side effects related to some of these interactions include tachycardia, tremor, and (possibly) male sexual dysfunction (associated with norepinephrine reuptake blockade); sedation (associated with histamine H1 blockade); orthostatic hypotension, dizziness, and reflex tachycardia (associated with alpha-1-adrenoceptor blockade), and blurred vision, dry mouth, and memory dysfunction (associated with muscarinic receptor blockade). Pharmacologic data that demonstrate the potencies and selectivities of the antidepressant drugs for reuptake blockade and receptor site antagonism might allow the clinician to make an informed, rational choice of antidepressant therapy. This paper presents data on drug potencies and selectivities, and attempts to relate these data to anticipated side effects and drug-drug interactions.
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PMID:Pharmacology of antidepressants. 289 25

Tricyclic antidepressants (for example, amitriptyline) and other types of antidepressants (for example, amoxapine and maprotiline) are competitive antagonists of muscarinic acetylcholine receptors, the predominant class of acetylcholine receptors in the brain. Some evidence suggests that this muscarinic receptor blockade in brain alleviates depression. However, all tricyclic antidepressants appear to be equally effective in treating depression despite having differences in their antimuscarinic potencies while having similar ranges of therapeutic blood levels. It is more likely that the antimuscarinic potency of antidepressants is related mainly to the frequency with which they cause such symptoms as blurred vision, dry mouth, and urinary retention. Information on the antimuscarinic potency and other receptor-blocking potencies of antidepressant agents can be helpful in minimizing or avoiding certain side effects when these drugs are given to patients.
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PMID:Antimuscarinic and other receptor-blocking properties of antidepressants. 613 Jan 92

N-(4-diethylamino-2-butynyl)-succinimide, or DKJ-21, is a muscarinic receptor antagonist with a high degree of selectivity for the central nervous system. In the present study of 6 rats maintained under a fixed-interval 50-sec schedule of food reinforcement, atropine and methylatropine reduced responding in a dose dependent manner, while DKJ-21 had little or no effect. Our findings suggest that the suppression caused by atropine and methylatropine may be the result of the dry mouth induced by these agents. Doses of DKJ-21 which had no effect on schedule performance antagonized the rate-lowering effects of physostigmine in all of the animals. Neither atropine nor methylatropine consistently antagonized the inhibitory effects of physostigmine. Some antagonism may be inferred, however, from the findings that response rates were suppressed less by combinations of atropine and physostigmine than by either drug alone.
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PMID:Effects of selective central muscarinic blockade on schedule-controlled behavior and on the rate-decreasing effects of physostigmine. 646 84

Two patients with Shy-Drager syndrome demonstrated unusually widespread and unequivocal cholinergic dysfunction as well as the usual evidence of adrenergic insufficiency. Progressive constipation preceded impotence, nocturia, hesitancy in micturition, anhidrosis, orthostatic hypotension, and xerostomia. Nonautonomic neurologic signs appeared several years later. Cholinergic dysfunction involved eyes, lacrimal glands, salivary glands, heart, gastrointestinal tract, urinary bladder, and sweat glands. Subcutaneous administration of bethanechol chloride--a muscarinic receptor agonist--improved tearing, salivation, sweating, and gastrointestinal and bladder functions. Daily administration of this drug resulted in symptomatic improvement of the autonomic functions, and relapse followed discontinuation of treatment.
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PMID:Shy-Drager syndrome: diagnosis and treatment of cholinergic dysfunction. 719 Oct 62

Tolterodine is a new, potent and competitive muscarinic receptor antagonist in clinical development for the treatment of urge incontinence and other symptoms of unstable bladder. Tolterodine has a high affinity and specificity for muscarinic receptors in vitro and it exhibits a selectivity for the urinary bladder over salivary glands in vivo. A major active metabolite, (PNU-200577) the 5-hydroxymethyl derivative of tolterodine, has a similar pharmacological profile. Based on pharmacological and pharmacokinetic data, it has been concluded that this metabolite contributes significantly to the therapeutic effect of tolterodine. The bladder selectivity demonstrated by tolterodine and PNU-200577 in vivo cannot be attributed to selectivity for a single muscarinic receptor subtype. Moreover, this favourable tissue-selectivity seems to occur also in humans. Tolterodine is well tolerated and it exerts a marked effect on bladder function in healthy volunteers. Phase II data indicate that tolterodine is an efficacious and safe treatment for patients with idiopathic detrusor instability or detrusor hyperreflexia. An optimal efficacy/side-effect profile is obtained with tolterodine, at a dosage of 1 or 2 mg twice daily, which seems to have less propensity to cause dry mouth than the currently available antimuscarinic drugs.
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PMID:Tolterodine--a new bladder selective muscarinic receptor antagonist: preclinical pharmacological and clinical data. 912 57

Tolterodine is a new competitive muscarinic receptor antagonist developed for the treatment of the unstable bladder. A total of 242 patients were enrolled in a multicenter, multinational, randomized, double-blind, placebo-controlled study conducted over a period of 4 weeks in patients with detrusor overactivity and symptoms of frequency, urgency, and urge incontinence. The objective of the study was to compare the efficacy and safety of tolterodine given at 1 or 2 mg b.i.d. versus placebo. At week 4 a statistically significant increase in the volume at first contraction (p = 0.030) and maximal cystometric capacity (p = 0.034) was only in the tolterodine 2 mg b.i.d. group. Tolterodine was safe and generally well tolerated. The incidence of dry mouth, as the most commonly reported adverse event, was only 9% and of mild to moderate intensity.
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PMID:Efficacy and safety of two doses of tolterodine versus placebo in patients with detrusor overactivity and symptoms of frequency, urge incontinence, and urgency: urodynamic evaluation. The International Study Group. 914 6

The sialogogic effect of SNI-2011, a novel muscarinic receptor agonist, (+/-)-cis-2-methylspilo [1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate, was compared with that of pilocarpine hydrochloride in a dose range in which the two muscarinic agonists exhibited approximately similar efficacy in eliciting salivation. Pilocarpine (0.66-2.0 mg/kg, i.d.) induced a marked but short-lasting salivation in rats, whereas the salivation induced by SNI-2011 (20-60 mg/kg, i.d.) lasted 1.4- to 1.8-fold longer. In dogs, the sialogogic effect of SNI-2011(1-3 mg/kg, i.v.) also lasted about 2-fold longer than that of pilocarpine (0.1-0.3 mg/kg, i.v.). The plasma SNI-2011 level that caused salivation at a rate of 0.4 ml/min was about 100 ng/ml and higher rates of salivation (over 0.4 ml/min) induced by 1 mg/kg SNI-2011 lasted for about 90 min in dogs. The plasma pilocarpine level that caused salivation at a rate of 0.4 ml/min was about 25 ng/ml and the higher rate of salivation (over 0.4 ml/min) induced by 0.1 mg/kg pilocarpine lasted only for 20 min in dogs. Effective plasma levels of SNI-2011 persisted longer than those of pilocarpine. These results indicate that SNI-2011 may be useful in the treatment of xerostomia because of its long-lasting sialogogic action.
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PMID:Long-lasting salivation induced by a novel muscarinic receptor agonist SNI-2011 in rats and dogs. 945 Jun 10

Tolterodine is a competitive muscarinic receptor antagonist which has recently been launched for the treatment of overactive bladder. Tolterodine shows functional selectivity for the bladder over the salivary glands in vivo, which is not attributable to muscarinic receptor subtype selectivity. It is as potent as oxybutynin in inhibiting bladder contraction, but is much less potent in inhibiting salivation, suggesting that it may have less propensity to cause dry mouth in clinical use. In patients with overactive bladder, toleterodine significantly reduces the frequency of micturition and number of incontinence episodes, while increasing the average volume voided. The onset of pharmacological action of tolterodine is < 1 hour and therapeutic efficacy is maintained during long term treatment. In comparative trials, tolterodine and oxybutynin are equivalent in terms of efficacy. However, tolterodine is significantly better tolerated than oxybutynin, particularly with respect to the incidence and severity of dry mouth. No clinically relevant ECG changes have been noted with tolterodine.
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PMID:Tolterodine. 961 96

Normal physiological voiding as well as generation of abnormal bladder contractions in diseased states is critically dependent on acetylcholine-induced stimulation of contractile muscarinic receptors on the smooth muscle (detrusor) of the urinary bladder. Muscarinic receptor antagonists are efficacious in treating the symptoms of bladder hyperactivity, such as urge incontinence, although the usefulness of available drugs is limited by undesirable side-effects. Detrusor smooth muscle is endowed principally with M2 and M3 muscarinic receptors with the former predominating in number. M3 muscarinic receptors, coupled to stimulation of phosphoinositide turnover, mediate the direct contractile effects of acetylcholine in the detrusor. Emerging evidence suggests that M2 muscarinic receptors, via inhibition of adenylyl cyclase, cause smooth muscle contraction indirectly by inhibiting sympathetically (beta-adrenoceptor)-mediated relaxation. In certain diseased states, M2 receptors may also contribute to direct smooth muscle contraction. Other contractile mechanisms involving M2 muscarinic receptors, such as activation of a non-specific cationic channel and inactivation of potassium channels, may also be operative in the bladder and requires further investigation. From a therapeutic standpoint, combined blockade of M2 and M3 muscarinic receptors would seem to be ideal since this approach would evoke complete inhibition of cholinergically-evoked smooth muscle contractions. However, if either the M2 or M3 receptor assumes a greater pathophysiological role in disease states, then selective antagonism of only one of the two receptors may be the more rational approach. The ultimate therapeutic strategy is also influenced by the extent to which pre-junctional M1 facilitatory and M2 inhibitory muscarinic receptors regulate acetylcholine release and also which subtypes mediate the undesirable effects of muscarinic receptor blockade such as dry mouth. Finally, the consequence of muscarinic receptor blockade in the central nervous system on the micturition reflex, an issue which is poorly studied and seldom taken into consideration, should not be ignored.
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PMID:Muscarinic receptor subtypes modulating smooth muscle contractility in the urinary bladder. 1006 5


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