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)

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

This study compared the clinical efficacy (determined from micturition diaries) and safety of 12 weeks' treatment with either tolterodine 2 mg twice daily, oxybutynin 5 mg three times daily or placebo in patients with an overactive bladder. A total of 277 patients were randomized and treated at 25 centers. Both tolterodine and oxybutynin significantly increased volume voided/micturition compared to placebo. Both treatment groups evoked greater decreases in micturitions per 24 hours and incontinence episodes per 24 hours compared to placebo; however, only tolterodine was significantly better than placebo in reducing micturition frequency. Tolterodine and oxybutynin were equivalent in their effectiveness. Tolterodine was significantly better tolerated than oxybutynin when adverse events (particularly frequency and intensity of dry mouth), dose reduction and patient withdrawals were considered. Oxybutynin is an effective drug whose frequent adverse effects limit its clinical usefulness. Tolterodine has equivalent efficacy to oxybutynin, but with less severe adverse effects. This will allow patients to receive more effective treatment for their condition, with better compliance.
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PMID:Clinical efficacy and safety of tolterodine compared to oxybutynin and placebo in patients with overactive bladder. 1054 35

Extended-release oxybutynin (Ditropan XL) uses an osmotic system (OROS) to deliver a controlled amount of oxybutynin chloride into the gastrointestinal tract over a 24-hour period when taken once daily. Oxybutynin binds to M3 muscarinic receptors on the detrusor muscle of the bladder, preventing acetylcholinergic activation and relaxing the muscle. Mean peak plasma concentrations are lower with extended-release oxybutynin 15mg once daily than with conventional immediate-release oxybutynin 5mg taken 3 times daily. Relative bioavailabilities of parent drug and metabolite N-desethoxybutynin are 153 and 69%, respectively, for extended-release oxybutynin when compared with immediate-release oxybutynin. In short (< or =6 weeks) randomised, double-blind clinical trials of patients with detrusor instability, extended-release oxybutynin 5 to 30mg once daily significantly reduced the mean weekly number of urge incontinence episodes by 84 to 90%. Extended-release oxybutynin had similar efficacy to immediate-release oxybutynin. Adverse events reported by patients taking extended-release oxybutynin were dose-related anticholinergic effects, most frequently dry mouth, somnolence, constipation, blurred vision and dizziness. A large noncomparative study demonstrated that approximately two thirds of the patients prescribed extended-release oxybutynin for detrusor instability were still taking the medication 6 months later.
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PMID:Extended-release oxybutynin. 1075 30

This article summarizes the quality of life (QOL), cost of illness, and cost-effectiveness considerations in the treatment and management of patients with overactive bladder (OAB). Most cost studies have focused primarily on urinary incontinence, which is only one possible symptom of OAB. Prevalence rates of urge and mixed incontinence in the United States ranged from 3% to 8% and 5% to 37%, respectively. The highest prevalence was found in geriatric and psychogeriatric populations, where 40% and 90%, respectively, were classified as incontinent. In patients with OAB, all aspects of QOL can be compromised including physical, social, occupational, domestic, and sexual activities, and associated costs can be substantial. Oxybutynin has been the mainstay of pharmacotherapy for OAB but its more frequent side effects (including dry mouth) may deter patients from full compliance with treatment. Tolterodine, a newer antimuscarinic drug, has proven safe and effective in the treatment of OAB, with fewer side effects and better tolerability than existing agents. Cost effectiveness reports are reviewed. Further research on OAB is needed to characterize the disease process and identify risk factors.
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PMID:Cost effectiveness and quality of life considerations in the treatment of patients with overactive bladder. 1126 9

Previously available antimuscarinic therapies for overactive bladder are poorly tolerated due to a high incidence of adverse events, notably dry mouth. Tolterodine is a bladder-selective, antimuscarinic agent for the treatment of frequency, urgency, and urge incontinence that characterize overactive bladder. In a 9-month open-label study, the safety, tolerability, and clinical efficacy of tolterodine 2 mg twice daily was evaluated in 854 patients with overactive bladder symptoms who had completed one of four 12 week randomized, controlled trials of tolterodine. Safety and tolerability were assessed in terms of adverse events and clinical/laboratory variables. Efficacy was assessed using micturition diaries and patient perception of their bladder condition. In all, 70% of patients remained on treatment for 9 months. Dry mouth was the most frequently reported adverse event, occurring in 28% of patients (intensity: 19% mild, 7% moderate, 2% severe). A total of 9% of patients withdrew due to adverse events. Dosage reduction occurred in 13% of patients. Significant improvements (P < 0.0001) in micturitions per 24 h (-22%), urge incontinence episodes per 24 h (-76%) and volume voided per micturition (+22%) were observed after 9 months of treatment, with 65% of patients reporting an improvement in perception of their bladder problems. The incidence of adverse events and improvements in micturition diary variables during open-label treatment were comparable with those observed during a 12 week randomized treatment. It was concluded that tolterodine is well tolerated and maintains its clinical efficacy during 9 months of treatment. The high proportion of patients remaining on treatment indicates that tolterodine is an effective long-term treatment for overactive bladder.
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PMID:Treatment of overactive bladder: long-term tolerability and efficacy of tolterodine. 1137 17

This analysis reviews clinical trials of the efficacy and safety of tolterodine for use in overactive bladder. It also compares the safety and efficacy of tolterodine and previously available pharmacotherapy. The MEDLINE database (1966 to present) was searched for all English language randomized controlled trials with keyword tolterodine. The search retrieved 10 randomized controlled trials involving tolterodine. Studies ranged from 2 to 12 weeks in duration. Nine trials studied tolterodine vs. placebo, 6 compared tolterodine vs. oxybutynin, 6 compared different doses of tolterodine, and 1 compared immediate-release and extended-release tolterodine. Doses of tolterodine were 0.5-4 mg bid or 4 mg extended-release daily, and doses of oxybutynin were 5 mg bid or tid. All studies found a benefit of tolterodine over placebo in decreasing symptoms of overactive bladder. Parameters significantly improved by tolterodine include number of voids per day, urine volume per void, number of incontinent episodes per day, pad use, maximal cystometric capacity, residual volume, volume at first detrusor contraction, and volume at normal desire to void. Tolterodine 2 mg bid was consistently of equal efficacy as oxybutynin 5 mg tid. Adverse events with both medications were mostly dose-related autonomic nervous system events. The most common adverse event was dry mouth, which was both more frequent and more severe with oxybutynin 5 mg tid than with tolterodine 2 mg bid. Dry mouth did not generally result in discontinuation of medication with either drug. Most drug withdrawal was because of blurred vision or headache. Tolterodine 2 mg bid caused less dose reduction, patient withdrawal, and adverse events, especially dry mouth, compared with oxybutynin 5 mg tid. A single trial found tolterodine extended-release 4 mg/day to have improved efficacy for decreasing urge incontinence episodes along with lower frequency of dry mouth vs. immediate-release tolterodine 2 mg bid. At 4 mg bid, tolterodine caused urinary retention. Neither drug significantly altered any laboratory tests, nor was there clear evidence of electrocardiographic abnormalities induced by either drug. In all randomized controlled trials to date, tolterodine 2 mg bid is an equally effective alternative to oxybutynin 5 mg tid, while causing less intense and less frequent dry mouth or need for treatment withdrawal.
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PMID:Tolterodine: a clinical review. 1170 85

Antimuscarinic agents are the most widely used therapy for urge incontinence, but have side effects such as constipation, tachycardia and dry mouth, resulting from a lack of selectivity for the bladder. M2 receptors are the predominant cholinoceptors present in urinary bladder, but mainly the minor population of M3 receptors mediate its contraction. M2 receptors modulate detrusor contraction by several mechanisms, and may contribute more to contraction of the bladder in pathological states such as bladder denervation or spinal cord injury. Prejunctional inhibitory M2 or M4 receptors and prejunctional facilitatory muscarinic Ml receptors in the bladder have all been reported. In clinical studies, tolterodine, a non-selective muscarinic antagonist, has been reported to be as effective as oxybutynin but inducing less dry mouth. Thus, although it is not certain which antimuscarinic drugs have the better efficacy and tolerability, the non-selective antimuscarinic drugs seem to be better than M3-selective antagonists in their clinical efficacies. However, controlled release, or intravesical, intravaginal, or rectal administrations of oxybutynin have been reported to cause fewer side effects. Darifenacin, a new M3 selective antagonist, has been reported to have selectivity for the bladder over the salivary gland in vivo. To verify which antimuscarinic drugs selective for the muscarinic subtypes have the best efficacy and tolerability, comparative clinical trials between M3 selective antagonists and non-selective compounds, such as olterodine, are required in the future.
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PMID:Which muscarinic receptor is important in the bladder? 1176 Jul 77

Overactive bladder (OAB) is a chronic and prevalent condition, the symptoms of which (urinary frequency and urgency, with or without urge incontinence) can exert a profound negative effect on a person's daily life activities. Tolterodine (Detrol in North America and Detrusitol in the rest of the world, Pharmacia), a competitive muscarinic antagonist, is the first agent of this class to be specifically developed for the treatment of OAB. This agent displays in vivo functional selectivity for the bladder over other tissues that contain muscarinic receptors (e.g., salivary glands, eye), which translates into good efficacy and tolerability in patients with OAB (including the elderly). Comparative, randomised, double-blind studies show that tolterodine (administered as immediate-release [IR] tablets 2 mg b.i.d.) is as effective as oxybutynin (5 mg t.i.d.) in improving all of the troublesome symptoms of OAB but with a significantly lower incidence and severity of dry mouth. The advent of a new extended-release (ER) capsule formulation of tolterodine (4 mg) for convenient once-daily treatment builds upon these findings, with significantly improved efficacy for reducing urge incontinence episodes and a lower frequency of dry mouth relative to the existing IR tablet (2 mg b.i.d.). Tolterodine can therefore be considered a valuable, well-tolerated treatment option for patients with OAB, providing improvements in symptoms that are both clinically meaningful to patients and sustained during long-term treatment.
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PMID:Evidence for the efficacy and safety of tolterodine in the treatment of overactive bladder. 1182 11

Treatment with the antimuscarinic agents tolterodine and oxybutynin is the mainstay of therapy for overactive bladder, a chronic and debilitating condition characterized by urinary urgency with or without urge incontinence, usually in combination with urinary frequency and nocturia. This study consisted of two trials; in one, patients with overactive bladder were randomized to 8 weeks of open-label treatment with either 2 mg or 4 mg of once-daily extended-release tolterodine (TER), and in the other to 5 mg or 10 mg of extended-release oxybutynin (OER). The study protocol and design were identical for the two trials and site selection ensured that there was no bias in either trial for the tendency of investigators to prescribe one drug rather than the other, or for geographical location. A total of 1289 patients were enrolled, 669 in the tolterodine trial (TER 2 mg, n = 333; TER 4 mg, n = 336) and 620 in the oxybutynin trial (OER 5 mg, n = 313; OER 10 mg, n = 307). Fewer patients prematurely withdrew from the trial in the TER 4 mg group (12%) than either the OER 5 mg (19%; p = 0.01) or OER 10 mg groups (21%; p = 0.002). More patients in the OER 10 mg group than the TER 4 mg group withdrew because of poor tolerability (13% vs 6%; p = 0.001). After 8 weeks, 70% of patients in the TER 4 mg group perceived an improved bladder condition, compared with 60% in the TER 2 mg group, 59% in the OER 5 mg group and 60% in the OER 10 mg group (all p < 0.01 vs TER 4 mg). Response to therapy was greater in a subgroup of patients whose perception of bladder condition was moderate to severe at baseline (TER 4 mg 77% vs OER 10 mg 65%; p < 0.01). Dry mouth was dose-dependent with both agents, although differences between doses only reached statistical significance in the oxybutynin trial (OER 5 mg vs OER 10 mg; p = 0.05). Patients treated with TER 4 mg reported a significantly lower severity of dry mouth compared with OER 10 mg. In conclusion, the greater efficacy and tolerability of tolterodine ER 4 mg suggests improved clinical effectiveness compared with oxybutynin ER 10 mg.
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PMID:Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: the antimuscarinic clinical effectiveness trial (ACET). 1242 62


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