human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The aim of this study was to determine the pharmacokinetics , pharmacodynamics , and safety of tolterodine following single oral and intravenous doses in healthy volunteers . A secondary aim was to identify major urinary metabolites and determine mass balance . Single oral doses of 0.2 , 0.4 , 0.8 , 1.6 , 3.2 , 6.4 , and 12.8 mg of tolterodine ( as the tartrate salt ) were given to 17 healthy male volunteers . Two intravenous doses ( 0.64 and 1.28 mg ) were administered to 8 of the volunteers and mass balance was studied after a single oral dose of 5 mg (14C)-tolterodine in 6 subjects . Tolterodine was rapidly absorbed following oral administration ( time to peak serum concentration 0.9 + /- 0.4 h ) . The absolute bioavailability was highly variable , ranging from 10 to 70 % . The volume of distribution at steady-state ranged from 0.9 to 1.6 l/kg and systemic clearance ranged from 0.23 to 0.52 l/h/kg , which result ed in a terminal half-life of 2 - 3 h. Tolterodine exhibited high first-pass metabolism and 2 hepatic metabolic pathways were identified : oxidation and dealkylation . Independent of route of administration , < 1 % of the parent compound was excreted unchanged in urine . Five metabolites were structurally identified in urine . Following oral administration of (14C)-tolterodine , the excretion of radioactivity into urine and feces was 77 + /- 4.0 % and 17 + /- 3.5 % , respectively . Tolterodine decreased stimulated salivation after 3.2 mg , increased heart rate after 6.4 mg , and nearpoint of vision after 12.8 mg . Six of 8 subjects reported micturition difficulties after a dose of 12.8 mg . The lack of a direct relationship between tolterodine  serum concentrations and effects on stimulated salivation suggested the presence of pharmacologically active metabolite(s ) To determine whether cytochrome P450 2D6 ( CYP2D6 ) is involved in the metabolism of tolterodine by investigating potential differences in pharmacokinetics and pharmacodynamics ( heart rate , accommodation , and salivation ) of tolterodine and its 5‐hydroxymethyl metabolite between poor metabolizers and extensive metabolizers of debrisoquin ( INN , debrisoquine ) OBJECTIVES To evaluate the efficacy and tolerability of a new extended-release ( ER ) , once-daily , capsule formulation of tolterodine , relative to placebo and the existing immediate-release ( IR ) , twice-daily , tablet formulation , for treatment of the overactive bladder . METHODS This was a double-blind , multicenter , r and omized , placebo-controlled trial . One thous and five hundred twenty-nine patients ( 81 % women ) with urinary frequency ( eight or more micturitions every 24 hours ) and urge incontinence ( five or more episodes per week ) were r and omized to oral therapy with tolterodine ER 4 mg once daily ( n = 507 ) , tolterodine IR 2 mg twice daily ( n = 514 ) , or placebo ( n = 508 ) for 12 weeks . Efficacy was assessed at the end of the treatment period on the basis of the micturition diary variables . Tolerability and safety were assessed by evaluating the adverse events , electrocardiogram parameters , laboratory values , and treatment withdrawals . RESULTS Tolterodine ER 4 mg once daily ( P = 0.0001 ) and tolterodine IR 2 mg twice daily ( P = 0.0005 ) both significantly reduced the mean number of urge incontinence episodes per week compared with placebo . The median reduction in these episodes as a percentage of the baseline values was 71 % for tolterodine ER , 60 % for tolterodine IR , and 33 % for placebo . The ER formulation was 18 % more effective than the IR formulation ( P < 0.05 ) . Treatment with both formulations of tolterodine was also associated with statistically significant improvements in all other micturition diary variables compared with placebo . For both formulations , the mean decreases in micturition frequency ( P < 0.0079 ) and pad usage ( P < 0.0145 ) were significant , and the mean volume voided per micturition increased ( P = 0.0001 ) . The rate of dry mouth ( of any severity ) was 23 % for tolterodine ER , 30 % for tolterodine IR , and 8 % for placebo . The overall dry mouth rate for patients taking tolterodine ER was 23 % lower than for tolterodine IR ( P < 0.02 ) , and the rate of severe dry mouth in the ER group was only 1.8 % . The rates of withdrawal were comparable for the two active groups and the placebo group . No safety concerns were noted . CONCLUSIONS Tolterodine ER 4 mg once daily is effective and well tolerated in the treatment of overactive bladder with no safety concerns . Tolterodine ER demonstrated an improved efficacy for reducing urge incontinence episodes and a lower frequency of dry mouth compared with the existing IR twice-daily formulation OBJECTIVE To compare the efficacy and tolerability of extended-release formulations of oxybutynin chloride and tolterodine tartrate in women with overactive bladder . PATIENTS AND METHODS The OPERA ( Overactive bladder : Performance of Extended Release Agents ) trial was a r and omized , double-blind , active-control study performed at 71 US study centers from November 21 , 2000 , to October 18,2001 . Extended-release formulations of oxybutynin at 10 mg/d or tolterodine at 4 mg/d were given for 12 weeks to women with 21 to 60 urge urinary incontinence ( UUI ) episodes per week and an average of 10 or more voids per 24 hours .  Episodes of UUI ( primary end point ) , total ( urge and nonurge ) incontinence , and micturition were recorded in 24-hour urinary diaries at baseline and at weeks 2 , 4 , 8 , and 12 and compared . Adverse events were also evaluated . RESULTS Improvements in weekly UUI episodes were similar for the 790 women who received extended-release formulations of oxybutynin ( n = 391 ) or tolterodine ( n = 399 ) . Oxybutynin was significantly more effective than tolterodine in reducing micturition frequency ( P = .003 ) , and 23.0 % of women taking oxybutynin reported no episodes of urinary incontinence compared with 16.8 % of women taking tolterodine ( P = .03 ) . Dry mouth , usually mild , was more common with oxybutynin ( P = .02 ) . Adverse events were generally mild and occurred at low rates , with both groups having similar discontinuation of treatment due to adverse events . CONCLUSIONS Reductions in weekly UUI and total incontinence episodes were similar with extended-release formulations of oxybutynin and tolterodine . In the oxybutynin group , micturition frequency was significantly lower , and the percentage of women reporting no urinary incontinence episodes was significantly higher compared with the tolterodine group . Dry mouth was more common with oxybutynin , but tolerability was otherwise comparable , including adverse events involving the central nervous system OBJECTIVES To summarize the efficacy and safety of tolterodine from the pooled data of four multicenter , r and omized , double-blind , placebo-controlled , dose-ranging , parallel-group Phase II studies in patients with urodynamically proved overactive bladder ( detrusor instability or detrusor hyperreflexia ) and to analyze the concentration-effect relation . METHODS After a 1-week run-in period to establish baseline values , 319 patients were r and omized to receive  placebo or tolterodine  0.5 , 1 , 2 , or 4 mg twice daily . Micturition diary and urodynamic variables and subjective urinary symptoms were assessed after 2 weeks of treatment . Patients were classified as " extensive " or " poor " metabolizers of tolterodine on the basis of serum levels of tolterodine . RESULTS A per- protocol analysis of efficacy in 262 patients showed dose-related improvements in micturition diary and urodynamic variables . A dosage of 4 mg twice daily was , however , associated with an increase in residual urinary volume . The incidence of adverse events ( mainly mild or moderate antimuscarinic effects ) was comparable between placebo and tolterodine dosages of 2 mg twice daily . No serious drug-related adverse events were observed , and tolterodine had no clinical ly significant impact on electrocardiographic or laboratory findings . Changes in urodynamic variables were found to be related to the sum of unbound serum concentrations of  tolterodine  and its major active 5-hydroxymethyl metabolite . In poor and extensive metabolizers of tolterodine , exposure to the sum of these active moieties was similar , and the efficacy and safety profiles were comparable . CONCLUSIONS The results of this pooled data analysis indicate that tolterodine offers an effective treatment for patients with urinary symptoms attributable to overactive bladder . The optimal dosage is 1 to 2 mg twice daily , irrespective of metabolic phenotype Objective To determine the multiple dose pharmacokinetics of a new extended release ( ER ) capsule formulation of tolterodine , compared with the existing immediate release ( IR ) tablet , in healthy volunteers . Design Nonblind , r and omised , 2-way crossover trial . Participants 19 healthy volunteers ( 7 females , 12 males ) , mean age 33 years ( range 18 to 55 years ) . Prior to the study , all volunteers were classified as either extensive or poor metabolisers by cytochrome P450 2D6 genotyping . Methods Volunteers received tolterodine ER 4 mg once daily or tolterodine IR 2 mg twice daily for 6 days ( all doses given as the L-tartrate salt ) . A washout period of 7 days separated the 2 treatments . Serum concentrations of tolterodine , its active 5-hydroxymethyl metabolite ( 5-HM ) and the active moiety ( extensive metabolisers : sum of unbound tolterodine + 5-HM ; poor metabolisers : unbound tolterodine ) were measured for up to 48 hours post-dose on day 6 ( steady state ) . Tolerability was also determined . Results 17 volunteers ( 13 extensive metabolisers , 4 poor metabolisers ) completed the study and were evaluable for both treatment periods . The 90 % confidence interval for the geometric mean ratio of area under the serum concentration-time curve to 24 hours ( AUC24 ) of the active moiety , for all volunteers combined , indicated equivalence for the 2 formulations . Pooled analysis also demonstrated that the peak serum concentration ( Cmax ) of the active moiety following administration of tolterodine ER was around 75 % of that observed for the IR tablet , whereas the trough concentration was around 1.5-fold higher . Overall , the pharmacokinetics of tolterodine ( irrespective of genotype ) and 5-HM ( extensive metabolisers only ) were consistent with sustained drug release over 24 hours .  Tolterodine  ER was well tolerated . Conclusions The new once daily ER formulation of tolterodine 4 mg shows pharmacokinetic equivalence ( AUC24 ) to the existing IR tablet given at a dose of 2 mg twice daily . Findings of lower Cmax for  tolterodine  ER may explain the significantly lower rate of dry mouth subsequently observed in patients with overactive bladder Antimuscarinics , used commonly to treat overactive bladder , may differ in their potential to increase heart rate via effects on cardiac muscarinic M2 receptors . This prospect i ve , 3-way crossover , r and omized , double-blind study assessed the heart rate effects of 7 days ' exposure to a nonselective M2/M3 receptor blocker ( tolterodine ; 4 mg/d ) , a highly selective M3 receptor blocker ( darifenacin ; 15 mg/d ) , and placebo in 162 healthy participants ≥50 years . Heart rate was measured by 24-hour Holter monitoring . Tolterodine significantly increased heart rate versus darifenacin and heart rate versus placebo , while darifenacin did not affect heart rate versus placebo . The proportion of participants with an increase in mean heart rate per 24 hours of ≥5 beats per minute was higher with tolterodine than with darifenacin ( P = .0004 ) or with placebo ( P = .0114 ) but did not differ between darifenacin and placebo . The results show that antimuscarinics exert differential effects on heart rate depending on their muscarinic receptor profile . This should be considered when selecting a treatment CONTEXT Men with overactive bladder and other lower urinary tract symptoms may not respond to monotherapy with antimuscarinic agents or alpha-receptor antagonists . OBJECTIVE To evaluate the efficacy and safety of tolterodine extended release ( ER ) , tamsulosin , or both in men who met research criteria for both overactive bladder and ben 
    Output:
    
agent
The efficacy and tolerability of tolterodine ER Vs .
A recent meta- analysis evaluating tolterodine in comparison with other antimuscarinic drugs demonstrated that tolterodine ER was significantly more effective than placebo in reducing micturition/24 h , urinary leakage episodes/24 h , urgency episodes/24 h , and urgency incontinence episodes/24 h. With regard to adverse events , tolterodine ER was associated with a good adverse event profile result ing in the third most favorable antimuscarinic .
Conclusion Tolterodine ER result ed effective in reducing frequency urgency and nocturia and urinary leakage in male patients with OAB/storage LUTS .
Dry mouth and constipation are the most frequently reported adverse events
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The aim of this study was to determine the pharmacokinetics , pharmacodynamics , and safety of tolterodine following single oral and intravenous doses in healthy volunteers . A secondary aim was to identify major urinary metabolites and determine mass balance . Single oral doses of 0.2 , 0.4 , 0.8 , 1.6 , 3.2 , 6.4 , and 12.8 mg of tolterodine ( as the tartrate salt ) were given to 17 healthy male volunteers . Two intravenous doses ( 0.64 and 1.28 mg ) were administered to 8 of the volunteers and mass balance was studied after a single oral dose of 5 mg (14C)-tolterodine in 6 subjects . Tolterodine was rapidly absorbed following oral administration ( time to peak serum concentration 0.9 + /- 0.4 h ) . The absolute bioavailability was highly variable , ranging from 10 to 70 % . The volume of distribution at steady-state ranged from 0.9 to 1.6 l/kg and systemic clearance ranged from 0.23 to 0.52 l/h/kg , which result ed in a terminal half-life of 2 - 3 h. Tolterodine exhibited high first-pass metabolism and 2 hepatic metabolic pathways were identified : oxidation and dealkylation . Independent of route of administration , < 1 % of the parent compound was excreted unchanged in urine . Five metabolites were structurally identified in urine . Following oral administration of (14C)-tolterodine , the excretion of radioactivity into urine and feces was 77 + /- 4.0 % and 17 + /- 3.5 % , respectively . Tolterodine decreased stimulated salivation after 3.2 mg , increased heart rate after 6.4 mg , and nearpoint of vision after 12.8 mg . Six of 8 subjects reported micturition difficulties after a dose of 12.8 mg . The lack of a direct relationship between tolterodine  serum concentrations and effects on stimulated salivation suggested the presence of pharmacologically active metabolite(s ) To determine whether cytochrome P450 2D6 ( CYP2D6 ) is involved in the metabolism of tolterodine by investigating potential differences in pharmacokinetics and pharmacodynamics ( heart rate , accommodation , and salivation ) of tolterodine and its 5‐hydroxymethyl metabolite between poor metabolizers and extensive metabolizers of debrisoquin ( INN , debrisoquine ) OBJECTIVES To evaluate the efficacy and tolerability of a new extended-release ( ER ) , once-daily , capsule formulation of tolterodine , relative to placebo and the existing immediate-release ( IR ) , twice-daily , tablet formulation , for treatment of the overactive bladder . METHODS This was a double-blind , multicenter , r and omized , placebo-controlled trial . One thous and five hundred twenty-nine patients ( 81 % women ) with urinary frequency ( eight or more micturitions every 24 hours ) and urge incontinence ( five or more episodes per week ) were r and omized to oral therapy with tolterodine ER 4 mg once daily ( n = 507 ) , tolterodine IR 2 mg twice daily ( n = 514 ) , or placebo ( n = 508 ) for 12 weeks . Efficacy was assessed at the end of the treatment period on the basis of the micturition diary variables . Tolerability and safety were assessed by evaluating the adverse events , electrocardiogram parameters , laboratory values , and treatment withdrawals . RESULTS Tolterodine ER 4 mg once daily ( P = 0.0001 ) and tolterodine IR 2 mg twice daily ( P = 0.0005 ) both significantly reduced the mean number of urge incontinence episodes per week compared with placebo . The median reduction in these episodes as a percentage of the baseline values was 71 % for tolterodine ER , 60 % for tolterodine IR , and 33 % for placebo . The ER formulation was 18 % more effective than the IR formulation ( P < 0.05 ) . Treatment with both formulations of tolterodine was also associated with statistically significant improvements in all other micturition diary variables compared with placebo . For both formulations , the mean decreases in micturition frequency ( P < 0.0079 ) and pad usage ( P < 0.0145 ) were significant , and the mean volume voided per micturition increased ( P = 0.0001 ) . The rate of dry mouth ( of any severity ) was 23 % for tolterodine ER , 30 % for tolterodine IR , and 8 % for placebo . The overall dry mouth rate for patients taking tolterodine ER was 23 % lower than for tolterodine IR ( P < 0.02 ) , and the rate of severe dry mouth in the ER group was only 1.8 % . The rates of withdrawal were comparable for the two active groups and the placebo group . No safety concerns were noted . CONCLUSIONS Tolterodine ER 4 mg once daily is effective and well tolerated in the treatment of overactive bladder with no safety concerns . Tolterodine ER demonstrated an improved efficacy for reducing urge incontinence episodes and a lower frequency of dry mouth compared with the existing IR twice-daily formulation OBJECTIVE To compare the efficacy and tolerability of extended-release formulations of oxybutynin chloride and tolterodine tartrate in women with overactive bladder . PATIENTS AND METHODS The OPERA ( Overactive bladder : Performance of Extended Release Agents ) trial was a r and omized , double-blind , active-control study performed at 71 US study centers from November 21 , 2000 , to October 18,2001 . Extended-release formulations of oxybutynin at 10 mg/d or tolterodine at 4 mg/d were given for 12 weeks to women with 21 to 60 urge urinary incontinence ( UUI ) episodes per week and an average of 10 or more voids per 24 hours .  Episodes of UUI ( primary end point ) , total ( urge and nonurge ) incontinence , and micturition were recorded in 24-hour urinary diaries at baseline and at weeks 2 , 4 , 8 , and 12 and compared . Adverse events were also evaluated . RESULTS Improvements in weekly UUI episodes were similar for the 790 women who received extended-release formulations of oxybutynin ( n = 391 ) or tolterodine ( n = 399 ) . Oxybutynin was significantly more effective than tolterodine in reducing micturition frequency ( P = .003 ) , and 23.0 % of women taking oxybutynin reported no episodes of urinary incontinence compared with 16.8 % of women taking tolterodine ( P = .03 ) . Dry mouth , usually mild , was more common with oxybutynin ( P = .02 ) . Adverse events were generally mild and occurred at low rates , with both groups having similar discontinuation of treatment due to adverse events . CONCLUSIONS Reductions in weekly UUI and total incontinence episodes were similar with extended-release formulations of oxybutynin and tolterodine . In the oxybutynin group , micturition frequency was significantly lower , and the percentage of women reporting no urinary incontinence episodes was significantly higher compared with the tolterodine group . Dry mouth was more common with oxybutynin , but tolerability was otherwise comparable , including adverse events involving the central nervous system OBJECTIVES To summarize the efficacy and safety of tolterodine from the pooled data of four multicenter , r and omized , double-blind , placebo-controlled , dose-ranging , parallel-group Phase II studies in patients with urodynamically proved overactive bladder ( detrusor instability or detrusor hyperreflexia ) and to analyze the concentration-effect relation . METHODS After a 1-week run-in period to establish baseline values , 319 patients were r and omized to receive  placebo or tolterodine  0.5 , 1 , 2 , or 4 mg twice daily . Micturition diary and urodynamic variables and subjective urinary symptoms were assessed after 2 weeks of treatment . Patients were classified as " extensive " or " poor " metabolizers of tolterodine on the basis of serum levels of tolterodine . RESULTS A per- protocol analysis of efficacy in 262 patients showed dose-related improvements in micturition diary and urodynamic variables . A dosage of 4 mg twice daily was , however , associated with an increase in residual urinary volume . The incidence of adverse events ( mainly mild or moderate antimuscarinic effects ) was comparable between placebo and tolterodine dosages of 2 mg twice daily . No serious drug-related adverse events were observed , and tolterodine had no clinical ly significant impact on electrocardiographic or laboratory findings . Changes in urodynamic variables were found to be related to the sum of unbound serum concentrations of  tolterodine  and its major active 5-hydroxymethyl metabolite . In poor and extensive metabolizers of tolterodine , exposure to the sum of these active moieties was similar , and the efficacy and safety profiles were comparable . CONCLUSIONS The results of this pooled data analysis indicate that tolterodine offers an effective treatment for patients with urinary symptoms attributable to overactive bladder . The optimal dosage is 1 to 2 mg twice daily , irrespective of metabolic phenotype Objective To determine the multiple dose pharmacokinetics of a new extended release ( ER ) capsule formulation of tolterodine , compared with the existing immediate release ( IR ) tablet , in healthy volunteers . Design Nonblind , r and omised , 2-way crossover trial . Participants 19 healthy volunteers ( 7 females , 12 males ) , mean age 33 years ( range 18 to 55 years ) . Prior to the study , all volunteers were classified as either extensive or poor metabolisers by cytochrome P450 2D6 genotyping . Methods Volunteers received tolterodine ER 4 mg once daily or tolterodine IR 2 mg twice daily for 6 days ( all doses given as the L-tartrate salt ) . A washout period of 7 days separated the 2 treatments . Serum concentrations of tolterodine , its active 5-hydroxymethyl metabolite ( 5-HM ) and the active moiety ( extensive metabolisers : sum of unbound tolterodine + 5-HM ; poor metabolisers : unbound tolterodine ) were measured for up to 48 hours post-dose on day 6 ( steady state ) . Tolerability was also determined . Results 17 volunteers ( 13 extensive metabolisers , 4 poor metabolisers ) completed the study and were evaluable for both treatment periods . The 90 % confidence interval for the geometric mean ratio of area under the serum concentration-time curve to 24 hours ( AUC24 ) of the active moiety , for all volunteers combined , indicated equivalence for the 2 formulations . Pooled analysis also demonstrated that the peak serum concentration ( Cmax ) of the active moiety following administration of tolterodine ER was around 75 % of that observed for the IR tablet , whereas the trough concentration was around 1.5-fold higher . Overall , the pharmacokinetics of tolterodine ( irrespective of genotype ) and 5-HM ( extensive metabolisers only ) were consistent with sustained drug release over 24 hours .  Tolterodine  ER was well tolerated . Conclusions The new once daily ER formulation of tolterodine 4 mg shows pharmacokinetic equivalence ( AUC24 ) to the existing IR tablet given at a dose of 2 mg twice daily . Findings of lower Cmax for  tolterodine  ER may explain the significantly lower rate of dry mouth subsequently observed in patients with overactive bladder Antimuscarinics , used commonly to treat overactive bladder , may differ in their potential to increase heart rate via effects on cardiac muscarinic M2 receptors . This prospect i ve , 3-way crossover , r and omized , double-blind study assessed the heart rate effects of 7 days ' exposure to a nonselective M2/M3 receptor blocker ( tolterodine ; 4 mg/d ) , a highly selective M3 receptor blocker ( darifenacin ; 15 mg/d ) , and placebo in 162 healthy participants ≥50 years . Heart rate was measured by 24-hour Holter monitoring . Tolterodine significantly increased heart rate versus darifenacin and heart rate versus placebo , while darifenacin did not affect heart rate versus placebo . The proportion of participants with an increase in mean heart rate per 24 hours of ≥5 beats per minute was higher with tolterodine than with darifenacin ( P = .0004 ) or with placebo ( P = .0114 ) but did not differ between darifenacin and placebo . The results show that antimuscarinics exert differential effects on heart rate depending on their muscarinic receptor profile . This should be considered when selecting a treatment CONTEXT Men with overactive bladder and other lower urinary tract symptoms may not respond to monotherapy with antimuscarinic agents or alpha-receptor antagonists . OBJECTIVE To evaluate the efficacy and safety of tolterodine extended release ( ER ) , tamsulosin , or both in men who met research criteria for both overactive bladder and ben 
    Output:
    