Prospective Randomized Controlled Trial of Extended-Release Oxybutynin Chloride and Tolterodine Tartrate in the Treatment of Overactive Bladder: Results of the OBJECT Study

Appell, Rodney A.; Sand, Peter K.; Dmochowski, Roger R.; Anderson, Rodney U.; Zinner, Norman R.; Lama, Daniel; Roach, Martha; Miklos, John R.; Saltzstein, Daniel R.; Boone, Timothy B.; Staskin, David R.; Albrecht, Detlef

doi:10.1016/s0025-6196(11)62382-3

Cited by 203 publications

(67 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1: (1) where C f_OXY and C f_DEOB are the plasma unbound concentrations for (R)-OXY and (R)-DEOB, respectively. K D_OXY and K D_DEOB are the receptor dissociation constants, estimated from the pA 2 values (K D ϭ10…”

Section: Measurement Of Micturition Pressure After Single IV Po mentioning

confidence: 99%

“…

…”

mentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats

Mizushima

Kinoshita

Abe

et al. 2007

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Oxybutynin ((R/S)-OXY) is an anticholinergic compound widely used by overactive bladder patients with symptoms of urge urinary incontinence 1,2) and several formulations with different pharmacokinetics (PK) profiles of (R/S)-OXY are available in the market. (R/S)-OXY and (R/S)-N-desethyloxybutynin ((R/S)-DEOB), a pharmacologically active metabolite of (R/S)-OXY, inhibit muscarinic acetylcholine receptors in the bladder, especially antagonizing M 2 and M 3 receptors, which mainly mediate direct contractile response in the bladder 3) and the affinities of both compounds for M 3 receptors are higher than those for M 2 receptors. 4,5) Both (R/S)-OXY and (R/S)-DEOB have an asymmetric carbon, and the (R)-enantiomers ((R)-OXY and (R)-DEOB, respectively) have an antimuscarinic effect on the bladder smooth muscle greater than their corresponding (S)-enantiomers ((S)-OXY and (S)-DEOB, respectively).6,7) Although several reports have evaluated the relationships between PK exposure and antimuscarinic effects after the administration of (R/S)-OXY, 3,[8][9][10][11][12][13] most of them were not focused on the binding to muscarinic receptors, the competition of (R/S)-DEOB with (R/S)-OXY for the muscarinic receptor binding sites or the difference of potency between (R)-and (S)-enantiomers. In addition, there are few reports elucidating the receptor occupancy to show suitable pharmacological effects of (R)-OXY and (R)-DEOB.For compounds which bind internal receptors such as histamine H 1 receptor, dopamine receptors, muscarinic receptors, the occupancies of these receptors were extensively examined in order to discover the PK/pharmacodynamic (PD) relationship in the target sites and to determine the appropriate receptor occupancies for their pharmacological effects, including their efficacies and side effects.14-18) These correlations between the receptor occupancies and the PD/safety parameters would be useful to optimize the dose regimen and formulation. 19) In the studies, positron emission tomography (PET) 14,15) and the receptor occupancy theory [16][17][18] were used for measuring or predicting the receptor occupancy. PET studies have an advantage in that they can measure the receptor occupancy directly, however, the synthesis of the positron emission substrate and the system of detection are sometimes impediments to conducting a study. On the other hand, the receptor occupancy theory is known as a useful method to predict receptor-mediated pharmacological actions by quantitatively calculating the receptor occupancy of a drug at a target receptor with free plasma concentrations of the drug. This theory has been successfully applied to adrenergic receptors, serotonin 5-HT receptors, dopamine D 2 receptors, histamine H 1 receptors, muscarinic acetylcholine receptors and so on. [16][17][18] Thus, to understand the PK/PD relationship of (R/S)-OXY and (R/S)-DEOB, the PK of the enantiomers of (R/S)-OXY and (R/S)-DEOB after intravenous (i.v.), oral (p.o.) and transdermal administrations and the unbound fractions in plasma were ex...

show abstract

Section: Measurement Of Micturition Pressure After Single IV Po mentioning

confidence: 99%

“…

…”

mentioning

confidence: 99%

Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats

Mizushima

Kinoshita

Abe

et al. 2007

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…With the recent release of several M 3 -selective muscarinic antagonists has come the realization that there are only slight di¡erences in the clinical e⁄cacy between the M 3 -selective antagonists (darifenacin and solifenacin) and the more M 2 /M 3 balanced antagonists (tolterodine and trospium). Clinically, distinctions between these new agents may appear to be in their side e¡ects [Drutz et al, 1999;Appell et al, 2001;Chancellor et al, 2001;Diokno et al, 2002;Rovner and Wein, 2002;Siami et al, 2002;Sussman and Garely, 2002;Halaska et al, 2003;Haab et al, 2004;Chapple et al, 2005;MacDiarmid et al, 2005]. No studies have been reported on M 2 -selective anticholinergic medications in humans.…”

Section: Introductionmentioning

confidence: 99%

M₂ mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors

Braverman¹,

Лебед²,

Linder³

et al. 2006

Neurourology and Urodynamics

View full text Add to dashboard Cite

Aims: Previous studies have shown increased density of M 2 receptors in hypertrophied rat bladders that possess an M 2 contractile phenotype. The aim of the current study is to determine whether human bladders with an M 2 contractile phenotype also have a greater density of bladder M 2 receptors. Materials and Methods: Human bladders were obtained from 24 di¡erent organ transplant donors. Darifenacin and methoctramine a⁄nity was determined by the rightward shift of cumulative carbachol concentration contractile response curves for each bladder. Radioligand binding and immunoprecipitation was used to quantify M 2 and M 3 subtypes in isolated detrusor muscle and urothelium. In addition, pig bladder muscle and urothelial receptors were quanti¢ed for comparison. Results: In the human urothelium total, M 2 and M 3 muscarinic receptor density is signi¢cantly negatively correlated with the a⁄nity of darifenacin for inhibition of contraction of the detrusor muscle. In the detrusor muscle there is no correlation between receptor density and darifenacin a⁄nity for inhibition of contraction. Muscarinic receptor density is greater in the muscle than in the urothelium in human bladders whereas in the pig bladder the density is greater in the urothelium than in the muscle. Conclusions: The greater density of urothelial muscarinic receptors in human bladders with lower darifenacin a⁄nity, indicative of a greater contribution of M 2 receptors to the contractile response, points towards a possible role of the urothelium in controlling M 2 mediated contractile phenotype. In comparison between human and pig bladders, the distribution of muscarinic receptor subtypes in the muscle and urothelium are quite di¡erent.

show abstract

“…Not one patient in these large trials has reported AACG as an adverse event. 23,24 It is therefore extremely difficult to assess the incidence of AACG in patients taking anticholinergic drugs, as high-risk patients have generally been excluded from trials. It is worth noting that the actual reported incidence of AACG with anticholinergics still remains incredibly low.…”

Section: Anticholinergic Therapy and Glaucomamentioning

confidence: 99%

Ophthalmic manifestations of urological drugs

Szamocki

Green

2016

Trends Urology & Men Health

View full text Add to dashboard Cite

show abstract

Prospective Randomized Controlled Trial of Extended-Release Oxybutynin Chloride and Tolterodine Tartrate in the Treatment of Overactive Bladder: Results of the OBJECT Study

Cited by 203 publications

References 16 publications

Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats

Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats

M₂ mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors

Ophthalmic manifestations of urological drugs

Contact Info

Product

Resources

About

Prospective Randomized Controlled Trial of Extended-Release Oxybutynin Chloride and Tolterodine Tartrate in the Treatment of Overactive Bladder: Results of the OBJECT Study

Cited by 203 publications

References 16 publications

Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats

Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats

M2 mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors

Ophthalmic manifestations of urological drugs

Contact Info

Product

Resources

About

M₂ mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors