Comparative Evaluation of Central Muscarinic Receptor Binding Activity by Oxybutynin, Tolterodine and Darifenacin Used to Treat Overactive Bladder

Oki, Tomomi; Kageyama, Aiko; Takagi, Yukiko; Uchida, Shinya; Yamada, Shizuo

doi:10.1016/j.juro.2006.09.079

Cited by 16 publications

(15 citation statements)

References 17 publications

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“…These data suggest that darifenacin induces the lowest incidence of CNS effects among antimuscarinic agents examined. This result agrees with our previous ex vivo findings (Oki et al, 2007) and previous clinical observations (Kay et al, , 2006Lipton et al, 2005), showing that the treatment with darifenacin may have little effect on the cognitive function in the elderly subjects. Several lines of evidence suggest that darifenacin is unlikely to cross the BBB.…”

Section: Discussionsupporting

confidence: 93%

“…(Oki et al, 2007) and greatly expanded their findings by using four different i.v. doses of clinically used five antimuscarinic agents under in vivo condition.…”

Section: Discussionmentioning

confidence: 96%

“…Oki et al (2007) have recently shown that oral administration of oxybutynin but not tolterodine and darifenacin bound significantly to muscarinic receptors in the mouse brain. However, these authors examined the effects of only single and low dose of each agent on brain muscarinic receptor binding.…”

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confidence: 99%

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In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

Maruyama¹,

Tsukada²,

Nishiyama³

et al. 2008

J Pharmacol Exp Ther

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We evaluated the effects of five clinically used antimuscarinic agents for overactive bladder (OAB) treatment on in vivo muscarinic receptor binding in rat brain by quantitative autoradiography. There was a dose-related decrease in in vivo specific (ϩ)N-[11 C]methyl-3-piperidyl benzilate ([ 11 C](ϩ)3-MPB) binding in each brain region of rats 10 min after i.v. injection of oxybutynin, propiverine, solifenacin, and tolterodine. Rank order of the i.v. dose for 50% receptor occupancy (RO 50 ) of antimuscarinic agents in rat brain regions was propiverine Ͼ solifenacin Ͼ tolterodine, oxybutynin. There was a good linear relationship between in vivo (pRO 50 values in the rat hippocampus) and in vitro (pK i values in human M 1 receptors) receptor binding activities of propiverine, solifenacin, and tolterodine. The observed RO 50 value of oxybutynin was approximately five times smaller than the predicted in vitro K i value. The dose ratios of antimuscarinic agents for the brain receptor occupancy (RO 50 ) to the inhibition of carbachol-and volume-induced increases in intravesical pressure (ID 50 ), which reflects in vivo selectivity for the urinary bladder over the brain, were greater for solifenacin, tolterodine, and propiverine than oxybutynin. Darifenacin displayed only a slight decrease in specific [11 C](ϩ)3-MPB binding in the rat brain regions, and it was not dose-related. In conclusion, in vivo quantitative autoradiographic analysis of brain muscarinic receptor occupancy may provide fundamental basis for managing central nervous system (CNS) side effects in antimuscarinic therapy for OAB. It is suggested that in the treatment of OAB, CNS side effects can be avoided by antimuscarinic agents with high selectivity for the urinary bladder over the brain.

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Section: Discussionsupporting

confidence: 93%

“…(Oki et al, 2007) and greatly expanded their findings by using four different i.v. doses of clinically used five antimuscarinic agents under in vivo condition.…”

Section: Discussionmentioning

confidence: 96%

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In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

Maruyama¹,

Tsukada²,

Nishiyama³

et al. 2008

J Pharmacol Exp Ther

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“…3 H]NMS in the rat brain homogenates were examined. Although the lower urinary tract is clinically important target of SPE, in this study, the brain tissue was used because of a similarity between brain and lower urinary tract of pharmacological agents and SPE in binding affinities of a 1 -adrenergic, muscarinic and 1,4-DHP receptors 10,20,21) and also because of less amount of nonspecific binding for each radioligand in the brain compared to the bladder and prostate. SPE (10-200 mg/ml) inhibited specific [ 3 H]prazosin binding in a concentration-dependent manner (Fig.…”

mentioning

confidence: 99%

Pharmacologically Relevant Receptor Binding Characteristics and 5.ALPHA.-Reductase Inhibitory Activity of Free Fatty Acids Contained in Saw Palmetto Extract

Abe

Ito

Oyunzul

et al. 2009

Biological & Pharmaceutical Bulletin

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Benign prostatic hyperplasia (BPH) and related lower urinary tract symptoms (LUTS) are common disorders in aging men. Plant extracts are widely used in the treatment of BPH and related LUTS. In fact, phytotherapeutic agents, including saw palmetto extract (SPE), are very popular in many European countries as herbal remedies, representing up to 80% of all drugs prescribed for these disorders.1,2) An analysis of many clinical trials showed mild to moderate improvements in symptom scores and urinary flow in patients with BPH.3)The most widely known effect of SPE is the inhibition of type 1 and 2 isozymes of 5a-reductase. 4,5) Other pharmacodynamic mechanisms of SPE have also been proposed, including anti-androgenic effects, anti-proliferative effects and anti-inflammatory effects. [6][7][8] Our recent study has shown that the intraduodenal administration of SPE in the rat cystometry resulted in a significant and dose-related increase in micturition interval as well as a decrease in micturition volume and bladder capacity caused by the infusion of 0.1% acetic acid.9) Furthermore, we have reported that SPE inhibited the specific binding of radioligands to a 1 -adrenergic, muscarinic and 1,4-dihydropyridine (1,4-DHP) calcium channel antagonist receptors in the lower urinary tract of rats.9-11) However, the exact active constituents of SPE remain to be identified. SPE contains mainly saturated and unsaturated fatty acids (90%). Among these fatty acids, the major constituents are oleic acid and lauric acid, which together compose more than 50% of SPE.12) The aim of this study is to investigate binding activities for pharmacologically relevant (a 1 -adrenergic, muscarinic, 1,4-DHP calcium channel antagonist) receptors of major fatty acids contained in SPE. In addition, with a newly developed method using LC/MS, the effects of SPE and its fatty acids on 5a-reductase activity in the rat liver were also examined. MATERIALS AND METHODSMaterials SPE (Serenoa repens purified extract) was kindly provided by Indena Japan (Tokyo, Japan). SPE was obtained with hypercritical CO 2 (SABAL SELECT, Indena S.p.A., Milan, Italy). The constituents contained in SPE are presented elsewhere.12) Oleic acid, lauric acid, myristic acid, palmitic acid and linoleic acid were purchased from Tokyo Chemical Industry (Tokyo, Japan), Nacalai Tesque (Kyoto, Japan), Sigma-Aldrich (St. Louis, MO, U.S.A.) and Wako Pure Chemicals (Osaka, Japan), respectively. [ Animals Male and female Sprague-Dawley rats at 8-10 weeks of age (Japan SLC Inc., Shizuoka, Japan) were housed in the laboratory with free access to a normal diet (CE-2, CREA Japan Inc., Tokyo, Japan) and water, and maintained on a 12-h light-dark cycle in a room with controlled temperature and humidity. The study was conducted in accordance with the guidelines of the Experimental Ani- to bind a a 1 -adrenergic, muscarinic and 1,4-dihydropyridine (1,4-DHP The results suggest that lauric acid and oleic acid bind noncompetitively to a a 1 -adrenergic, muscarinic and 1,4-DHP calcium channel antagonist...

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“…Low selectivity for M1 receptors is believed to minimize the risk of treatment-related cognitive impairment, such as somnolence and dizziness. 57,58 However, M3 selectivity is unlikely to reduce the incidence of the most common anticholinergic event, dry mouth, because M3 receptors are the predominant subtype in the submaxillary salivary gland but not in the bladder. 59 In fact, darifenacin In addition, both solifenacin and darifenacin have been associated with a relatively high incidence of constipation in phase 3 studies (9.1%, solifenacin 10 mg/day; 14.4%, darifenacin 7.5 mg/day); only 1.3% treatment-related constipation has been reported with OTG (placebo, 1.0%).…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

Transdermal Oxybutynin: What Role in the Management of Overactive Bladder?

Davila

2010

Clinical Medicine Insights: Therapeutics

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Overactive bladder (OAB), a bothersome condition that is frequently associated with incontinence, commonly affects middleaged and elderly people. OAB not only has a negative effect on physical and mental well-being but also accounts for billions of dollars in health care costs and lost productivity. Although OAB can be treated effectively with muscarinic acetylcholine receptor antagonists, these agents often cause anticholinergic adverse effects, such as dry mouth and constipation, which are believed to be a major reason for low treatment persistence. Oxybutynin is an established OAB treatment that is available in oral and transdermal formulations. Oxybutynin chloride topical gel (OTG) (Gelnique ® , Watson Pharmaceuticals, Corona, CA, USA.) is a new formulation that was approved by the US Food and Drug Administration in January 2009. Results of a 12-week, placebo-controlled US phase 3 study demonstrated that OTG is efficacious in patients with OAB and rarely causes anticholinergic adverse events. Only dry mouth occurred significantly more often with OTG than placebo (6.9% vs. 2.8% of patients). Furthermore, OTG showed very little propensity to cause application site skin reactions. In conclusion, the efficacy and good tolerability of OTG make it a valuable treatment option for patients with OAB.

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Comparative Evaluation of Central Muscarinic Receptor Binding Activity by Oxybutynin, Tolterodine and Darifenacin Used to Treat Overactive Bladder

Abstract: Significant binding of brain muscarinic receptors in mice was observed by the oral administration of oxybutynin but not tolterodine and darifenacin.

Cited by 16 publications

References 17 publications

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

Pharmacologically Relevant Receptor Binding Characteristics and 5.ALPHA.-Reductase Inhibitory Activity of Free Fatty Acids Contained in Saw Palmetto Extract

Transdermal Oxybutynin: What Role in the Management of Overactive Bladder?

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