![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NEUROPHARMACOLOGY
Department of Pharmacokinetics and Pharmacodynamics, Medical Biochemistry and Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (S.M., N.O., S.Y.); and Central Research Laboratory, Hamamatsu Photonics, Hamamatsu, Shizuoka, Japan (H.T., S.N., T.K., D.F.)
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
). Because the muscarinic receptor mediates the excitatory and inhibitory actions of acetylcholine in the central and peripheral nervous systems, various systemic adverse effects may occur by the administration of antimuscarinic agents for OAB. In fact, dry mouth occurs most commonly and thereby decreases the quality of life of patients. Therefore, numerous studies involving antimuscarinic agents to treat OAB have focused to the selectivity for the urinary bladder over the salivary gland. The incidence of central nervous system (CNS) side effects by antimuscarinic agents is generally lower than that of dry mouth, but CNS side effects may be of great concern in elderly patients because of an increase of blood-brain barrier (BBB) permeability with aging (Pakulski et al., 2000; Ouslander, 2004). In fact, short-term and chronic administration of oxybutynin in elderly subjects resulted in a nondegenerative mild cognitive dysfunction (Katz et al., 1998; Ancelin et al., 2006). Moreover, clinical studies have demonstrated the increased cognitive sensitivity to scopolamine (Flicker et al., 1992; Molchan et al., 1992) and a reduced density of brain muscarinic receptors in the elderly (Norbury et al., 2004).
Tolterodine seems to be less associated with cognitive impairment than oxybutynin because it is less lipophilic and, therefore, less likely to cross the BBB (Chapple, 2000; Clemett and Jarvis, 2001). However, Diefenbach et al. (2005) showed that oxybutynin and tolterodine administration resulted in statistically significant reductions in rapid eye movement sleep and a slight increase in rapid eye movement latency. Newly developed antimuscarinic agents such as solifenacin and darifenacin compared with oxybutynin may exert relatively fewer CNS effects than oxybutynin. Darifenacin did not affect cognitive function in elderly subjects (Kay et al., 2005, 2006; Lipton et al., 2005). Solifenacin compared with oxybutynin has shown less effect on the acquisition and consolidation of memory by passive avoidance test in rats (Suzuki et al., 2007). To our knowledge, the CNS effect of propiverine was little reported previously.
Antimuscarinic agents are considered to exert CNS side effects by binding to brain muscarinic receptors. 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. Oxybutynin, propiverine, and tolterodine form active metabolites after oral administration; thus, these metabolites may contribute to the efficacy and tolerability in vivo (Michel and Hegde, 2006). Because metabolites are generally more hydrophilic than the parent agents, however, the CNS pharmacological effect may be mainly due to the parent agents. In fact, the brain concentration of active metabolite (desethyloxybutynin) after oral oxybutynin (0.25–2.54 µmol/kg) was less than 1% when compared with that of the parent compound (S. Maruyama, H. Tsukada, and S. Yamada, unpublished data). To clarify the risk of CNS side effects in OAB treatment by antimuscarinic agents, therefore, we have quantitatively compared brain muscarinic receptor binding in rats after the i.v. injection of oxybutynin, propiverine, solifenacin, tolterodine, and darifenacin (Fig. 1A) at four different doses.
|
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Materials. (+)N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB) (Fig. 1B) was synthesized by N-methylation of nor-compound (+)3-piperidyl benzilate with [11C]methyl iodide (Takahashi et al., 1999; Tsukada et al., 2001). Oxybutynin hydrochloride was purchased from Sigma-Aldrich (St. Louis, MO). Propiverine hydrochloride, solifenacin succinate, tolterodine L-tartrate, and darifenacin hydrobromide were donated from Taiho Pharmaceutical Co., Ltd. (Tokushima, Japan), Astellas Pharma Inc. (Tokyo, Japan), Pharmacia Co. Ltd. (Tokyo, Japan), and Pfizer Co. Ltd. (Tokyo, Japan), respectively. All other chemicals were purchased from commercial sources. Darifenacin was dissolved in dimethylsulfoxide and diluted in physiological saline. [11C](+)3-MPB and the other compound were dissolved and diluted in physiological saline. The injection volumes of [11C](+)3-MPB and antimuscarinic agents were 0.5 and 0.25 ml, respectively.
Animal Treatment and Autoradiography. Rats that were i.p. anesthetized with chloral hydrate (400 mg/kg) received an i.v. injection of saline, oxybutynin (0.08–2.54 µmol/kg), propiverine (0.74–24.8 µmol/kg), solifenacin (0.62–20.8 µmol/kg), tolterodine (0.21–6.31 µmol/kg), or darifenacin (0.20–5.91 µmol/kg). At 10 min after the injection, [11C](+)3-MPB (150 MBq) was i.v. injected. At 30 min after the injection of [11C](+)3-MPB, rats were sacrificed, and the brain tissues were rapidly removed for the autoradiography. The brains were cut into 2-mm-thick coronal sections using a brain matrix (Muromachi Co. Ltd., Kyoto, Japan) at room temperature. The sections were placed on an imaging plate for 10 min, and the plate was scanned with a bioimaging analyzer (type BAS 1500; FUJIX; Fuji Photo Film Co. Ltd., Tokyo, Japan). Regions of interest were placed on the cerebral cortex, corpus striatum, hippocampus, amygdala, thalamus, hypothalamus, pons, and cerebellum by using a Macintosh computer (Image Reader version 1.2, Fuji Film). The value of picomoles per gram of wet tissue was calculated from the value of photostimulated luminescence units per millimeter squared. For the quantification, individual calibration standards were prepared for each set of brain sections exposed to the same imaging plate. The standard (10 µl) of [11C](+)3-MPB solution at the known concentration was placed on Advantec filter paper no. 2 (Toyo Roshi Kaisha, Ltd., Tokyo, Japan) and exposed simultaneously with the brain sections. From the radioactivity of standard sample, the amount of substance expressed in becquerels was calculated. The total counts over the standard, measured by the PhosphorImaging system, allowed the calculation of a calibration factor in counts per becquerel. The signal measured for region of interest in a structure of a brain slice was given as average counts per pixel. From the pixel size, the value to counts per millimeter squared was calculated, and, using the calibration factor, it was converted to megabecquerels per millimeter squared (and megabecquerels per gram of tissue). Before the calculation, the average counts per pixel of the background area close to the brain slices were subtracted from the average counts of the region of interest. The value of picomoles per gram of tissue was estimated from specific activity of [11C](+)3-MPB. The data were corrected for decay.
Specific binding of [11C](+)3-MPB was defined as the difference of radioactivity between each brain region and cerebellum because even a high dose of atropine failed to lower in vivo [3H]quinuclidinyl benzilate (QNB) binding in the rat cerebellum (Yamamura et al., 1974). Receptor occupancy (RO) was calculated from the degree of reduction (percentage) by antimuscarinic agents in in vivo specific [11C](+)3-MPB binding in each brain region.
Data Analysis. The dose-receptor occupancy curves were fitted to the following hyperbolic function with an assumption of single binding site by GraphPad Prism 4 (GraphPad Software Inc., San Diego, CA). RO values were calculated with eq. 1:
 | (1) |
is the Hill coefficient. RO50 is the dose at which a half-maximal receptor occupancy is obtained. The graphs shown in the figures were drawn using the fitting constants.
Because the M1 subtype is the most abundant in the hippocampus, which plays important roles in working and reference memory, the binding affinities (inhibition constant, Ki) of antimuscarinic agents in human recombinant M1 receptor subtypes were used as an index of in vitro affinities of these agents (Maruyama et al., 2006). A relationship between in vivo (RO50 values in rat hippocampus) and in vitro (Ki values in human M1 receptor) affinities of antimuscarinic agents were examined by a linear regression analysis using GraphPad Prism 4. The ratio for brain receptor occupancy (RO50) to the pharmacological potency in the urinary bladder (ID50) of antimuscarinic agents was calculated. The ID50 value, the dosage of antimuscarinic agent needed to inhibit 50% of carbachol- and volume-induced increases in the intraurethral pressure in rats, was cited from previous literature (Ikeda et al., 2002; Modiri et al., 2002; Ohtake et al., 2004).
All data are expressed as the mean ± S.E.M. or with 95% confidence interval (CI). The statistically significant difference was analyzed by Williams' test. Differences with p < 0.05 were considered statistically significant.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
), who showed the rank of regional distribution of muscarinic receptors in the rat brain, being corpus striatum > cerebral cortex > hippocampus > midbrain and pons, thalamus, hypothalamus >> cerebellar cortex. Even a high dose of atropine failed to lower in vivo [3H]QNB binding in the rat cerebellum (Yamamura et al., 1974).
|
|
Solifenacin at i.v. doses of 2.08 to 20.8 µmol/kg induced significant decreases in specific [11C](+)3-MPB binding in all brain regions compared with control values, and the decreases in the cerebral cortex, corpus striatum, hippocampus, amygdala, thalamus, hypothalamus, and pons ranged from 30.6 to 78.3%. This effect at these doses seemed to be not necessarily dose-related. The lower dose (0.62 µmol/kg) of solifenacin had little significant effect on the brain [11C](+)3-MPB binding.
After i.v. injection of tolterodine (0.21–6.31 µmol/kg), specific [11C](+)3-MPB binding was significantly decreased in the hippocampus (21.0–90.2%), amygdala (25.7–91.6%), thalamus (31.3–90.5%), hypothalamus (35.1–95.6%), and pons (43.8–90.6%) in a dose-dependent manner. The i.v. injection of tolterodine (0.63–6.31 µmol/kg) showed a significant decrease of specific [11C](+)3-MPB in the cerebral cortex (48.2–91.4%) and corpus striatum (43.5–91.4%). In contrast, darifenacin (0.20–5.91µmol/kg) displayed little significant change in specific [11C](+)3-MPB binding.
On the basis of the data in Fig. 3, we estimated the dose-receptor occupancy curves in each brain region after i.v. injection of oxybutynin, propiverine, solifenacin, and tolterodine (Fig. 4; Table 1). As shown in Table 1, the rank order of average RO50 values of antimuscarinic agents in the rat brain regions was propiverine (10.0–40.5 µmol/kg) > solifenacin (3.3–10.7 µmol/kg) > tolterodine (0.34–0.98 µmol/kg), oxybutynin (0.28–0.57 µmol/kg). In the case of darifenacin, the RO50 value could not be estimated by the lack of dose-dependent inhibition of specific [11C](+)3-MPB binding. The average RO50 values of oxybutynin seemed to be similar among each brain region, whereas RO50 values of propiverine and tolterodine tended to be larger in the corpus striatum and hippocampus than in the hypothalamus and pons.
|
|
Figure 5 shows a relationship between in vivo (pRO50 values in the rat hippocampus) and in vitro (pKi values in human M1 receptors; Maruyama et al., 2006) receptor binding affinity of antimuscarinic agents. The linear regression analysis between propiverine, solifenacin, and tolterodine showed a good fitness (r2 = 0.9999) by the equation: pRO50 = 0.6946 x pKi - 0.001054. By this equation, the in vivo affinity (pRO50 value) of these agents from in vitro affinity (pKi value) could be predicted. Table 2 compares the observed and predicted values of RO50 in the rat hippocampus of antimuscarinic agents with their ratios after the i.v. injection. The predicted values of propiverine, solifenacin, and tolterodine corresponded nicely to the observed values, but the predicted value of oxybutynin was approximately five times larger than the observed value.
|
|
The selectivity for the urinary bladder over the brain region of antimuscarinic agents in rats was evaluated by ratios for the brain receptor occupancy (RO50) to the pharmacological potency in the urinary bladder (ID50). The pharmacological potency (ID50) of each agent in the urinary bladder was cited from previous literatures of inhibitory effects of carbachol- and volume-induced increases in the intravesical pressure of rats (Ikeda et al., 2002; Modiri et al., 2002; Ohtake et al., 2004). The rank order of the ratio (RO50/ID50) in brain regions to the urinary bladder was solifenacin (8.1–46.7), tolterodine (3.6–17.9), propiverine (2.2–8.9) > oxybutynin (1.4–3.4) (Table 3). Thus, the selectivity for the urinary bladder over the hippocampus was greater for solifenacin (11.2, 20.0), tolterodine (9.5, 16.3), and propiverine (5.4) than oxybutynin (2.5–3.0). Similar tendency was observed also in other brain regions.
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
; Tsukada et al., 2001). The autoradiographic technique to measure various receptors is well established with long-lived radiotracers (e.g., 3H and 14C, etc.), but the major disadvantage is to take several weeks as the exposure time of film for the data analysis due to the low-energy emitting radionuclides. In contrast, the merit of use of high-energy β+-emitting radionuclides such as 11Cor 18Fisto make the exposure time markedly shorter, being usually only several minutes or hours. Moreover, the autoradiographic method using β+-emitting radionuclides could apply to positron emission tomography. The in vivo competition binding assay by the quantitative autoradiographic method is a powerful way to analyze directly muscarinic receptor occupancy of antimuscarinic agents in the brain, making it possible to quantify the penetration of antimuscarinic agents into brain tissues.
To clarify the risk of CNS side effects in OAB treatment, using the quantitative autoradiographic method, we have comparatively characterized brain muscarinic receptor binding after the i.v. injection of oxybutynin, propiverine, solifenacin, tolterodine, and darifenacin. The i.v. doses of antimuscarinic agents used in the present study were determined on the basis of pharmacologically relevant doses to impair learning in rat passive avoidance response (Suzuki et al., 2007). The i.v. injection of oxybutynin, propiverine, tolterodine, and solifenacin significantly decreased in vivo specific [11C](+)3-MPB binding in each brain region of rats in a dose-dependent manner. According to the estimated RO50 values, the potency of muscarinic receptor occupancy by each agent in the rat brain seemed to be greatest in oxybutynin, followed by tolterodine, solifenacin and propiverine. Furthermore, it was shown that in vivo potencies (pRO50) of propiverine, solifenacin, and tolterodine in occupying in vivo hippocampal receptors after the i.v. injection correlated well with their in vitro binding affinities in human M1 muscarinic receptor subtype (Maruyama et al., 2006) (Fig. 5). However, the observed RO50 value of oxybutynin was approximately five times smaller than the value predicted by the linear correlation between propiverine, solifenacin, and tolterodine. These data suggest that oxybutynin crosses more easily through the BBB than other antimuscarinic agents examined.
Antimuscarinic agents must first pass the BBB to occupy central muscarinic receptors. The observed difference among antimuscarinic agents in the potency of brain muscarinic receptor occupancy may be defined by BBB permeability, which is responsible for CNS effects in patients. The passive penetration of antimuscarinic agents through this physiologic barrier generally depends on physicochemical factors such as high lipophilicity, low degree of ionization (neutral charge), and small molecular size (Scheife and Takeda, 2005). The characteristics of chemical properties of oxybutynin relative to tolterodine, lipophilicity (Log Ko/w, 4.68 versus 1.83) (Abrams, 2001; Watanabe, 2007) and neutral polarity (pKa, 6.44 versus 9.87) (Yokoyama et al., 1996; Abrams, 2001), make it the most likely to cross the BBB (Kay and Granville, 2005). Påhlman et al. (2001) have revealed that the distribution of radioactivity in the brain was the lowest among other tissues from the mice received oral [14C]tolterodine. This may be consistent with the relatively lower in vivo binding activity of brain muscarinic receptors by tolterodine compared with the pharmacological activity in the bladder. In addition, solifenacin, like tolterodine, may have molecular characteristics that make it unlikely to cross the BBB.
RO50 values of antimuscarinic agents (Table 1) were similar to i.v. doses inhibiting learning/memory behavior in rats (Suzuki et al., 2007). Thus, these values could be regarded as the index of CNS pharmacological effects following the blockade of brain muscarinic receptors. We subsequently evaluated the selectivity for the urinary bladder over the brain of antimuscarinic agents by using pharmacological data in the rat urinary bladder (Ikeda et al., 2002; Modiri et al., 2002; Ohtake et al., 2004). It was shown that antimuscarinic agents inhibited significantly carbachol- and volume-induced increases in the intravesical pressure in rats. The dose ratios (RO50/ID50) of antimuscarinic agents for the brain receptor occupancy to the inhibitory potency of increases in intravesical pressure were considered to reflect in vivo pharmacological selectivity for the urinary bladder over the brain. This ratio was relatively large in solifenacin (8.1–46.7), tolterodine (3.6–17.9), and propiverine (2.2–8.9), compared with oxybutynin (1.4–3.4) (Table 3). Thus, the selectivity for the urinary bladder over the brain was relatively low for oxybutynin, suggesting a high feasibility of CNS side effects at pharmacological doses to treat OAB. This finding seems to be in a reasonable agreement with previous observations of oxybutynin shown by pharmacological (Sugiyama et al., 1999) and ex vivo receptor binding (Oki et al., 2001) studies in rats and also by clinical studies (Pietzko et al., 1994; Katz et al., 1998; Todorova et al., 2001; Ancelin et al., 2006). In fact, CNS side effect by oxybutynin occurred in patients with OAB and in older subjects receiving this drug (Scheife and Takeda, 2005; Kay et al., 2006). It was shown that only the higher dose (24.8 µmol/kg i.v.) of propiverine induced CNS effects in rats (Suzuki et al., 2007) and bound to muscarinic receptors in rat brain (Oki et al., 2001). Thus, propiverine may exhibit lower incidence of CNS effects than that of oxybutynin in patients with OAB.
The selectivity for the urinary bladder over the brain of solifenacin and tolterodine was clearly higher than that of oxybutynin in rats. In a clinical study, the incidence of CNS side effect of tolterodine was shown to be lower than that of oxybutynin and comparable with that with placebo (Chapple, 2000; Clemett and Jarvis, 2001; Scheife and Takeda, 2005). Thus, these data suggest that solifenacin and tolterodine have advantages in the treatment of OAB because of a lower CNS effect. Todorova et al. (2001) comparatively evaluated electrophysiologic effects of antimuscarinic agents on the CNS in healthy male volunteers by using quantitative electrocephalography (qEEG). They found that oxybutynin significantly altered qEEG activity, whereas tolterodine and trospium induce only a slight effect on qEEG activity. Similar electrophysiological results in healthy males with oxybutynin have been shown by Pietzko et al. (1994).
Darifenacin at pharmacologically effective doses did not significantly reduce in vivo specific [11C](+)3-MPB binding so that the RO50 value could not be estimated. 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., 2005, 2006; Lipton 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. Darifenacin is a substrate for P-glycoprotein (Skerjanec, 2006), an active transporter system that carries back across the BBB.
In addition, muscarinic receptor subtype selectivity of antimuscarinic agents may be implicated in the appearance of the CNS effect. All of five muscarinic receptor subtypes are expressed in the brain (Flynn et al., 1997; Oki et al., 2005). The M1 receptor was abundant in the cortex and hippocampus. In the striatum, the M1 and M4 receptors were distributed. In contrast, the M2 receptor was predominantly localized in the brainstem and cerebellum. The M3 receptor displays lower density in the brain when compared with M1, M2, and M4 receptor expressions. The cognitive dysfunction by antimuscarinic agents may be mediated mainly by the M1 and M2 receptors in the CNS (Kay et al., 2005). Oxybutynin shows selectivity for the M1, M3, and M4 receptors, whereas tolterodine and propiverine are relatively nonselective to muscarinic receptor subtypes (Maruyama et al., 2006; Ohtake et al., 2007). Solifenacin and darifenacin show higher selectivity to the M3 receptor than M1, M2, and M4 receptors. Thus, M1 selectivity in addition to high BBB permeability of oxybutynin may be more apt to cause CNS side effects. Such muscarinic receptor subtype selectivity may be partly associated with an observed difference among antimuscarinic agents in the in vivo potency of brain receptor occupancy (Fig. 4; Table 1). Taken together, the present study has basically confirmed ex vivo binding data in mouse brain obtained by a single oral dose of oxybutynin, tolterodine, and darifenacin (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.
In conclusion, analysis of brain muscarinic receptor occupancy in vivo may provide fundamental basis for antimuscarinic agent-induced CNS side effects in OAB treatment. The use in OAB patients would require careful dose adjustment to avoid the risk of side effects associated with brain receptor binding. Relatively newer generation of antimuscarinic agents that have high selectivity of the urinary bladder rather than the brain could be advantageous to treat OAB.
|
Footnotes |
|---|
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: OAB, overactive bladder; CNS, central nervous system; BBB, blood-brain barrier; [11C](+)3-MPB, (+)N-[11C]methyl-3-piperidyl benzilate; QNB, quinuclidinyl benzilate; RO, receptor occupancy; CI, confidence interval; qEEG, quantitative electrocephalography.
Address correspondence to: Dr. Shizuo Yamada, Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. E-mail: yamada{at}u-shizuoka-ken.ac.jp
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Abrams P (2001) Evidence for the efficacy and safety of tolterodine in the treatment of overactive bladder. Exp Opin Pharmacother 2: 1685-1701.[CrossRef][Medline]
Ancelin ML, Artero S, Portet F, Dupuy AM, Touchon J, and Ritchie K (2006) Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study. BMJ 332: 455-459.
Andersson KE (2004) Antimuscarinics for treatment of overactive bladder. Lancet Neurol 3: 46-53.[CrossRef][Medline]
Chapple CR (2000) Muscarinic receptor antagonists in the treatment of overactive bladder. Urology 55 (Suppl 5A): 33-46.[CrossRef][Medline]
Clemett D and Jarvis B (2001) Tolterodine: a review of its use in the treatment of overactive bladder. Drugs Aging 18: 277-304.[CrossRef][Medline]
Diefenbach K, Arold G, Wollny A, Schwantes U, Haselmann J, and Roots I (2005) Effects on sleep of anticholinergics used for overactive bladder treatment in healthy volunteers aged 
50 years. BJU Int 95: 346-349.[CrossRef][Medline]
Flicker C, Ferris SH, and Serby M (1992) Hypersensitivity to scopolamine in the elderly. Psychopharmacology 107: 437-441.[CrossRef][Medline]
Flynn DD, Reever CM, and Ferrari-DiLeo G (1997) Pharmacological strategies to selectivity label and localize muscarinic receptor subtypes. Drug Dev Rev 40: 104-116.[CrossRef]
Ikeda K, Kobayashi S, Suzuki M, Miyata K, Takeuchi M, Yamada T, and Honda K (2002) M3 receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland. Naunyn Schmiedebergs Arch Pharmacol 366: 97-103.[CrossRef][Medline]
Katz IR, Sands LP, Bilker W, DiFilippo S, Boyce A, and D'Angelo K (1998) Identification of medications that cause cognitive impairment in older people: the case of oxybutynin chloride. J Am Geriatr Soc 46: 8-13.[Medline]
Kay G, Crook T, Rekeda L, Lima R, Ebinger U, Arguinzoniz M, and Steel M (2006) Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol 50: 317-326.[CrossRef][Medline]
Kay GG, Abou-Donia MB, Messer WS Jr, Murphy DG, Tsao JW, and Ouslander JG (2005) Antimuscarinic drugs for overactive bladder and their potential effects on cognitive function in older patients. J Am Geriatr Soc 53: 2195-2201.[CrossRef][Medline]
Kay GG and Granville LJ (2005) Antimuscarinic agents: implications and concerns in the management of overactive bladder in the elderly. Clin Ther 27: 127-138.[CrossRef][Medline]
Lipton RB, Kolodner K, and Wesnes K (2005) Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol 173: 493-498.[CrossRef][Medline]
Maruyama S, Oki T, Otsuka A, Shinbo H, Ozono S, Kageyama S, Mikami Y, Araki I, Takeda M, Masuyama K, et al. (2006) Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder. J Urol 175: 365-369.[CrossRef][Medline]
Michel MC and Hegde SS (2006) Treatment of the overactive bladder syndrome with muscarinic receptor antagonists-a matter of metabolites? Naunyn Schmiedebergs Arch Pharmacol 374: 79-85.[CrossRef][Medline]
Modiri AR, Alberts P, and Gillberg PG (2002) Effect of muscarinic antagonists on micturition pressure measured by cystometry in normal, conscious rats. Urology 59: 963-968.[CrossRef][Medline]
Molchan SE, Martinez RA, Hill JL, Weingartner HJ, Thompson K, Vitiello B, and Sunderland T (1992) Increased cognitive sensitivity to scopolamine with age and a perspective on the scopolamine model. Brain Res Brain Res Rev 17: 215-226.[CrossRef][Medline]
Norbury R, Travis MJ, Erlandsson K, Waddington W, Owens J, Ell PJ, and Murphy DG (2004) SPET imaging of central muscarinic receptors with (R,R)[123I]-I-QNB: methodological considerations. Nucl Med Biol 31: 583-590.[CrossRef][Medline]
Ohtake A, Ukai M, Hatanaka T, Kobayashi S, Ikeda K, Sato S, Miyata K, and Sasamata M (2004) In vitro and in vivo tissue selectivity profile of solifenacin succinate (YM905) for urinary bladder over salivary gland in rats. Eur J Pharmacol 492: 243-250.[CrossRef][Medline]
Ohtake A, Saitoh C, Yuyama H, Ukai M, Okutsu H, Noguchi Y, Hatanaka T, Suzuki M, Sato S, Sasamata M, et al. (2007) Pharmacological characterization of a new antimuscarinic agent, solifenacin succinate, in comparison with other antimuscarinic agents. Biol Pharm Bull 30: 54-58.[CrossRef][Medline]
Oki T, Kageyama A, Takagi Y, Uchida S, and Yamada S (2007) Comparative evaluation of central muscarinic receptor binding activity by oxybutynin, tolterodine and darifenacin used to treat overactive bladder. J Urol 177: 766-770.[CrossRef][Medline]
Oki T, Takagi Y, Inagaki S, Taketo MM, Manabe T, Matsui M, and Yamada S (2005) Quantitative analysis of binding parameters of [3H]N-methylscopolamine in central nervous system of muscarinic acetylcholine receptor knockout mice. Brain Res Mol Brain Res 133: 6-11.[Medline]
Oki T, Yamada S, Tohma A, and Kimura R (2001) Muscarinic receptor binding characteristics in rat tissues after oral administration of oxybutynin and propiverine. Biol Pharm Bull 24: 491-495.[CrossRef][Medline]
Ouslander JG (2004) Management of overactive bladder. N Engl J Med 350: 786-799.
Påhlman I, d'Argy R, and Nilvebrant L (2001) Tissue distribution of tolterodine, a muscarinic receptor antagonist, and transfer into fetus and milk in mice. Arzneimittelforschung 51: 125-133.[Medline]
Pakulski C, Drobnik L, and Millo B (2000) Age and sex as factors modifying the function of the blood-cerebrospinal fluid barrier. Med Sci Monit 6: 314-318.[Medline]
Pietzko A, Dimpfel W, Schwantes U, and Topfmeier P (1994) Influences of trospium chloride and oxybutynin on quantitative EEG in healthy volunteers. Eur J Clin Pharmacol 47: 337-343.[Medline]
Scheife R and Takeda M (2005) Central nervous system safety of anticholinergic drugs for the treatment of overactive bladder in the elderly. Clin Ther 27: 144-153.[CrossRef][Medline]
Skerjanec A (2006) The clinical pharmacokinetics of darifenacin. Clin Pharmacokinet 45: 325-350.[CrossRef][Medline]
Sugiyama T, Park YC, and Kurita T (1999) Oxybutynin disrupts learning and memory in the rat passive avoidance response. Urol Res 27: 393-395.[CrossRef][Medline]
Suzuki M, Noguchi Y, Okutsu H, Ohtake A, and Sasamata M (2007) Effect of antimuscarinic drugs used for overactive bladder on learning in a rat passive avoidance response test. Eur J Pharmacol 557: 154-158.[CrossRef][Medline]
Takahashi K, Murakami M, Miura S, Iida H, Kanno I, and Uemura K (1999) Synthesis and autoradiographic localization of muscarinic cholinergic antagonist (+)N-[11C]methyl-3-piperidyl benzilate as a potent radioligand for positron emission tomography. Appl Radiat Isot 50: 521-525.[CrossRef][Medline]
Todorova A, Vonderheid-Guth B, and Dimpfel W (2001) Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous system. J Clin Pharmacol 41: 636-644.[Abstract]
Tsukada H, Takahashi K, Miura S, Nishiyama S, Kakiuchi T, Ohba H, Sato K, Hatazawa J, and Okudera T (2001) Evaluation of novel PET ligands (+)N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB) and its stereoisomer [11C](-)3-MPB for muscarinic cholinergic receptors in the conscious monkey brain: a PET study in comparison with [11C]4-MPB. Synapse 39: 182-192.[CrossRef][Medline]
Watanabe T (2007) The present conditions and the prospects of a skin application drug. Drug Delivery System 22: 450-457.[CrossRef]
Yamamura HI, Kuhar MJ, and Snyder SH (1974) In vivo identification of muscarinic cholinergic receptor binding in rat brain. Brain Res. 80: 170-176.[CrossRef][Medline]
Yamamura HI and Snyder SH (1974) Muscarinic cholinergic binding in rat brain. Proc Natl Acad Sci U S A 71: 1725-1729.
Yokoyama O, Ishiura Y, Nakamura Y, and Ohkawa M (1996) Urodynamic effects of intravesical oxybutynin chloride in conscious rats. J Urol 155: 768-771.[CrossRef][Medline]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
), propiverine (
), solifenacin (
), and tolterodine (
). Rats received i.v. injection of [11C](+)3-MPB (150 MBq) 10 min after i.v. injection of oxybutynin, propiverine, solifenacin, and tolterodine. The muscarinic receptor occupancy was determined from the degree of reduction (percentage) by antimuscarinic agents of in vivo specific [11C](+)3-MPB binding in each brain region as described under Materials and Methods. Each point represents the mean ± S.E.M. of three rats.