Comparing factors related to perceived control and preventive behaviors from COVID-19 between Japanese and American nursing students: A cross-sectional study.

AIM: Higher levels of perceived control are important to maintain health. The difference in factors related to perceived control and preventive behaviors during the COVID-19 pandemic between Japanese and American nursing students remains unknown. This study aimed to compare factors related to perceived control and infection preventive behaviors between the two countries. METHODS: This cross-sectional study included nursing students attending four universities in Japan and one in the United States. Using Google Forms, the participants answered a survey comprising sociodemographic data, the Perceived Control and Self-Efficacy Scale, the Perceived Health Competence Scale, and a preventive behavior questionnaire. The data were collected from November 2020 to May 2021. Linear and logistic regressions were used to analyze the factors related to perceived control and preventive behaviors, respectively. RESULTS: Data from 878 students were analyzed. University/campus emerged as a strong predictor for perceived control and preventive behaviors in both countries, with a positive correlation between perceived control and preventive behaviors. Older age, less frequent alcohol consumption, higher perceived health competence, less frequent work in Japan; and chronic conditions in the United States were associated with frequent preventive behaviors. Younger age was correlated with higher perceived control in Japan, while religion and increased workload were potential factors for American students. CONCLUSION: Individual factors were pivotal in Japan, whereas interpersonal factors were more likely related to perceived control in the United States. Additionally, in both countries, policy or organizational factors significantly influenced students' preventive behaviors.

Cross-sectional study of factors related to COVID-19 vaccination uptake among university healthcare students.

Introduction: Healthcare students are more likely to become infected than other university students as they may encounter patients with COVID-19 during clinical training. Vaccination uptake is essential to prevent infection. This study explored factors related to COVID-19 vaccination uptake among healthcare students. Methods: This cross-sectional study conducted online surveys of undergraduate and graduate nursing and healthcare graduate students from four medical universities in the Tokyo Metropolitan Area of Japan. Data were collected from June to August 2022, when the fourth vaccination program was initiated. Results: Data from 1,169 students were analyzed (response rate = 37.3%). The mean age was 25.1 ± 7.6 years, and most were female (82.3%). Academic majors included nursing (68.0%), medicine (16.3%), dentistry (9.3%), and others (6.4%). Thirty students (2.6%) were not vaccinated, one student (0.1%) had received one vaccination, 997 (85.3%) had received three, and 27 (2.3%) had received four. The major reason for not being vaccinated was insufficient confirmation of its safety (n = 25). Students who had received at least one vaccination (n = 1,139), 965 (84.7%) reported experiencing adverse side effects, the most frequent being pain at the injection site (76.2%), followed by fever (68.3%). In the logistic regression, a greater number of vaccinations (3-4 times) was associated with older age (odds ratio, OR = 1.53), working (OR = 1.67), and more frequent infection-preventive behaviors (OR = 1.05). Significantly fewer students were vaccinated at University B than at University A (OR = 0.46). Additionally, those majoring in subjects other than nursing (OR = 0.28), and students from non-Asian countries (OR = 0.30) were less likely to be vaccinated. Discussion: It is necessary to pay attention to and encourage the vaccination of students who engage in low levels of preventive behavior, students who are young, international, or unemployed, and those in non-healthcare professional majors.

Relationship Between Resilience and Perceived Control After Acute Coronary Syndrome: A Prospective Study.

BACKGROUND: Patients with acute coronary syndrome report poor health-related quality of life and decreased levels of perceived control. Perceived control is a person's belief that they can cope with negative events. Resilience is an adaptation that gives people the capacity to recover from difficult situations, and higher levels of resilience may impact recovery after an acute event. OBJECTIVE: The aim of this study was to analyze the relationship between resilience, perceived control, and health outcomes of patients hospitalized with acute coronary syndrome within 6 months of discharge. METHODS: Data were collected prospectively from adult patients hospitalized with acute coronary syndrome in 3 university hospitals in the Tokyo Metropolitan area, Japan. All data were collected between December 2015 and December 2019. The Sukemune-Hiew Resilience Test (part 1) was used to measure resilience, which includes 3 domains of social support, self-efficacy, and sociality. The Control Attitudes Scale-Revised was used to measure perceived control. Linear regression and path analysis were used to statistically analyze the relationship among variables. RESULTS: Higher resilience, especially self-efficacy, was associated with higher perceived control during admission. Higher resilience, especially social support, during admission was associated with perceived control at 6 months after adjusting for income and education. Higher resilience during admission was associated with better perceived control at 3 months, which was associated with better health outcomes at 6 months. Higher income and lower depression were related to higher resilience. CONCLUSIONS: Nurses should make sure patients with depression, low income, and low social support are connected with appropriate treatment and social support resources.

Factors related to mental health effect among nursing students in Japan and the United States during the coronavirus pandemic: A cross-sectional study.

In the context of mental health, university students have been considered a vulnerable population. However, limited studies have underscored the association between preventive health behaviour levels and mental health effects among nursing students. The current cross-sectional study provides a comparative analysis of the impact of mental health factors on nursing students in Japan and the United States (US) in the context of the coronavirus disease 2019 (COVID-19) pandemic. The study consisted of 878 participants, comprising both undergraduate and graduate nursing students from four universities in Japan, and one from the US. Hierarchical logistic regression was used to analyse the participant data in this study. In contrast to the American students, the Japanese students demonstrated significantly lower levels of perceived control and significantly higher levels of preventive health behaviours. Furthermore, Japanese students exhibited significantly higher levels of stress and/or symptoms of depression induced by the social distancing orders compared to the American students (z = -4.218, P < 0.001). However, no difference was observed after adjusting for perceived control, individual factors, socio-economic factors, and preventive behaviours. During the pandemic, risk factors that can worsen mental health among the nursing students included younger age [odds ratio (95%CI) = 0.62 (0.48-0.81)], women [OR = 2.17 (1.02-4.61)], higher preventive health behaviour [OR = 1.05 (1.02-1.08)], lower perceived control [OR = 0.97 (0.94-0.99)], and lower perceived health competence [OR = 0.93 (0.90-0.96)]. Thus, this study recommends establishing training programmes that enhance perceived control and perceived health competence while encouraging preventive behaviour to support the mental health of nursing students, particularly young female students.

Perceived Control, Preventative Health Behaviors, and the Mental Health of Nursing Students During the COVID-19 Pandemic: A Cross-Sectional Study.

Introduction: Perceived control is an individual's subjective beliefs about the amount of control he or she has over the environment or outcome. Objective: To examine the relationship between perceived control, preventive health behaviors, and mental health effects of undergraduate nursing students during the COVID-19 pandemic. Methods: This cross-sectional correlational study used online self-administered questionnaires. Participants were nursing students attending 3 universities in Tokyo, Japan. Relationships among variables were quantitatively analyzed using linear regressions and a structural equation modeling after adjusting for demographic factors. Results: A total of 557 students participated in the survey. The analysis indicated that higher levels of perceived control were significantly related to higher levels of preventive health behaviors. Although higher preventive health behaviors were related to negative mental health effects, higher levels of perceived health competence translated to improved mental health effects. Perceived control was not directly related to mental health effects but positively related to perceived health competence. Long work hours per week and short hours of sleep per day were associated with lower preventive health behaviors. There were significant differences in the levels of perceived control and preventive health behaviors among students at the 3 universities. Discussion: To improve health behaviors and health competence and subsequently alleviate the mental health effects caused by strictly adhering to recommended health behaviors, students may be supported by the strategies that increase their perceived control. In addition to institutional support, students also require adequate sleep and financial stability to help prevent infections while protecting their mental health.

Factors related to perceived control and health-related quality of life of patients after acute coronary syndrome during admission and after discharge.

AIM: To explore the relationship between demographic factors, acute coronary syndrome-related factors, perceived control and health-related quality of life during admission, 3 months and 6 months after discharge, in patients with acute coronary syndrome. METHODS: Participants were recruited for this longitudinal study after admission for acute coronary syndrome in three university hospitals in the Tokyo metropolitan area, Japan. Self-administered questionnaires included demographic data, perceived control, health-related quality of life, acute coronary syndrome symptoms, fatigue, depression and anxiety. RESULTS: Participants (N = 137) had an average age of 62.8 (SD 11.6) years and 80.3% were male. As a result of Path analysis, higher perceived control (ß = 0.258, p = .001), lower anxiety (ß = -0.226, p = .009) and lower fatigue (ß = -0.231, p = .010), were significantly related to better health-related quality of life (General health). Only annual income was significantly related to perceived control (ß = 0.187, p = .029). Eighty-two (59.9%) participants at 3 months and 54 (39.4%) participants at 6 months completed the questionnaires. Perceived control (F = 7.074, p = .001) and General health (χ2 = 10.22, p = .006) significantly increased over the 6 months. Perceived control during admission was significantly related with health-related quality of life at 3 months. Perceived control at 3 months was significantly related with health-related quality of life at 6 months. CONCLUSION: Perceived control was an important factor for health-related quality of life of the Japanese patients with acute coronary syndrome. It is necessary to investigate whether nursing interventions to enhance perceived control lead to improvement of health-related quality of life.

Successful delivery following intracytoplasmic sperm injection with calcium ionophore A23187 oocyte activation in a partially globozoospermic patient.

PURPOSE: To describe a successful pregnancy outcome following intracytoplasmic sperm injection (ICSI) with assisted oocyte activation (AOA) in a case of partial globozoospermia. METHODS: AOA was accomplished with calcium ionophore A23187. Sperm morphology was observed via light, fluorescent and electron microscopy following a Diff-Quik stain and fluorescein isothiocyanate-labeled peanut agglutinin (FITC-PNA) staining. An activation ability test was employed using a mouse oocyte exposed to strontium chloride. RESULTS: Via light microscopy, it was found that a large number of sperm possessed deficient acrosomes and a sharply rounded head; however, we observed both normal and the aforementioned abnormal sperm via FITC-PNA staining of a semen specimen. Mouse oocyte activation was 87.5 % via natural activation without AOA. With AOA after ICSI, 100 % oocyte activation was observed. Five oocytes were retrieved, and AOA with A23187 after ICSI resulted in a high fertilization rate (4 of 5, 80 %). Two embryos developed and the patient subsequently delivered a healthy female infant without any congenital abnormalities. CONCLUSIONS: We report a successful pregnancy outcome using an early stage embryo, which developed following ICSI using sperm from a partially globozoospermic patient who possessed temporary potential oocyte activation.

Muscarinic Receptor Binding and Plasma Drug Concentration after the Oral Administration of Propiverine in Mice.

OBJECTIVES: The current study was undertaken to characterize the binding of propiverine to muscarinic receptors in mouse tissues by measuring plasma concentrations of the drug and its metabolite. METHODS: At 0.5-24 h after the oral administration of propiverine at pharmacologically relevant doses, muscarinic receptors in tissue homogenates were measured by a radioligand binding assay using [N-methyl- (3) H]scopolamine (NMS), along with the drug's concentration in plasma by the liquid chromatography-tandem mass spectrometric method. RESULTS: In the in vitro experiments, propiverine and its metabolite 1-methy-4-piperidyl benzilate N-oxide competed with [(3) H]NMS for binding sites in the bladder, submaxillary gland and heart of mice in a concentration-dependent manner. After the oral administration of propiverine, dose- and time-dependent increases in the dissociation constant for specific [(3) H]NMS binding were observed in the bladder and other tissues of mice, indicating that orally administered propiverine and/or its metabolite undergo significant binding to muscarinic receptors in mouse tissues. A longer-lasting binding of muscarinic receptor was seen in the bladder than in the submaxillary gland at relatively low doses of propiverine. Furthermore, the decrease in maximal number of binding sites values for [(3) H]NMS binding was more remarkable in the bladder than submaxillary gland of propiverine treated mice. There was a dose-dependent rise in the plasma concentrations of propiverine and 1-methy-4-piperidyl benzilate N-oxide in mice after the oral administration of propiverine. CONCLUSION: The oral administration of propiverine exerts a more prominent and longer-lasting effect in the bladder than in the submaxillary gland of mice. The N-oxide metabolite may contribute significantly to the blockade of muscarinic receptors caused by oral propiverine.

Quantitative analysis of the loss of muscarinic receptors in various peripheral tissues in M1-M5 receptor single knockout mice.

BACKGROUND AND PURPOSE: To compare loss in binding to muscarinic receptor (mAChR) subtypes with their known functions, the total density of muscarinic receptors was measured in peripheral tissues from wild type (WT) and mAChR knockout (KO) mice. EXPERIMENTAL APPROACH: Binding parameters of [N-methyl-3H]scopolamine methyl chloride ([3H]NMS) were determined in 10 peripheral tissues of WT and M1-M5 receptor KO mice. Competition between [3H]NMS and darifenacin (selective M3 receptor antagonist) was also measured. KEY RESULTS: There was an extensive loss of [3H]NMS-binding sites (maximal number of binding sites, Bmax) in heart and smooth muscle from M2KO mice, compared with WT mice. Smooth muscle from M3KO mice also showed a moderate loss of Bmax. Bmax fell in pancreas and bladder of M4KO mice and in prostate in M1KO and M3KO mice. There was a large loss of Bmax in exocrine and endocrine glands of M3KO mice with a moderate decrease in M2KO mice. Darifenacin inhibited specific [3H]NMS binding in submandibular gland and bladder of WT, M2KO and M3KO mice. Ki (inhibition constant) values for darifenacin in the submandibular gland were the same in WT and M2KO mice but increased in M3KO mice. However, Ki values in bladder were decreased in M2KO mice and increased in M3KO mice. CONCLUSIONS AND IMPLICATIONS: Single mAChR KO mice exhibit a loss of mAChR in peripheral tissues that generally paralleled the reported loss of function. Quantitative analysis of data, however, also suggested that, in some instances, normal expression of a receptor subtype depended on expression of other subtypes.

Associated reaction and spasticity among patients with stroke.

OBJECTIVES: The objectives were to investigate the relationship between associated reaction (AR) and clinical spasticity in the paretic arm. DESIGN: The participants were ten patients with hemiparetic stroke, mean age of 65.2 yrs, and duration of stroke of 13.3 mos. The AR of the hemiparetic arm was analyzed with surface EMG, and AR ratio was calculated on the basis of comparison of the surface amplitude of the affected side to that of the nonaffected side. Simultaneously, we measured M-, H-, and T-wave amplitudes and calculated H/M and T/M in the paretic arm. The AR ratio, H/M, and T/M were compared with spasticity as assessed with the modified Ashworth scale (MAS). We repeated the same measurements after median nerve block to examine its effects on the parameters. RESULTS: The AR ratio correlated significantly with MAS (P < 0.01), whereas H/M and T/M did not. Median nerve block did not alter these relationships. CONCLUSION: AR, which could be elicited easily in patients with spastic hemiparesis, correlated strongly with spasticity, both before and after the median nerve block. However, the so-called monosynaptic reflex (H- and T reflexes) did not correlate significantly with spasticity. These results indicate that AR and spasticity partially share common pathways.

Muscarinic and alpha 1-adrenergic receptor binding characteristics of saw palmetto extract in rat lower urinary tract.

OBJECTIVES: To elucidate the in vitro and ex vivo effects of saw palmetto extract (SPE) on autonomic receptors in the rat lower urinary tract. METHODS: The in vitro binding affinities for alpha 1-adrenergic, muscarinic, and purinergic receptors in the rat prostate and bladder were measured by radioligand binding assays. Rats received vehicle or SPE (0.6 to 60 mg/kg/day) orally for 4 weeks, and alpha 1-adrenergic and muscarinic receptor binding in tissues of these rats were measured. RESULTS: Saw palmetto extract inhibited specific binding of [3H]prazosin and [N-methyl-3H]scopolamine methyl chloride (NMS) but not alpha, beta-methylene adenosine triphosphate [2,8-(3)H]tetrasodium salt in the rat prostate and bladder. The binding activity of SPE for muscarinic receptors was four times greater than that for alpha 1-adrenergic receptors. Scatchard analysis revealed that SPE significantly reduced the maximal number of binding sites (Bmax) for each radioligand in the prostate and bladder under in vitro condition. Repeated oral administration of SPE to rats brought about significant alteration in Bmax for prostatic [3H]prazosin binding and for bladder [3H]NMS binding. Such alteration by SPE was selective to the receptors in the lower urinary tract. CONCLUSIONS: Saw palmetto extract exerts significant binding activity on autonomic receptors in the lower urinary tract under in vitro and in vivo conditions.

Binding activities by propiverine and its N-oxide metabolites of L-type calcium channel antagonist receptors in the rat bladder and brain.

The present study was undertaken to characterize the binding activities of propiverine and its N-oxide metabolites (1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide: P-4(N-->O), 1-methyl-4-piperidyl benzilate N-oxide: DPr-P-4(N-->O)) toward L-type calcium channel antagonist receptors in the rat bladder and brain. Propiverine and P-4(N-->O) inhibited specific (+)-[(3)H]PN 200-110 binding in the rat bladder in a concentration-dependent manner. Compared with that for propiverine, the K(i) value for P-4(N-->O) in the bladder was significantly greater. Scatchard analysis has revealed that propiverine increased significantly K(d) values for bladder (+)-[(3)H]PN 200-110 binding. DPr-P-4(N-->O) had little inhibitory effects on the bladder (+)-[(3)H]PN 200-110 binding. Oxybutynin and N-desethyl-oxybutynin (DEOB) also inhibited specific (+)-[(3)H]PN 200-110 binding in the rat bladder. Propiverine, oxybutynin and their metabolites inhibited specific [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS) binding in the rat bladder. The ratios of K(i) values for (+)-[(3)H]PN 200-110 to [(3)H]NMS were markedly smaller for propiverine and P-4(N-->O) than oxybutynin and DEOB. Propiverine and P-4(N-->O) inhibited specific binding of (+)-[(3)H]PN 200-110, [(3)H]diltiazem and [(3)H]verapamil in the rat cerebral cortex in a concentration-dependent manner. The K(i) values of propiverine and P-4(N-->O) for [(3)H]diltiazem were significantly smaller than those for (+)-[(3)H]PN 200-110 and [(3)H]verapamil. Further, their K(i) values for [(3)H]verapamil were significantly smaller than those for (+)-[(3)H]PN 200-110. The K(i) values of propiverine for each radioligand in the cerebral cortex were significantly (P<0.05) smaller than those of P-4(N-->O). In conclusion, the present study has shown that propiverine and P-4(N-->O) exert a significant binding activity of L-type calcium channel antagonist receptors in the bladder and these effects may be pharmacologically relevant in the treatment of overactive bladder after oral administration of propiverine.

Urodynamics and bladder muscarinic receptors in rats with cerebral infarction and bladder outlet obstruction.

We characterized muscarinic receptor binding and urodynamic parameters in rats with cerebral infarction and chronic bladder outlet obstruction as models of detrusor overactivity. Bladder weight showed little significant difference between the cerebral-infarcted and sham rats, but the bladder weight was about three times greater in the bladder outlet-obstructed rats. Bladder capacity and voided volume were significantly lower (36.7 and 55.1%, respectively) in the cerebral-infarcted than in the sham rats. Involuntary contractions before micturition were seen in the bladder outlet-obstructed rats but not in sham rats. The bladder outlet-obstructed rats showed significant increases (2.65 and 2.57 times, respectively) in bladder capacity and voided volume, compared with those in sham rats. Bmax values for specific [N-methyl-3H]scopolamine ([3H]NMS) binding in the bladder were significantly (34%) increased in the cerebral-infarcted rats compared with sham rats, whereas Kd was unaffected by infarction. On the other hand, there was little significant change in Kd and Bmax for specific [3H]NMS binding in the bladder-obstructed rats compared with sham rats. In conclusion, the present study shows that cerebral infarction but not bladder outlet obstruction in rats causes up-regulation of bladder muscarinic receptors, and that such regulation of bladder muscarinic receptors may be at least partly associated with the symptoms of detrusor overactivity subsequent to cerebral infarction.

Comparative evaluation of central muscarinic receptor binding activity by oxybutynin, tolterodine and darifenacin used to treat overactive bladder.

PURPOSE: We characterized muscarinic receptor binding in the mouse cerebral cortex after oral administration of anticholinergic agents used to treat overactive bladder. MATERIALS AND METHODS: Muscarinic receptors in the mouse cerebral cortex and bladder after oral administration of anticholinergic agents were measured using [(3)H]N-methylscopolamine. RESULTS: In vitro binding affinities of tolterodine and its metabolite 5-hydroxymethyl metabolite in the mouse cerebral cortex and bladder were considerably greater than those of oxybutynin and darifenacin. Also, muscarinic receptor binding affinity of oxybutynin and its metabolite N-desethyl-oxybutynin in the cerebral cortex compared with that in the bladder was 2 to 3 times higher, whereas that of tolterodine and 5-hydroxymethyl metabolite was approximately 2 times lower. Oral administration of oxybutynin (76.1 micromol/kg), tolterodine (6.31 micromol/kg) and darifenacin (59.1 micromol/kg) showed binding activity that was approximately equal to that of bladder muscarinic receptors. Oral administration of oxybutynin (76.1 micromol/kg) showed significant binding of cerebral cortical muscarinic receptors in mice, as indicated by about a 2-fold increase in K(d) values for specific [(3)H]N-methylscopolamine binding 0.5 and 2 hours later. On the other hand, tolterodine and darifenacin given at oral doses that would exert a similar extent of bladder receptor binding activity as oxybutynin showed only a low level of binding activity of central muscarinic receptors in mice. CONCLUSIONS: Significant binding of brain muscarinic receptors in mice was observed by the oral administration of oxybutynin but not tolterodine and darifenacin.

Effects of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in healthy volunteers.

This study was undertaken to clarify the influence of repeated oral administration of Ginkgo biloba extract (GBE) on CYP2C9 and CYP3A4. CYP2C9 probe (tolbutamide, 125 mg) and CYP3A4 probe (midazolam, 8 mg) were orally administered to 10 male healthy volunteers before and after GBE intake (360 mg/d) for 28 days, and they received 75 g glucose after the dosing of tolbutamide. Plasma drug concentrations and blood glucose levels were measured. The area under concentration versus time curve (AUC0-infinity) for tolbutamide after GBE intake was slightly but significantly (16%) lower than that before GBE intake. Concomitantly, GBE tended to attenuate AUC0-2 of blood glucose-lowering effect of tolbutamide. AUC0-infinity for midazolam was significantly (25%) increased by GBE intake and oral clearance was significantly (26%) decreased. Thus, it is suggested that the combination of GBE and drugs should be cautious in terms of the potential interactions, especially in elderly patients or patients treated with drugs exerting relatively narrow therapeutic windows.

In vivo demonstration of M3 muscarinic receptor subtype selectivity of darifenacin in mice.

A novel muscarinic receptor antagonist, darifenacin, inhibited specific binding of [N-methyl-(3)H]scopolamine ([(3)H]NMS) in the mouse bladder, submaxillary gland and heart in a concentration-dependent manner. The inhibitory effect was most potent in the submaxillary gland, followed by the bladder and heart. In addition, darifenacin inhibited specific [(3)H]NMS binding in the membranes of CHO-K1 cell lines expressing muscarinic M(2) and M(3) receptor subtypes, and the potency was significantly (22-fold) greater at the M(3) than at the M(2) subtype. At 0.5 to 12 h after oral administration of darifenacin, a significant increase in K(d) values for specific [(3)H]NMS binding was seen in the bladder, submaxillary gland and lung of mice, compared with control values. Also, there was a sustained decrease in the B(max) values in the submaxillary gland. These data suggest that muscarinic receptor binding of oral darifenacin is rapid in onset and of a long duration. On the other hand, oral darifenacin exerted only temporary or little binding of muscarinic receptors in the heart and colon. Pilocarpine-induced salivary secretion in mice was continuously suppressed by oral darifenacin. The time-course of suppression coincided well with that for the muscarinic receptor binding in the submaxillary gland. The antagonistic effect of darifenacin against the dose-response curves for pilocarpine appeared to be insurmountable. In conclusion, the present study has shown that oral darifenacin may exert a pronounced and long-lasting binding of muscarinic receptors in tissues expressing the M(3) subtype.

Comparative evaluation of exocrine muscarinic receptor binding characteristics and inhibition of salivation of solifenacin in mice.

Anticholinergic agents such as oxybutynin are clinically useful in the treatment of overactive bladder. However, oral administration of oxybutynin is frequently accompanied by side effects such as dry mouth, and novel bladder-selective anticholinergic agents such as solifenacin and tolterodine are now under development. The aim of the present study was to characterize the suppression of cholinergic salivation and exocrine muscarinic receptor binding of solifenacin on oral administration to mice in comparison with those of oxybutynin. Results showed that both drugs produced a significant increase in K(d) values for specific [N-Methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS) binding in the mouse submaxillary gland, compared with control values. However, this enhancement in K(d) values was significantly smaller with solifenacin than with oxybutynin. Moreover, the inhibitory effect of solifenacin on pilocarpine-induced salivary secretion was significantly weaker than that of oxybutynin. Solifenacin dissociated more readily from muscarinic receptors in the mouse submaxillary gland than oxybutynin. In conclusion, the present study indicates that the weak suppression of cholinergic salivation by solifenacin compared with oxybutynin may be partially attributed to its relatively fast dissociation kinetics from exocrine muscarinic receptors.

Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder.

PURPOSE: We characterized the binding affinities of several antimuscarinic agents in human muscarinic receptors. MATERIALS AND METHODS: Competitive inhibitory effects of antimuscarinic agents on specific NMS [H] (PerkinElmer Life Sciences, Boston, Massachusetts) binding were examined in human tissue homogenates and in CHO-K1 cell membranes expressing human muscarinic receptor subtypes. RESULTS: Oxybutynin, propiverine, tolterodine, the respective metabolites DEOB, DPr-P-4(N-->O) and 5-HM, and darifenacin inhibited in concentration dependent fashion specific [(3)H]NMS binding in homogenates of the human bladder and parotid gland as well as in membranes of CHO-K1 cell lines expressing human muscarinic M(1) to M(5) receptor subtypes. Based on inhibition constant values the inhibitory effects of tolterodine, 5-HM and DPr-P-4(N-->O) were 1.4 to 1.7 times greater in the bladder than in the parotid gland, whereas the inhibitory effects of oxybutynin, DEOB, propiverine and darifenacin were 2 to 10 times greater in the parotid gland. Consequently tolterodine, 5-HM and DPr-P-4(N-->O) compared with oxybutynin, DEOB, propiverine and darifenacin were found to show 3 to 4 times greater affinity to muscarinic receptors in the human bladder than in the parotid gland. Tolterodine and 5-HM were 2-fold more potent for inhibiting specific [(3)H]NMS binding at cell membranes expressing the M(2) vs the M(3) subtype. Conversely oxybutynin, DEOB, propiverine, DPr-P-4(N-->O) and darifenacin showed 2 to 22 times higher affinity to the M(3) than to the M(2) subtype. CONCLUSIONS: Compared with oxybutynin, tolterodine, 5-HM and DPr-P-4(N-->O) may bind more selectively to muscarinic receptors in the human bladder than in the parotid gland.

Characterization of muscarinic receptor binding and inhibition of salivation after oral administration of tolterodine in mice.

The current study was undertaken to characterize the effects of oral administration of tolterodine on muscarinic receptor binding in the bladder and submaxillary gland and on salivation in mice. In the in vitro experiment, tolterodine and its metabolite (5-hydroxymethyl metabolite: 5-HM) competed concentration-dependently with [N-methyl-(3)H]-scopolamine ([(3)H]NMS) in the mouse bladder, submaxillary gland and heart, and the potencies of both agents were greater than that of oxybutynin. After oral administration of tolterodine (6.31, 21.0 micromol/kg) and oxybutynin (76.1 micromol/kg), there was a dose and time-dependent increase in K(d) values for specific [(3)H]NMS binding in the bladder, prostate, submaxillary gland, heart, colon and lung, compared with control values, suggesting significant muscarinic receptor binding in each tissue. The K(d) increase in each tissue by oral oxybutynin reached a maximum value of 0.5 h after oral administration and then rapidly declined, while that by tolterodine was greatest 2 h after the administration and it was maintained for at least 6 or 12 h, depending on the dose and on the tissue. Thus, muscarinic receptor binding of oral tolterodine was slower in onset and of a longer duration than that of oxybutynin. Also, oral oxybutynin showed relatively greater receptor binding in the submaxillary gland as compared with other tissues, but such high selectivity to the exocrine gland muscarinic receptors was not observed by oral tolterodine. Oral administration of tolterodine and oxybutynin reduced significantly the pilocarpine-induced salivary secretion in mice, and the attenuation of oral tolterodine appeared more slowly and it was more persistent than that of oral oxybutynin. The antagonistic effect of oral tolterodine on the dose-response curves to pilocarpine was significantly weaker than that of oxybutynin. These data suggest that oral tolterodine, compared with the case of oral oxybutynin, binds more selectively to muscarinic receptors in the mouse bladder than in the submaxillary gland, which may be advantageous in treating patients with overactive bladder.

Advantages for transdermal over oral oxybutynin to treat overactive bladder: Muscarinic receptor binding, plasma drug concentration, and salivary secretion.

To clarify pharmacological usefulness of transdermal oxybutynin in the therapy of overactive bladder, we have characterized muscarinic receptor binding in rat tissues with measurement of plasma concentrations of oxybutynin and its metabolite N-desethyl-oxybutynin (DEOB) and salivation after transdermal oxybutynin compared with oral route. At 1 and 3 h after oral administration of oxybutynin, there was a significant increase in apparent dissociation constant (Kd) for specific [N-methyl-3H]scopolamine ([3H]NMS) binding in the rat bladder, submaxillary gland, heart, and colon compared with control values. Concomitantly, submaxillary gland and heart showed a significant decrease in maximal number of binding sites (Bmax) for [3H]NMS binding, which lasted until 24 h. Transdermal application of oxybutynin caused dose-dependent increases in Kd values for specific [3H]NMS binding in rat tissues. The increment of Kd values by transdermal oxybutynin was dependent on the application time. Plasma concentrations of oxybutynin and DEOB peaked at 1 h after oral oxybutynin. In contrast, plasma concentrations of oxybutynin increased slowly, depending on the transdermal application time of this drug until 12 h. Suppression of pilocarpine-induced salivation in rats due to transdermal oxybutynin was significantly weaker and more reversible than that by oral oxybutynin, which abolished salivary secretion. The present study has shown that transdermal oxybutynin binds significantly to rat bladder muscarinic receptors without producing both long-lasting occupation of exocrine receptors and cessation of cholinergic salivation evoked by oral oxybutynin. Thus, the present study provides further pharmacological basis for advantage of transdermal over oral oxybutynin in the therapy of overactive bladder.