Adverse events in therapeutic apheresis: a single center survey of various therapies.

The aim of the study was to review the adverse events associated with various treatment modalities performed in a single apheresis facility. A total of 854 sessions with 10 types of apheresis therapies were performed and 154 (18.0%) adverse events were observed over a four-year period. Of the adverse events, 77 were related to operational problems and another 77 were complications associated with treatment. A transmembranous pressure abnormality constituted more than 80% of the operational problems. Nausea was the most frequent complication, accounting for 19 of the 77 treatment-related events. A total of 26 (16.9%) adverse events occurred in the early stage of the sessions, 40 (26.0%) in the middle stage, and 88 (57.1%) in the late stage. The information in this study can be used to improve the safety and efficacy of apheresis therapy.

Executive dysfunction using behavioral assessment of the dysexecutive syndrome in Parkinson's disease.

The objective of this study was to evaluate the executive dysfunction (ExD) in Parkinson's disease (PD) using the Behavioral Assessment of the Dysexecutive Syndrome (BADS), which provides a wide-range assessment of ExD. The BADS and the Unified Parkinson's Disease Rating Scale (UPDRS) were investigated in 63 nondemented PD patients who revealed scores of >or=24 points on the Mini-Mental State Examination based on the DSM-IV. Multiple logistic regression analysis was performed to evaluate the predisposing factors to ExD, which was defined as <70 points on the age-controlled standardized score. The total score on the UPDRS was a significant independent predisposing factor to ExD. Among the various parts of the UPDRS, part II was the significant factor for ExD. The profile scores of all subtests on the BADS in patients with ExD were significantly lower than those of patients without ExD. All profile scores decreased with severity of PD, but the changes among these scores differed. ExD in nondemented PD predisposed to a greater severity of PD, particularly as regards the activity of daily living impairment. Nondemented PD revealed wide-range components of ExD. All components of ExD were impaired with severity of PD, but the patterns of each component exhibited variety.

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.

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.

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.

Quantitative analysis of binding parameters of [3H]N-methylscopolamine in central nervous system of muscarinic acetylcholine receptor knockout mice.

We have studied binding parameters (Kd, Bmax) of [3H]N-methylscopolamine ([3H]NMS) in various brain regions and spinal cord of wild-type (WT) and muscarinic acetylcholine receptor (mAChR) subtype (M1-M5) knockout (KO) mice. In the M1-M4 KO mice, the number of [3H]NMS binding sites (Bmax) was decreased throughout the central nervous system (CNS) with significant regional differences. Our results collectively suggest that M1 receptor was present in a relatively high density in the cerebral cortex and hippocampus, and the densities of M1 and M4 subtypes were highest in the corpus striatum. M2 receptor appeared to be the major subtype in the thalamus, hypothalamus, midbrain, pons-medulla, cerebellum and spinal cord. These findings may contribute significantly not only to the further understanding of the physiological roles of mAChR subtypes in the central cholinergic functions, but also to the development of selective therapeutic agents targeting specific subtype.