1 We investigated the effects of N0-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, on the performance of rats in a radial arm maze and in habituation tasks, and on monoamine metabolism in the brain. 2 Daily administration of L-NAME (10-60 mg kg-') resulted in a dose-dependent impairment of performance during the acquisition of the radial arm maze task, while it failed to affect performance in those rats that had previously acquired the task. 3 The rate of decrease in locomotor activity in the habituation task in the L-NAME-treated rats was significantly less than that in control rats. 4 N -nitro-D-argimne methyl ester (D-NAME, a less active inhibitor of NO synthase) showed no effects in the above behavioural tasks. 5 NO synthase activity was significantly decreased in both the L-NAME and D-NAME-treated rats, with the magnitude of inhibition being greater in the L-NAME-treated animals. 6 The content of 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus and the 5-HIAA/5-hydroxytry_, tamine ratio in the hippocampus and cortex were significantly decreased in the L-NAME (60 mg kg )-treated rats compared with these values in the controls. 7 Striatal 3,4-dihydroxyphenylacetic acid (DOPAC) content was significantly increased in the L-NAME (60 mg kg-l)-treated rats compared with the values in the controls, while the DOPAC/dopamine ratio was not changed. 8 These results suggest that: (i) NO may play an important role in performance during the acquisition, but not retention, of the radial arm maze task, and (ii) that endogenous NO may be involved in the regulation of monoamine metabolism. Keywords: Nitric oxide; nitric oxide synthase; learning and memory; radial arm maze; habituation task; dopamine; 5-hydroxytryptamine IntroductionNitric oxide (NO) plays an important role in several biological systems Ignarro, 1990;Garthwaite, 1991). In the central nervous system, this free radical gas acts as a diffusible intercellular signalling molecule (Bredt & Snyder, 1992;Snyder, 1992). NO is synthesized from L-arginine, in a NADPH-dependent reaction, by NO synthase. Neuronal and endothelial NO synthases appear to be constitutive calcium-dependent enzymes, whereas other NO synthase isozymes, i.e., those found in smooth muscle and macrophages, are expressed as a result of activation by various cytokines and are calcium-independent (Garthwaite, 1991;Dawson & Snyder, 1994). The localization of a brain-specific isozyme of NO synthase suggests that NO has widespread action in the central nervous system (Vincent & Kimura, 1992;Southam & Garthwaite, 1993). Activation of N-methyl-D-aspartate (NMDA) receptors has been shown to induce NO synthesis (Garthwaite et al., 1988), which then activates soluble guanylate cyclase (Knowles et al., 1989) and leads to the formation of guanosine 3',5'-cyclic monophosphate (cyclic GMP) in the brain (Bredt & Snyder, 1989; Garthwaite et al., 1989, East & Garthwaite, 1991.Further, recent studies have demonstrated the feedback inhibition of NMDA receptors by NO (Lei et a...
BackgroundMale stress urinary incontinence is a prevalent condition after radical prostatectomy. While the standard recommendation for the management of urine leakage is pelvic floor muscle training, its efficacy is still unsatisfactory. Therefore, we have focused on regenerative therapy, which consists of administering a periurethral injection of autologous regenerative cells from adipose tissue, separated using the Celution® system. Based on an interim data analysis of our exploratory study, we confirmed the efficacy and acceptable safety profile of this treatment. Accordingly, we began discussions with Japanese regulatory authorities regarding the development of this therapy in Japan. The Ministry of Health, Labour and Welfare suggested that we implement a clinical trial of a new medical device based on the Pharmaceutical Affaires Act in Japan. Next, we discussed the design of this investigator-initiated clinical trial (the ADRESU study) aimed at evaluating the efficacy and safety of this therapy, in a consultation meeting with the Pharmaceuticals and Medical Device Agency.MethodsThe ADRESU study is an open-label, multi-center, single-arm study involving a total of 45 male stress urinary incontinence patients with mild-to-moderate urine leakage persisting more than 1 year after prostatectomy, in spite of behavioral and pharmacological therapies. The primary endpoint is the rate of patients at 52 weeks with improvement of urine leakage volume defined as a reduction from baseline greater than 50% by 24-h pad test. Our specific hypothesis is that the primary endpoint result will be higher than a pre-specified threshold of 10%.DiscussionThe ADRESU study is the first clinical trial of regenerative treatment for stress urinary incontinence by adipose-derived regenerative cells using the Celution® system based on the Japanese Pharmaceutical Affaires Act. We will evaluate the efficacy and safety in this trial to provide an adequate basis for marketing approval with the final objective of making this novel therapy widely available for Japanese patients.Trial registrationThis trial was registered at the University Hospital Medical information Network Clinical Trial Registry (UMIN-CTR Unique ID: UMIN000017901; Registered July 1, 2015) and at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT02529865; Registered August 18, 2015).
Objectives: To report the outcome of the ADRESU study, a multicenter, single-arm, investigator-initiated clinical trial to confirm the efficacy and safety of regenerative treatment for male patients with stress urinary incontinence. Methods: The participants were male patients with mild-to-moderate stress urinary incontinence persisting for >1 year after prostatectomy. Autologous adipose-derived regenerative cells were isolated using the Celution system from adipose tissue obtained by liposuction. Adipose-derived regenerative cells and mixture of adipose-derived regenerative cells with adipose tissue were transurethrally injected into the rhabdosphincter and submucosal space of the urethra, respectively. The primary endpoint was the proportion of patients with improvement of the urine leakage volume at 52 weeks (or last visit within 52 weeks). Improvement of leakage volume was defined as a decrease from baseline >50% by the 24-h pad test. A total of 10 secondary end-points were set. Results: A total of 45 patients satisfying the eligibility criteria were enrolled. The primary end-point was met; the proportion of patients with improvement in leakage volume at 52 weeks was 37.2% (95% confidence interval 23.0-53.3%). No serious adverse events with causal relationships to the adipose-derived regenerative cells were encountered. There was a progressive improvement in secondary end-points. In the King's Health Questionnaire, improvement of quality of life scores showed greater improvement in responders, as compared with non-responders. Conclusions: Findings from the ADRESU study suggest the efficacy and safety of regenerative treatment for male patients with mild-to-moderate stress urinary incontinence.
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