Biomedical subjects

Y Ukai

Publications and source records attributed to Y Ukai.

At least 55 records · Page 3Linked to original sources

PubMed1997

Effect of NS-21, an anticholinergic drug with calcium antagonistic activity, on lower urinary tract function in a rat model of urinary frequency.

BACKGROUND: NS-21 is under development for the treatment of urinary frequency and urinary incontinence. The purpose of this study was to investigate the effects of NS-21 and its active metabolite, RCC-36, on lower urinary tract function in an experimental rat model of urinary frequency. METHODS: Cystometrograms were recorded in anesthetized rats with bilaterally transected hypogastric nerves. All drugs were administered intraduodenally. RESULTS: In sham-operated rats, NS-21 (> or = 50 mg/kg) significantly increased the bladder capacity without significantly decreasing micturition pressure, while RCC-36 (100 mg/kg) significantly increased bladder capacity, and at a dose of > or = 30 mg/kg, also caused a decrease in micturition pressure. This increase in bladder capacity appeared at lower doses of both NS-21 and RCC-36 in the hypogastric nerve-transected rats. Propiverine (100 mg/kg) increased bladder capacity and at > or = 30 mg/kg, decreased micturition pressure in both sham-operated and nerve-transected rats. Oxybutynin (100 mg/kg) and atropine (30 mg/kg) decreased the micturition pressure in both sham-operated and nerve-transected rats without increasing the bladder capacity, while a similar anticholinergic calcium antagonist, terodiline (100 mg/kg) had no effect on bladder capacity in either sham-operated or nerve-transected rats. Flavoxate (500 mg/kg) significantly increased bladder capacity without significantly decreasing micturition pressure in both sham-operated and nerve-transected rats, while 50 mg/kg of verapamil significantly increased bladder capacity without significantly decreasing the micturition pressure in nerve-transected rats. CONCLUSIONS: NS-21 and RCC-36 increased bladder capacity at lower doses in hypogastric nerve-transected rats than in sham-operated rats. Furthermore, NS-21 increased the bladder capacity without suppressing micturition pressure, suggesting that NS-21 may be a more effective therapeutic drug than propiverine, oxybutynin or flavoxate for the treatment of urinary frequency and urinary incontinence.

Animals↗

PubMed1997

Effect of the anticholinergic drug with calcium antagonistic activity, (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate, on lower urinary tract function in decerebrated dogs.

NS-21 ((+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate, CAS 129927-33-4) is a novel compound designed for the treatment of bladder dysfunction. The effects of NS-21 and its active metabolite, RCC-36 ((+/-)-4-ethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride), on the urodynamics of decerebrated dogs are reported. Dogs were decerebrated at the precollicular-postmamillary level and the urodynamic effects of intravenously administered NS-21, RCC-36, and various reference drugs were compared by cystometry. NS-21 (0.3-1 mg/kg) and RCC-36 (0.1 mg/kg) caused an increase in bladder capacity without affecting the micturition pressure or residual volume, and thus caused a significant increase in functional bladder capacity. Oxybutynin caused a dose-dependent increase in bladder capacity at 0.1 mg/ kg and higher doses; however, the associated decrease in micturition pressure resulted in a significant increase in residual volume and a decrease in functional bladder capacity. These effects of oxybutynin were similar to those of atropine. Propiverine (0.1-10 mg/kg) and terodiline (0.1-10 mg/kg) caused no significant increase in bladder capacity. In conclusion, in decerebrated dogs, NS-21 and RCC-36 increased the bladder capacity without increasing the residual volume. NS-21 thus had more favorable therapeutic effects than any of the reference drugs tested and is therefore a promising candidate drug for the treatment of pollakiuria and urinary incontinence.

Animals↗

PubMed1997

Effect of the anticholinergic drug with calcium antagonistic activity, (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate, on lower urinary tract function in rhesus monkeys.

NS-21 ((+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate, CAS 129927-33-4) and its active metabolite, RCC-36 ((+/-)-4-ethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride), have both anticholinergic and calcium antagonistic activities. NS-21 is under development for the treatment of bladder dysfunction. This study was designed to compare the effects of NS-21 and RCC-36 on the bladder function of monkeys with the effects of various reference drugs. Male rhesus monkeys were anesthetized with a mixture of enflurane and nitrous oxide, a transurethral catheter was inserted into the urinary bladder from the external urethral orifice, and cystometrograms were recorded. Drugs were administered intravenously. NS-21 at doses of 0.3 and 1 mg/kg caused an increase in bladder capacity without affecting the micturition pressure. RCC-36 also caused an increase in bladder capacity, but it was accompanied by a significant decrease in micturition pressure. Oxybutynin, atropine and verapamil all caused decreases in micturition pressure at doses which caused an increase in bladder capacity. Of the drugs examined, only NS-21 caused an increase in the bladder capacity of rhesus monkeys without affecting the micturition pressure. This drug is therefore a promising candidate for the clinical treatment of pollakiuria and urinary incontinence.

Animals↗

PubMed1996

NS-49, an alpha 1A-adrenoceptor agonist, selectively increases intraurethral pressure in dogs.

The effects of NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethane sulfonanilide hydrochloride), an alpha 1A-adrenoceptor-selective agonist, on intraurethral pressure and blood pressure were investigated in anesthetized dogs. In addition, the contractile effects of NS-49 on the isolated dog urethra and carotid artery were compared with those of non-selective alpha 1-adrenoceptor agonists. Intravenously (i.v.) administered NS-49 at 0.3 microgram/kg or more significantly increased intraurethral pressure in a dose-dependent manner. Much higher doses of NS-49 were needed to increase blood pressure. In contrast, ST-1059 (1-(2',5'-dimethoxyphenyl)-2-aminoethanol) (an active metabolite of midodrine) at 30 micrograms/kg or more significantly increased both intraurethral pressure and blood pressure. NS-49 was 11-fold more selective for intraurethral pressure than ST-1059, NS-49, ST-1059, phenylephrine and noradrenaline caused concentration-dependent contraction of the isolated dog urethra. NS-49 caused only a slight contraction of the dog carotid artery even at high concentrations, whereas the reference drugs caused contractions of the artery with high efficacy. The alpha 1A-adrenoceptor-selective antagonists 5-methyl-urapidil and WB-4101 also showed high affinity for alpha 1-adrenoceptors in the dog urethra in inhibiting [3H]prazosin binding. In conclusion, the alpha 1A-selective agonist NS-49 selectively increased intraurethral pressure in dogs, and produced selective contraction of the dog urethra. These results suggest that the alpha 1A-adrenoceptor subtype is responsible for the contraction of the urethra and the regulation of intraurethral pressure, and that NS-49 might be useful for the treatment of stress incontinence with little effect on the cardiovascular system.

Adrenergic alpha-Agonists↗

PubMed1996

CNS-mediated influence of TRH and its analog, NS-3, on the function of the rabbit lower urinary tract.

The effects of thyrotropin-releasing hormone (TRH) and its new analog, NS-3 (montireline), on the lower urinary tract in rabbits were investigated. TRH and NS-3 elicited transient increases in intravesical pressure and micturition. They also caused long-lasting increases in intraurethral pressure and EMG activity of the external urethral sphincter, which were not affected by prazosin or transection of the hypogastric nerve, but were eliminated by transection of the pudendal nerve. In animals decerebrated at the supracollicular post-mammillary level, these drugs did not increase intravesical pressure or micturition, but they did elicit increases in intraurethral pressure and sphincter EMG activity. No binding sites for TRH were found in the lower urinary tract. These findings suggest that the sites of action of TRH and NS-3 which elicit intravesical pressure increase or micturition might be located in the area rostral to the pons, and that the sites of action which elicit increases in intraurethral pressure and sphincter EMG activity might be located caudal to the rostral pons.

Animals↗

PubMed1996

Brain pertussis toxin-sensitive G proteins are involved in the flavoxate hydrochloride-induced suppression of the micturition reflex in rats.

The effect of flavoxate hydrochloride (flavoxate), an anti-pollakiurea agent, on cyclic AMP (cAMP) formation was investigated in the rat brain and a possible involvement of brain G proteins in the action of flavoxate on the bladder function was subsequently examined. Flavoxate (10(-8)-10(-5) M) inhibited cAMP formation in a concentration-dependent manner, an action which was completely abolished by pretreating the membranes with pertussis toxin (PTX). The inhibitory effect of flavoxate was also completely antagonized by combined treatment with any two antagonists for adenosine A1 (8-cyclopentyl-1,3-dipropylxanthine), dopamine D2 (sulpiride) or adrenergic alpha 2 (yohimbine) receptors, although each antagonist alone did not significantly block the flavoxate-induced inhibition of cAMP formation. Radioligand binding studies indicated that flavoxate at micro- or submicromolar concentrations has affinity for Gi-coupled receptors such as A1, D2 and alpha 2 receptors. Therefore, flavoxate may inhibit cAMP formation by the stimulation of A1, D2 and alpha 2 receptors. To clarify the involvement of brain Gi proteins in the flavoxate-induced inhibition of the micturition reflex, the effect of pretreatment with PTX (i.c.v.) on the flavoxate-induced inhibition of isovolumetric rhythmic bladder contractions was examined in rats. Flavoxate (3 mg/kg, i.v.) completely abolished rhythmic bladder contractions in vehicle-pretreated rats, but not in PTX-pretreated rats. These findings suggest that signal transduction via Gi-coupled receptors is involved, at least in part, in the inhibition of the micturition reflex by flavoxate in rats. These results also provide the first evidence suggesting a negative role of brain PTX-sensitive G proteins in the micturition reflex.

Animals↗

PubMed1996

NS-3, a TRH-analog, reverses memory disruption by stimulating cholinergic and noradrenergic systems.

The effects of a TRH-analog, N[[(3R,6R)-6-methyl-5-oxo-3-thiomorpholinyl]carbonyl]-L-histidyl-L - prolinamide tetrahydrate (NS-3, CG3703, montirelin hydrate) were compared with those of physostigmine on learning and memory disruption in the passive avoidance response (PAR) induced by either electrolytic lesion of the nucleus basalis magnocellularis (NBM) or by treatment with the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) in rats. a) In NBM-lesioned rats, both NS-3 and physostigmine significantly reversed disruption of memory consolidation examined 15 min after the training session when these drugs were injected IP immediately after the training session. In addition, reversal by NS-3 (0.1 mg/kg) of the disruption of memory was observed even in the retention test conducted 24 h after the training session. b) NS-3 (0.5 mg/kg) significantly reversed the disruption of memory retrieval, when the drug was administered 15 min before the test session. c) DSP4 (50 mg/kg IP) caused memory disruption when the retention tests were conducted between 1 and 48 h after the acquisition session. NS-3 (0.1 mg/kg), but not physostigmine, significantly reversed the disruption of memory induced by DSP4 treatment. These findings suggest that the consistent antiamnestic action of NS-3 is due to the enhancement of both central cholinergic and noradrenergic systems, possibly via facilitation of the release of these transmitters.

Acetylcholine↗

PubMed1996

Protein kinases are involved in prolonged acetylcholine release from rat hippocampus induced by thyrotropin-releasing hormone analogue NS-3.

The effects of various protein kinase inhibitors on acetylcholine release from the rat hippocampus induced by the local application of NS-3 (montirelin hydrate, CG-3703), a thyrotropin-releasing hormone analogue, into the medial septum-diagonal band were examined using in vivo microdialysis. Perfusion of NS-3 (1 microM) into the medial septum-diagonal band for 20 min produced a pronounced and prolonged increase in the hippocampal acetylcholine efflux. Pretreatment of the medial septum-diagonal band with either K-252a, a nonselective protein kinase inhibitor, or selective protein kinase A inhibitor H-89 almost completely blocked the acetylcholine efflux evoked by NS-3, and selective protein kinase C inhibitor calphostin C inhibited the action of NS-3. On the other hand, NS-3 (0.1-10 microM) or TRH (1-100 microM) increased the cyclic AMP efflux from the medial septum-diagonal band in a concentration-dependent manner, as measured by microdialysis. These findings suggest that protein kinases A and C in the neurons of the medial septum-diagonal band are involved in the mechanism of the prolonged stimulation of acetylcholine release from the hippocampus induced by thyrotropin-releasing hormone and its analogue, NS-3.

Acetylcholine↗

PubMed1996

Mechanisms of the suppression of the bladder activity by flavoxate.

BACKGROUND: This study was designed to clarify the primary site of action of flavoxate, clinically used for the treatment of urinary frequency. METHODS: In rats, the effect of flavoxate on contractile responses in isolated detrusor strips, bladder contraction induced by pelvic nerve stimulation, isovolumetric rhythmic bladder contractions, and pelvic nerve activity were examined. In decerebrated cats, flavoxate was microinjected into the nuclei in the pons, and its effect on reflex micturition was observed. RESULTS: Flavoxate suppressed carbachol- and calcium ion (Ca2+)-induced contractions of isolated detrusor strips in a noncompetitive and a competitive manner, respectively. Intravenous flavoxate suppressed both initial phasic, and later tonic, bladder contractions induced by electrical stimulation of the distal end of the pelvic nerve. It abolished isovolumetric rhythmic bladder contractions and the associated efferent pelvic nerve activity, without affecting baseline vesical pressure and afferent pelvic nerve activity. When administered intracerebroventricularly or intrathecally, it abolished isovolumetric rhythmic bladder contractions. Flavoxate microinjected into the nucleus reticularis pontis oralis (PoO; pontine micturition inhibitory region) of decerebrated cats inhibited the reflex micturition, but had no effect when microinjected into the locus coeruleus alpha (pontine micturition center) or locus subcoeruleus (pontine urine storage center). CONCLUSIONS: Flavoxate suppressed the micturition reflex primarily by facilitating the inhibitory action of the PoO on the descending pathways from the pontine micturition center to the sacral parasympathetic intermediolateral nuclei.

Animals↗

PubMed1996

Enhancement of brain noradrenaline and dopamine turnover by thyrotropin-releasing hormone and its analogue NS-3 in mice and rats.

The effects of intravenous injections of thyrotropin-releasing hormone and its analog NS-3 (montirelin hydrate, CG3703) on the dynamics of brain monoamines were examined in mice and rats. In mice, both NS-3 (0.1-1 mg/kg) and thyrotropin-releasing hormone (10 and 30 mg/kg) increased the concentrations of 4-hydroxy-3-methoxyphenylglycol, 3,4-dihydroxyphenylacetic acid and homovanillic acid. The turnover rates, estimated either by depletion of catecholamines after treatment with alpha-methyl-p-tyrosine or by probenecid-induced accumulation of homovanillic acid, were enhanced by these peptides. In contrast, none of the compounds had any influence on the serotonin turnover. In rats, both NS-3 and thyrotropin-releasing hormone produced a regionally specific increase in the concentrations of the catecholamine metabolites. A microdialysis study demonstrated that NS-3 significantly increased the release of dopamine in the nucleus accumbens as well as the striatum of conscious rats, while thyrotropin-releasing hormone caused a weak but significant enhancement of dopamine release only in the nucleus accumbens. These findings indicate that NS-3 was far more potent than thyrotropin-releasing hormone in facilitating the turnover of catecholamines without affecting serotonin turnover in the mouse and rat brain.

Animals↗

PubMed1996

[Montirelin hydrate (NS-3), a TRH analog, improved the disturbance of consciousness caused by head concussion and pentobarbital in mice].

Effects of a novel TRH analog, montirelin hydrate (NS-3), on the coma caused by head concussion and narcosis induced by pentobarbital were compared with those of TRH in mice. Head concussion caused a behavioral comatose state with loss of the righting reflex and spontaneous motor activity. NS-3 shortened the latent periods to the recovery of the righting reflex (0.03-0.1 mg/kg, i.v.) and spontaneous motor activity (0.1 mg/kg, i.v.) following the head concussion. In the case of TRH, higher doses were needed to induce such effects. NS-3 (0.1-0.3 mg/kg, i.v.) reversed the pentobarbital-induced narcosis in a dose-dependent manner. A similar effect was elicited by 30- to 100-fold higher doses of TRH than NS-3. The analeptic effect of NS-3 in the pentobarbital-narcotized mice was antagonized by SCH23390, a dopamine D1 antagonist or by the combined treatment with prazosin and scopolamine, while neither prazosin nor scopolamine alone antagonized the analeptic effect of NS-3. Taken together with the finding that NS-3 did not bind to dopamine, adrenaline or muscarine receptors, it is suggested that NS-3 may restore the disturbance of consciousness by activating the brain dopamine, noradrenaline and acetylcholine neurons without stimulating these receptors directly.

Anesthesia↗

PubMed1996

[Montirelin hydrate (NS-3), a TRH analog, improved disturbance of consciousness in cats: electroencephalographical studies].

Central effects of montirelin hydrate (NS-3) were electroencephalographically investigated in cats with experimentally induced disturbance of consciousness. All experiments were conducted under the gallamine-immobilized and artificially ventilated acute experimental condition. NS-3 and TRH produced EEG activation in cats with lesions in the midbrain reticular formation in a dose-dependent manner. Similar effects were observed in cats with bilateral lesions of the posterior hypothalamic area. These effects of NS-3 were 30 to 100 times more potent than those of TRH. NS-3 at doses higher than 0.003 mg/kg restored the suppressed EEG dose-dependently in cats with cerebral ischemia produced by clamping the bilateral common carotid arteries and basilar artery. TRH showed no effect at a dose of 10 mg/kg. These results indicate that NS-3 might be an effective drug for treating the disturbance of consciousness.

Animals↗

PubMed1996

[EEG studies on the analeptic effect of montirelin hydrate (NS-3), a TRH analog, in posterior hypothalamic area-lesioned rats].

Effects of a novel TRH analog, montirelin hydrate (NS-3), on the EEG were compared with those of TRH in intact and posterior hypothalamic area (PHA)-lesioned rats. In the intact rats, NS-3 at 0.01 mg/kg and TRH at 1 mg/kg produced no changes in the sleep-waking cycle. NS-3 at 0.1 mg/kg caused an increase in the time spent in the arousal stage and delayed the onset of the slow wave sleep (SS). On the other hand, TRH at 10 mg/kg increased the time spent in the SS stage and decreased the time in the A1 stage during 2 to 4 hr after injection without increasing the arousal stage, although it delayed the onset of SS. No abnormal EEG was observed after NS-3 or TRH administration in the intact rats. Electrolytic ablation of the PHA elicited continuous behavioral resting and caused increases in the slow-wave components in the cortical EEG and loss of generation of the hippocampal rhythmic slow activity. NS-3 at 0.01 mg/kg and TRH at 1 mg/kg caused the reappearance of the hippocampal rhythmic slow activity. In addition, NS-3 at 0.1 mg/kg and TRH at 10 mg/kg decreased the slow-wave components and increased the fast-wave components in the cortical EEG. In conclusion, NS-3 showed a distinct analeptic effect with a 100-fold higher potency than that of TRH in both the intact and PHA-lesioned rats.

Animals↗

PubMed1996

A novel synthetic inhibitor of endopeptidase-24.15.

A novel synthetic inhibitor of endopeptidase-24.15 (EP-24.15, EC 3.4.24.15), N-[(2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidine carbonyl] -L-phenylalanine (SA898) is described. This compound inhibited rat EP-24.15 competitively with an IC50 of 23 nM and Ki of 9.1 nM. These values were, respectively, 9.6 times and 6.3 times smaller than those for N-(1-carboxy-3-phenylpropyl)-alanyl-alanyl-phenylalanyl-p-aminobenzoate (cFP-AAF-pAB), which was one of the most potent inhibitors thus far reported. The inhibitory effect of SA898 on other endopeptidases, angiotensin converting enzyme (ACE, EC 3.4.15.1) and endopeptidase-24.11 (EP-24.11, EC 3.4.24.11) was also studied. SA898 inhibited ACE significantly, but the potency was about 20-fold lower than that for EP-24.15 in terms of the Ki value. The inhibitory effect of SA898 on EP-24.11 was almost negligible (Ki = 28 microM). In addition, the inhibitory activities of several SA898-related compounds were examined. Based on these data, the structure-activity relationships for EP-24.15 inhibitors are discussed.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Inhibitory influence from the nucleus reticularis pontis oralis on the micturition reflex induced by electrical stimulation of the pontine micturition center in cats.

An inhibitory influence from the nucleus reticularis pontis oralis on the micturition induced by electrical stimulation of the pontine micturition center was investigated in decerebrate cats at the supracollicular level. Monopolar electrical stimulation (30-50 microA, 0.2 ms, 50 Hz, 3 s) of the nucleus locus coeruleus alpha (pontine micturition center) produced micturition similar to that induced by distending the bladder by saline infusion. The intravesical pressure increase and micturition induced by electrical stimulation of the nucleus locus coeruleus alpha were suppressed by electrical stimulation of the nucleus reticularis pontis oralis in the intensity range 20-100 microA in a stimulus-intensity-dependent manner. These findings indicate that the nucleus reticularis pontis oralis has an inhibitory influence on the functions of the micturition center.

Animals↗

PubMed1995

NS-3 (CG3703), an analog of thyrotropin-releasing hormone, ameliorates cognitive impairment in rats.

The effects of thyrotropin-releasing hormone (TRH) and its analog, N-[[(3R,6R)-6-methyl-5-oxo-thiomorpholinyl] carbonyl]-L-histidyl-L- prolinamide tetrahydrate (NS-3, CG3703) on disturbance of memory of a passive avoidance response (PAR) and an escape response in rats were investigated. NS-3 improved amnesia caused by scopolamine, electroconvulsive shock (ECS), and cycloheximide (CXM), but TRH improved only the ECS-induced amnesia. NS-3 reversed learning deficits caused by hypercapnia, but TRH had no effect. These differences in the effect between NS-3 and TRH may be due to their biological half-life in rat plasma. These results suggest that NS-3 possesses more potent antiamnestic effects than TRH in rats.

Amino Acid Sequence↗

PubMed1995

NS-3(CG3703), a TRH analog, ameliorates scopolamine-induced memory disruption in rats.

The effects of a metabolically stable TRH analog, N-[[(3R, 6R)-6-methyl-5-oxo-3-thiomorpholinyl]carbonyl]-L-histidyl-L- prolinamide tetrahydrate (NS-3, CG3703) on the scopolamine-induced memory disruption in maze performance tests were investigated in rats. a) In the delayed nonmatching-to-sample (DNMS) task using a T-maze, NS-3 (0.3 mg/kg) produced a significant reversal of the marginal disruption of choice accuracy induced by scopolamine (0.3 mg/kg) at the short (5 s) and long (120, 480 s) interval delays. Physostigmine (0.5 mg/kg) produced a significant reversal only at a 5-s interval delay. b) In the eight-arm radial maze task, NS-3 (0.3 mg/kg) significantly reversed the deficit of choice accuracy induced by scopolamine (0.3 mg/kg), whereas neither TRH (3-30 mg/kg) nor physostigmine (0.1-1 mg/kg) had any effect. The consistent reversal of these maze-learning performances by NS-3, but not by TRH or physostigmine, may be due to its potent enhancement of cholinergic and noradrenergic neuronal activities.

Animals↗

PubMed1995

Permeability of NS-3, a thyrotropin-releasing hormone analogue, into the brain after its systemic administration in rats: a microdialysis study.

The concentration of NS-3 (montirelin hydrate, CG 3703), a thyrotropin-releasing hormone (TRH) analogue, in the cerebral cortex of urethane-anaesthetized rats was measured after its systemic administration (1 mg kg-1, i.v.), using in-vivo microdialysis coupled with a radioimmunoassay. The concentration in microdialysates was highest (24 nM) during the first 20 min after injection, and it fell below the detection limit (3.5 nM) 100 min after treatment. The maximal interstitial concentration was estimated to be 0.51 microM. From these results, it is suggested that NS-3 can readily penetrate into the brain.

Animals↗