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Biomedical subjects

Ken Ikeda

Publications and source records attributed to Ken Ikeda.

At least 37 records · Page 2Linked to original sources
PubMed2004

In vitro and in vivo tissue selectivity profile of solifenacin succinate (YM905) for urinary bladder over salivary gland in rats.

Solifenacin succinate [YM905; (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate] is a new muscarinic receptor antagonist developed for the treatment of overactive bladder. The aim of the present study was to evaluate the in vitro and in vivo bladder selectivity profile of solifenacin over salivary gland in the same animal species, and to compare the results with those obtained for tolterodine, oxybutynin, darifenacin and atropine. Solifenacin and the other antimuscarinic drugs inhibited carbachol-induced increases in intracellular Ca(2+) levels in bladder smooth muscle cells and salivary gland cells isolated from rats in a concentration-dependent manner. The inhibitory effect of solifenacin for bladder smooth muscle cells (pK(i)=8.12) was 3.6-fold more potent than that for salivary gland cells (pK(i)=7.57). In contrast, the inhibitory effects of the other antimuscarinic drugs for bladder smooth muscle cells were 1.7- to 2.2-fold more potent than those for salivary gland cells. In anesthetized rats, solifenacin dose-dependently inhibited carbachol-induced intravesical pressure elevation and salivary secretion, and exhibited functional selectivity (3.7- to 6.5-fold) for urinary bladder over salivary gland. Tolterodine was also 2.2- to 2.4-fold more selective in inhibition of bladder response. In contrast, oxybutynin, darifenacin and atropine did not show functional selectivity for urinary bladder. These results indicate that solifenacin exerts greater selectivity for urinary bladder over salivary gland than tolterodine, oxybutynin, darifenacin and atropine, and may consequently provide symptomatic benefit in the treatment of overactive bladder with less dry mouth than currently used antimuscarinic drugs.

Animals↗
PubMed2004

Comparison of in vitro selectivity profiles of solifenacin succinate (YM905) and current antimuscarinic drugs in bladder and salivary glands: a Ca2+ mobilization study in monkey cells.

We investigated the effects of the new muscarinic receptor antagonist solifenacin succinate [YM905; (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate] and the current antimuscarinic drugs for the treatment of overactive bladder (oxybutynin, tolterodine and darifenacin) on intracellular Ca(2+) mobilization in response to M(3) muscarinic receptor activation in bladder smooth muscle and submandibular gland cells isolated from Cynomolgus monkeys. Solifenacin concentration-dependently inhibited carbachol-induced Ca(2+) mobilization, with affinity constant values (pKi) of 8.5 +/- 0.053 in bladder smooth muscle cells and 8.2 +/- 0.051 in submandibular gland cells (n = 5). The pKi value of solifenacin was almost equivalent to the values of oxybutynin, tolterodine and darifenacin in bladder smooth muscle cells (8.7, 8.5 and 8.4, respectively), while being lower than those in submandibular gland cells (9.0, 8.7 and 8.8, respectively). The bladder-selectivity index (Ki ratio: submandibular gland/bladder) for solifenacin (2.1) was statistically higher, moreover, than those for oxybutynin, tolterodine and darifenacin (0.51, 0.65 and 0.46, respectively). These findings consequently indicate solifenacin's unique profile in terms of its selectivity for bladder smooth muscle cells over salivary gland cells in non-human primates, relative to oxybutynin, tolterodine and darifenacin. Solifenacin may, therefore, confer a promising therapeutic advantage for reducing adverse effects, such as dry mouth, exhibited by current antimuscarinic therapy for overactive bladder.

Animals↗
PubMed2004

T-588 protects motor neuron death following axotomy.

R(-)-1-(benzo [b] thiophen-5-yl)-2-[2-(N,N-diethylamino)ethoxy] ethanol hydrochloride) (T-588) enhances acetylcholine release. This compound slows the motor deterioration of wobbler mouse motor neuron disease and enhances neurite outgrowth and choline acetyltransferase activity in cultured rat spinal motor neurons. We examined the ability of T-588 on axotomized spinal motor neuron death in the rat spinal cord. After the postnatal unilateral section of sciatic nerve, there was approximately a 50% survival of motor neurons in the fourth lumbar segment. In comparison with vehicle, intraperitoneal injection of T-588 for 14 consecutive days rescued spinal motor neuron death. Our results showing in vivo neurotrophic activity of T-588 for motor neurons support the applicability of T-588 for the treatment of motor neuron diseases, such as amyotrophic lateral sclerosis and motor neuropathies.

Animals↗
PubMed2003

Influence of temocapril on cultured ventral spinal cord neurons.

Temocapril, a angiotensin-converting enzyme (ACE) inhibitor, was tested for neurotrophic activity in primary explant cultures of ventral spinal cord of fetal rats (VSCC). Temocapril had a remarkable effect on neurite outgrowth with a 4.2- to 5.1-fold increased over that of control VSCC at their effective concentrations. In temocapril-treated VSCC, choline acetyltransferase (ChAT) activity was also increased 2.4-3.2 times over that of control at 10(-9) and 10(-8) M, respectively. Our data suggest that temocapril is a candidate for neurotrophic factors on spinal motor neurons in vitro. A possible therapeutic role for temocapril in damaged motor neurons, such as in motor neuropathy and amyotrophic lateral sclerosis, remains to be defined.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

T-588 protects motor neuron death against glutamate-induced neurotoxicity.

To examine the possible neuroprotective effect of T-588 against glutamate-induced neurotoxicity, we analyzed the pharmacological utility of T-588 in a postnatal organotypic culture model of motor neuron degeneration. Treatment with 10(-5) M of glutamate resulted a motor neuron loss and decreased activity of choline acetyltransferase (ChAT). Cotreatment of 10(-5) M of glutamate and T-588 revealed a protective effect against motor neuron death and decreased ChAT activity. We concluded that T-588 may play important roles in the survival and maintenance of spinal motor neurons in its neuroprotection against glutamate-induced neurotoxicity. Our data may provide a rationale for designing a therapeutic strategy for protection against pathologically induced motor neuron damage or cell death such as amyotrophic lateral sclerosis and motor neuropathy.

Animals↗
PubMed2003

Temocapril prevents motor neuron damage and upregulation of cyclooxygenase-II in glutamate-induced neurotoxicity.

To examine the possible neuroprotective effect of temocapril, one kind of angiotensin-converting enzyme inhibitor, against glutamate-induced neurotoxicity, we analyzed the pharmacologic utility of temocapril in a post-natal organotypic culture model of motor neuron degeneration. Treatment with 10(-5) M of glutamate resulted in a motor neuron loss and decreased activity of choline acetyltransferase (ChAT). Cotreatment of 10(-5) M of glutamate and temocapril revealed protective effect on motor neuron death and decreased activity of ChAT. Next we performed reverse transcription-PCR analysis for cyclooxygenase-II (COX-II). COD-II mRNA was upregulated in glutamate-treated culture. Cotreatment with temocapril and glutamate inhibited upregulation of COX-II. Taken together, temocapril may have therapeutic potential for diseases which associate with upregulation of COX-II, in addition to its role in glutamate excitotoxicity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Oral administration of a neuroprotective compound T-588 prevents motoneuron degeneration after facial nerve avulsion in adult rats.

OBJECTIVE: R(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino) ethoxylethanol hydrochloride (T-588), a synthetic compound, has been shown to have neuroprotective potentials for neuronal cells. We investigated whether orally administered T-588 can rescue injured motoneurons after facial nerve avulsion in adult rats. METHODS: The right facial nerves of adult Fischer 344 male rats were avulsed and the animals were freely administered solution of 0.05% (w/v) T-588 or received T-588 (3-30 mg/kg/day) through an oral tube for 1-4 weeks. Facial motoneurons on both sides of the facial nuclei were counted in Nissl-stained sections, and choline acetyltransferase (ChAT) immunoreactivity in injured motoneurons and ChAT enzyme activities in the ventral brain stem tissue containing the facial nuclei were examined. RESULTS: Both free oral administration of 0.05% T-588 solution and oral tube administration of T-588 (30mg/kg/day) improved the survival of facial motoneurons at 3 or 4 weeks after avulsion. These treatments ameliorated ChAT immunoreactivity in injured motoneurons and the tissue ChAT enzyme activities at 1-week postoperation examined. CONCLUSION: These results indicate that oral administration of T-588 ameliorates the survival of injured motoneurons and supports their neuronal function after facial nerve avulsion in adult rats. T-588 may have therapeutic potential in motoneuron injury or motor neuron diseases in humans.

Administration, Oral↗
PubMed2002

M(3) receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland.

The antimuscarinic profile of the experimental drug solifenacin/YM905 [(+)-(1 S,3' R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate] for the treatment of overactive bladder was compared with the commonly prescribed agent oxybutynin. In radioligand binding assays, p K(i) values of solifenacin for M(1), M(2), and M(3) receptors were 7.6, 6.9, and 8.0, respectively. These values for oxybutynin were 8.6 (M(1)), 7.7 (M(2)), and 8.9 (M(3)). Solifenacin and oxybutynin antagonized the contractile effect of carbachol (CCh) on isolated guinea pig urinary bladder smooth muscle (detrusor), displaying the negative logarithm of antagonist apparent affinity constant (p K(b) value) of 7.1 for solifenacin and 7.4 for oxybutynin. To study the tissue selectivity between bladders and salivary glands, guinea pig detrusor and mouse submandibular gland cells were stimulated with CCh and monitored for intracellular Ca2+, as determined by Fura 2 fluorescence. Ca2+ mobilization of detrusor cells was inhibited equipotently by solifenacin (p K(i)=8.4) and oxybutynin (p K(i)=8.6), whereas that of the gland cells was antagonized less potently by solifenacin (p K(b)=7.4) than by oxybutynin (p K(b)=8.8), although the M(3) subtype mediated both cell responses. In anesthetized rats, solifenacin (63-2100 nmol kg(-1) or 0.03-1 mg kg(-1)) dose-dependently inhibited CCh-stimulated increases in urinary bladder pressure, while its inhibitory effects on salivation and bradycardia were apparent only at a dose of 2100 nmol kg(-1). In contrast, oxybutynin within a dose range of 77-770 nmol kg(-1) (0.03-0.3 mg kg(-1)) inhibited responses of the bladder and salivary gland slightly more potently than that of the heart. In addition, inhibitory effects of darifenacin indicated a major role of M(3) receptors in the bladder and salivary gland. Therefore, M(3) receptor antagonism by solifenacin could be bladder-selective. This selectivity remains to be elucidated and may provide new approaches to the pharmacotherapy of overactive bladder.

Animals↗
PubMed2002

The diagnostic interval in amyotrophic lateral sclerosis.

We studied whether there are any parameters that influence the period between onset of symptoms and confirmation of diagnosis in 117 patients with ALS (65 male, 52 female). The mean age of diagnosis was 57 years for men and 59 years for women. Bulbar-onset patients were older at diagnosis than limb-onset patients both men and women. Patients with bulbar-onset appeared to be more frequent in women (33:19). Contrariwise, limb-onset patients were more frequently male (43:22). The time to confirmation was much shorter with symptoms of bulbar-onset (10.5 months in male, 9.8 months in female) than for those with limb-onset (13.7 months in male, 14.8 months in female) in male, respectively, female ALS patients. The diagnosis of ALS was established in all cases by neurologists in our study.

Adult↗
PubMed2002

T-588 enhances neurite outgrowth and choline acetyltransferase in cultured rat spinal ventral horn neurons.

T-588(R(-)-1-(benzo(b)thiophen-5yl)-2-[2(N,N-diethylamino)ethoxy]ethanol hydrochloride) is a novel compound which has been shown to exhibit a wide range of neurotrophic effects both in vivo and in vitro. This compound can slow the motor deterioration of wobbler mouse motor neuron disease. However, it is not known whether this compound has a trophic effect on spinal motor neurons. We have studied the effect of T-588 on neurite outgrowth and choline acetyltransferase(ChAT) activity in primary explant cultures of ventral spinal cord of fetal rats(VSCC). Cultures were treated with T-588 from day 1 to 1 week. T-588 treated VSCC, compared with control VSCC, had a significant neurite promoting effect at ranged between 10(-8) molar(M) and 10(-5) M, with 2.3 to 5.3 fold increased over that of control VSCC. In T-588 treated VSCC, ChAT activity was increased 1.5 times over that of control at 10(-6), and 10(-5) M respectively. Our data showing T-588 has neurotrophic action on VSCC and suggests a potential use of T-588 in treating diseases that involve degeneration and death of spinal motor neurons, such as motor neuropathy and motor neuron disease.

Animals↗
PubMed2002

Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson's disease.

Adenosine A2A receptors are abundant in the caudate-putamen and involved in the motor control in several species. In MPTP-treated monkeys, A2A receptor-blockade with an antagonist alleviates parkinsonian symptoms without provoking dyskinesia, suggesting this receptor may offer a new target for the antisymptomatic therapy of Parkinson's disease. In the present study, a significant neuroprotective effect of A2A receptor antagonists is shown in experimental models of Parkinson's disease. Oral administration of A2A receptor antagonists protected against the loss of nigral dopaminergic neuronal cells induced by 6-hydroxydopamine in rats. A2A antagonists also prevented the functional loss of dopaminergic nerve terminals in the striatum and the ensuing gliosis caused by MPTP in mice. The neuroprotective property of A2A receptor antagonists may be exerted by altering the packaging of these neurotoxins into vesicles, thus reducing their effective intracellular concentration. We therefore conclude that the adenosine A2A receptor may provide a novel target for the long-term medication of Parkinson's disease, because blockade of this receptor exerts both acutely antisymptomatic and chronically neuroprotective activities.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗