The Experts below are selected from a list of 78 Experts worldwide ranked by ideXlab platform
P G M Luiten - One of the best experts on this subject based on the ideXlab platform.
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oral post lesion administration of 5 ht1a receptor agonist Repinotan hydrochloride bay x 3702 attenuates nmda induced delayed neuronal death in rat magnocellular nucleus basalis
Neuroscience, 2001Co-Authors: Tibor Harkany, Csaba Nyakas, Jan Mulder, K M Horvath, Johannes Keijser, E K Van Der Meeberg, P G M LuitenAbstract:Recent evidence indicates that stimulation of postsynaptic 5-HT(1A) receptors abates excitotoxic neuronal death. Here we investigated whether oral post-lesion administration of the 5-HT(1A) receptor agonist (-)-(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide monohydrochloride (Repinotan HCl) attenuates N-methyl-D-aspartate (NMDA) excitotoxicity (60 nmol/microl) in the rat magnocellular nucleus basalis. Repinotan HCl (1 mg/kg) was administered from day 1, 2, 3, or 6 post-surgery twice daily for five consecutive days. This delayed drug administration protocol was employed to investigate the initiation period during which 5-HT(1A) receptor agonists may significantly influence ongoing neurodegeneration processes. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1 mg/kg) served as reference compound. Twenty-four hours after drug delivery a small open-field test, while on day 14 post-surgery a passive avoidance test was performed. Effects of Repinotan HCl treatment on the survival of cholinergic magnocellular nucleus basalis neurons and their cortical projections were determined by quantitative acetylcholinesterase (AChE) and choline-acetyltransferase (ChAT) histochemistry. Moreover, AChE and ChAT activities were biochemically measured both in the cerebral cortex and in the magnocellular nucleus basalis. Repinotan HCl treatment markedly increased spontaneous activities in the small open-field at any time-point investigated. Improved memory performance was only demonstrated when Repinotan HCl was administered from day 1 post-lesion on wards. Repinotan HCl treatment from day 2 and 3 post-lesion on markedly attenuated both histochemical and neurochemical characteristics of NMDA excitotoxicity on cholinergic magnocellular nucleus basalis neurons and on their cortical projections. Whereas the neuroprotective profile of Repinotan HCl was superior to that of 8-OH-DPAT, oral administration of both 5-HT(1A) receptor agonists yielded largely equivalent behavioral recovery after NMDA infusion in the magnocellular nucleus basalis. In conclusion, the present data indicate the potent neuroprotective action of the 5-HT(1A) receptor agonist Repinotan HCl with a peak efficacy of delayed (2-3 day) post-lesion drug treatment in vivo. Post-lesion treatment with 5-HT(1A) receptor agonists may therefore be of significance in the intervention of neuronal damage associated with acute excitotoxic conditions.
Andreas Hoeft - One of the best experts on this subject based on the ideXlab platform.
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selective 5 ht 1a r agonist Repinotan prevents remifentanil induced ventilatory depression and prolongs antinociception
Anesthesiology, 2012Co-Authors: Ulf Guenther, Michael Boettcher, Nils Theuerkauf, Daniel Huse, Georg Wensing, Christian Putensen, Andreas HoeftAbstract:Background 5-HT(1A)-R-agonist Repinotan was shown to counteract a morphine-induced ventilatory depression but had pronociceptive effects at small doses (0.2 μg/kg). It remained to be clarified (1) whether a moderate dose of Repinotan, sufficient to stimulate spontaneous breathing, impairs antinociception if plasma concentration decreases over time, and if (2) moderate doses prevent ventilatory depression if given before the opioid. Methods A dose-response curve of the Repinotan effects on spontaneous minute ventilation during continuous remifentanil infusion in anesthetized rats was established to identify moderate doses: (1) tail-flick reflex latencies to assess nociception were recorded until 60 min after cessation of a continuous remifentanil infusion with or without a concomitant moderate Repinotan dose (10 μg/kg), and (2) remifentanil boluses (2.5 μg/kg) were given after Repinotan (10 and 20 μg/kg). Results (1) Remifentanil-induced antinociception lasted only 5 min after infusion was stopped (tail-flick reflex latencies; median [interquartile range], 97 [54-100]% of maximum possible effect; P = 0.034), but was extended by Repinotan (10 μg/kg) to 30 min (tail-flick reflex latencies, 100 [75-100]% of maximum possible effect; P = 0.031). Repinotan (10 μg/kg) alone did not have any significant antinociceptive effect. (2) The ventilatory depression by remifentanil boluses (2.5 μg/kg; minute ventilation, -65 [-81 to -56]%; P = 0.031, n = 5) was blunted by Repinotan (20 μg/kg; minute ventilation, -24 [-53 to 13]%; P = 0.313, compared with the pretreatment level). Conclusions Repinotan prevented remifentanil-induced ventilatory depression in spontaneously breathing, anesthetized rats. Although Repinotan did not depress nociception itself, it prolonged the profound antinociception after discontinuation of remifentanil infusion.
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Repinotan a selective 5 ht1a r agonist antagonizes morphine induced ventilatory depression in anesthetized rats
Anesthesia & Analgesia, 2010Co-Authors: Ulf Guenther, Nils Theuerkauf, Georg Wensing, Christian Putensen, Hermann Wrigge, M F Boettcher, Jorg Zinserling, Andreas HoeftAbstract:BACKGROUND: Spontaneous breathing during mechanical ventilation improves arterial oxygenation and cardiovascular function, but is depressed by opioids during critical care. Opioid-induced ventilatory depression was shown to be counteracted in anesthetized rats by serotonin(1A)-receptor (5-HT 1A R)-agonist 8-OH-DPAT, which cannot be applied to humans. Repinotan hydrochloride is a selective 5-HT 1A -R-agonist already investigated in humans, but the effects on ventilation and nociception are unknown. In this study, we sought to establish (a) the effects of Repinotan on spontaneous breathing and nociception, and (b) the interaction with the standard opiate morphine. METHODS: The dose-dependent effects of Repinotan, given alone or in combination with morphine, on spontaneous minute ventilation (MV) and nociceptive tail-flick reflex latencies (TFLs) were measured simultaneously in spontaneously breathing anesthetized rats. An additional series with NaCl 0.9% and the 5-HT 1A -R-antagonist WAY 100 135 served as controls. RESULTS: (a) Repinotan dose-dependently activated spontaneous breathing (MV, mean [95% confidence interval]; 53% [29%-77%]) of pretreatment level) and suppressed nociception (TLF, 91% maximum possible effect [68%―114%]) with higher doses of Repinotan (2-200 μg/kg). On the contrary, nociception was enhanced with a small dose of Repinotan (0.2 μg/kg; TFL, -47% maximum possible effect [-95% to 2%]). Effects were prevented by 5-HT 1A -antagonist WAY 100 135. (B) Morphine-induced depression of ventilation (MV, -72% [―100% to -44%]) was reversed by Repinotan (20 μg/kg), which returned spontaneous ventilation to pretreatment levels (MV, 18% [-40% to 77%]). The morphine-induced complete depression of nociception was sustained throughout Repinotan and NaCl 0.9% administration. Despite a mild decrease in mean arterial blood pressure, there were no serious cardiovascular side effects from Repinotan. CONCLUSIONS: The 5-HT 1A -R-agonist Repinotan activates spontaneous breathing in anesthetized rats even in morphine-induced ventilatory depression. The potency of 5-HT 1A -R-agonists to stimulate spontaneous breathing and their antinociceptive effects should be researched further.
Monika Fierus - One of the best experts on this subject based on the ideXlab platform.
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a randomized double blind placebo controlled trial to evaluate the efficacy safety tolerability and pharmacokinetic pharmacodynamic effects of a targeted exposure of intravenous Repinotan in patients with acute ischemic stroke modified randomized exposure controlled trial mrect
Stroke, 2009Co-Authors: Philip Teal, Stephen M Davis, Werner Hacke, Markku Kaste, Patrick D Lyden, Monika FierusAbstract:mRECT demonstrated the feasibility of conducting a rigorous trial using a short therapeutic window demanding clinical and radiographic criteria to optimize patient selection and a Point-of-Care test to achieve a targeted exposure to Repinotan. The study failed to demonstrate a clinical benefit of Repinotan. The development of Repinotan in acute ischemic stroke was discontinued.
Tibor Harkany - One of the best experts on this subject based on the ideXlab platform.
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oral post lesion administration of 5 ht1a receptor agonist Repinotan hydrochloride bay x 3702 attenuates nmda induced delayed neuronal death in rat magnocellular nucleus basalis
Neuroscience, 2001Co-Authors: Tibor Harkany, Csaba Nyakas, Jan Mulder, K M Horvath, Johannes Keijser, E K Van Der Meeberg, P G M LuitenAbstract:Recent evidence indicates that stimulation of postsynaptic 5-HT(1A) receptors abates excitotoxic neuronal death. Here we investigated whether oral post-lesion administration of the 5-HT(1A) receptor agonist (-)-(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide monohydrochloride (Repinotan HCl) attenuates N-methyl-D-aspartate (NMDA) excitotoxicity (60 nmol/microl) in the rat magnocellular nucleus basalis. Repinotan HCl (1 mg/kg) was administered from day 1, 2, 3, or 6 post-surgery twice daily for five consecutive days. This delayed drug administration protocol was employed to investigate the initiation period during which 5-HT(1A) receptor agonists may significantly influence ongoing neurodegeneration processes. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1 mg/kg) served as reference compound. Twenty-four hours after drug delivery a small open-field test, while on day 14 post-surgery a passive avoidance test was performed. Effects of Repinotan HCl treatment on the survival of cholinergic magnocellular nucleus basalis neurons and their cortical projections were determined by quantitative acetylcholinesterase (AChE) and choline-acetyltransferase (ChAT) histochemistry. Moreover, AChE and ChAT activities were biochemically measured both in the cerebral cortex and in the magnocellular nucleus basalis. Repinotan HCl treatment markedly increased spontaneous activities in the small open-field at any time-point investigated. Improved memory performance was only demonstrated when Repinotan HCl was administered from day 1 post-lesion on wards. Repinotan HCl treatment from day 2 and 3 post-lesion on markedly attenuated both histochemical and neurochemical characteristics of NMDA excitotoxicity on cholinergic magnocellular nucleus basalis neurons and on their cortical projections. Whereas the neuroprotective profile of Repinotan HCl was superior to that of 8-OH-DPAT, oral administration of both 5-HT(1A) receptor agonists yielded largely equivalent behavioral recovery after NMDA infusion in the magnocellular nucleus basalis. In conclusion, the present data indicate the potent neuroprotective action of the 5-HT(1A) receptor agonist Repinotan HCl with a peak efficacy of delayed (2-3 day) post-lesion drug treatment in vivo. Post-lesion treatment with 5-HT(1A) receptor agonists may therefore be of significance in the intervention of neuronal damage associated with acute excitotoxic conditions.
E Horvath - One of the best experts on this subject based on the ideXlab platform.
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neuroprotective efficacy of Repinotan hcl a 5 ht1a receptor agonist in animal models of stroke and traumatic brain injury
Journal of Cerebral Blood Flow and Metabolism, 2005Co-Authors: Frank Mauler, E HorvathAbstract:Repinotan is a highly potent 5-HT1A receptor agonist with strong neuroprotective efficacy in animal models of middle cerebral artery occlusion and traumatic brain injury. In this study, we characte...
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the selective 5 ht1a receptor agonist Repinotan hcl attenuates histopathology and spatial learning deficits following traumatic brain injury in rats
Neuroscience, 2001Co-Authors: Anthony E Kline, E Horvath, Donald W Marion, C E DixonAbstract:The selective 5-HT1A receptor agonist Repinotan HCl (BAY x3702) has been reported to attenuate cortical damage and improve functional performance in experimental models of cerebral ischemia and acute subdural hematoma. Using a clinically relevant contusion model of traumatic brain injury, we tested the hypothesis that a 4-h continuous infusion of Repinotan HCl (10 μg/kg/h i.v.) commencing 5 min post-injury would ameliorate functional outcome and attenuate histopathology. Forty isoflurane-anesthetized male adult rats were randomly assigned to receive either a controlled cortical impact (2.7 mm tissue deformation, 4 m/s) or sham injury (Injury/Vehicle=10, Injury/MK-801=10, Injury/Repinotan HCl=10, Sham/Vehicle=10), then tested for vestibulomotor function on post-operative days 1–5 and for spatial learning on days 14–18. Neither Repinotan HCl nor the non-competitive N-methyl-D-aspartate receptor antagonist MK-801, which served as a positive control, improved vestibulomotor function on beam balance and beam walk tasks relative to the Injury/Vehicle group, but both did significantly attenuate spatial learning and memory deficits on a water maze task. Repinotan HCl also reduced hippocampal CA1 and CA3 neuronal loss, as well as cortical tissue damage, compared to the Injury/Vehicle group at 4 weeks post-trauma. No significant difference in histological outcome was revealed between the Repinotan HCl- and MK-801-treated groups. These findings extend the therapeutic efficacy of Repinotan HCl to a contusion model of experimental brain injury and demonstrate for the first time that 5-HT1A receptor agonists confer neuroprotection and attenuate spatial learning deficits following controlled cortical impact injury. This treatment strategy may be beneficial in a clinical context where memory impairments are common following human traumatic brain injury.