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Kennedy R. Lees – One of the best experts on this subject based on the ideXlab platform.
Safety and Tolerability Study of Aptiganel Hydrochloride in Patients With an Acute Ischemic StrokeStroke, 1999Co-Authors: A. G. Dyker, K. R. Edwards, Pierre B. Fayad, J. T. Hormes, Kennedy R. LeesAbstract:
Background and Purpose—Aptiganel (CNS 1102) is a selective, noncompetitive antagonist that acts on the ion channel associated with the N-methyl-d-aspartate (NMDA) receptor and is neuroprotective in experimental focal cerebral ischemia models at a plasma concentration of 10 ng/mL. In human volunteers, dose-limiting effects of Aptiganel are blood pressure increases and central nervous system (CNS) excitation or depression. This study assessed the safety and tolerability of non–weight-adjusted doses of Aptiganel in patients with acute ischemic stroke. Methods—This was a double-blind, randomized, placebo-controlled multicenter study in patients presenting within 24 hours of acute ischemic stroke. Ascending single intravenous bolus doses of Aptiganel (3, 4.5, 6, and 7.5 mg) were assessed in 21 patients with a 3:1 active drug:placebo randomization schedule. In 15 subsequent patients, selected bolus doses were followed by constant intravenous infusion for 6 to 12 hours (6 mg plus 1 mg/h, n=10; then 4.5 mg plus 0…
Cerestat and other NMDA antagonists in ischemic stroke.Neurology, 1997Co-Authors: Kennedy R. LeesAbstract:
Article abstract-A wealth of experimental evidence demonstrates that cerebral ischemia causes excessive release of glutamate and that glutamate contributes to ischemic injury. Glutamate antagonism by any of several mechanisms can ameliorate the extent of infarction. These antagonists comprise noncompetitive blockers of the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor [e.g., Aptiganel (Cerestat)], competitive antagonists of the glutamate recognition site of the NMDA receptor (e.g., selfotel) or of the glycine recognition site (e.g., ACEA 1021, GV150526), antagonists at the polyamine site (e.g., eliprodil), and drugs that may interfere with glutamate release by sodium channel blockade as well as having other actions (e.g., lubeluzole, 619C89). Clinical experience suggests that although some NMDA antagonists are poorly tolerated at putative neuroprotective doses (e.g., selfotel), potentially neuroprotective plasma concentrations can be achieved in humans with others (e.g., Aptiganel), though tolerable adverse effects are frequently observed. These clinical effects include hypertension (which is probably preferable to the hypotension seen with nimodipine and lifarizine), sedation, confusion or hallucinations and, at high doses, catatonia. Glycine antagonists may be associated with fewer adverse effects, but preclinical studies suggest that brain penetration may be low. Although recent studies with selfotel and eliprodil have been discontinued because of insufficient evidence for a satisfactory risk/benefit ratio, encouraging experience with Aptiganel, magnesium, and glycine antagonists has prompted continued clinical trials with these agents. To be of sufficient size to detect a clinically useful improvement in outcome, these trials need to be large (600-1,000 patients). Present trials with Aptiganel (Cerestat) are comparing the efficacy and tolerability of two doses vs. placebo in patients treated within 6 hours of ischemic stroke. Outcome is assessed by the modified Rankin Scale at 3 months.
Effects of prolonged infusions of the NMDA antagonist Aptiganel hydrochloride (CNS 1102) in normal volunteers.Clinical neuropharmacology, 1997Co-Authors: Keith W. Muir, Donald G. Grosset, Kennedy R. LeesAbstract:
Blockade of the N-methyl D-aspartate (NMDA) receptor by the ion-channel-blocking drug Aptiganel hydrochloride (CNS 1102, Cerestat) is neuroprotective in focal cerebral ischemia. Short intravenous infusions of up to 30 microg/kg have been well tolerated by healthy male volunteers. We undertook a randomized, double-blind, placebo-controlled study in 20 male volunteers to examine the safety, tolerability, and cardiovascular and psychomotor effects of a dosing paradigm similar to that envisaged for therapeutic use. Aptiganel HCl was infused over 4 h in total doses of 15, 32, 50, or 73 microg kg. Mean arterial pressure increased significantly with dose group (p < 0.01, analysis of covariance). Motor reaction time was related to maximal plasma concentration (r2 = 0.21, p < 0.001). Transient symptoms and signs of peripheral paresthesiae, light-headedness, and euphoria were seen at total doses of 32 microg/ kg. Higher doses were associated with motor retardation, perceptual disturbances, and hallucinations (one case). Clearance was 125 +/- 55 L/h, and volume of distribution was 537 +/- 1,261. Total doses of up to 32 microg/kg of Aptiganel HCl infused over 4 h are well tolerated by healthy males. Aptiganel HCl causes elevation of blood pressure and is associated with central nervous system symptoms and signs similar to other noncompetitive NMDA antagonists.
Richard M. Kream – One of the best experts on this subject based on the ideXlab platform.
Differential immediate-early gene expression in ovine brain after cardiopulmonary bypass and hypothermic circulatory arrest.Anesthesiology, 1998Co-Authors: Paula M. Bokesch, Peter A. Seirafi, Kenneth G. Warner, James E. Marchand, Richard M. Kream, Bruce D TrappAbstract:
BACKGROUND This study determined the induction profiles of immediate-early genes in the ovine brain after cardiopulmonary bypass (CPB) and hypothermic circulatory arrest (HCA), and the effects of the noncompetitive N-methyl-D-aspartate antagonist, Aptiganel, on immediate-early gene expression, neuronal necrosis, and functional outcome. METHODS Cannulas were inserted into isoflurane-anesthetized neonatal lambs undergoing CPB. One group received 2.5 mg/kg intravenous Aptiganel. Animals underwent 90 or 120 min of HCA at 16 degrees C, were rewarmed to 38 degrees C, and were weaned from CPB. One hour after CPB was discontinued, brain perfusion was fixed and removed for immunohistochemical analysis in one half of the animals. The other half survived 2 or 3 days before their brains were evaluated for neuronal degeneration. Data were analyzed using analysis of variance; P < 0.05 was considered significant. RESULTS Cardiopulmonary bypass and HCA differentially induced c-Jun and Fos proteins in the hippocampal formation, with c-Jun expression increasing with the duration of HCA, whereas Fos protein expressions were greatest after 90 min of HCA. The c-Jun protein was expressed in all neurons except the dentate gyrus. The Fos proteins were expressed in all neurons, including the dentate gyrus. Neuronal necrosis was observed in CA1 (73%) and CA3 (29%) neurons but not in the dentate gyrus after 120 min of HCA. Aptiganel completely inhibited c-Jun expression (P < 0.001) but not Fos, improved functional outcome, and attenuated neuronal necrosis (P < 0.05). CONCLUSIONS The c-Jun and c-Fos proteins are expressed differentially in hippocampal neurons after CPB and HCA. Expression of c-Jun is associated with neuronal necrosis, whereas Fos protein expression is associated with survival. Aptiganel inhibits c-Jun expression, attenuates neuronal necrosis, and improves outcome.
Immediate-Early Gene Expression in Ovine Brain After Hypothermic Circulatory Arrest: Effects of AptiganelThe Annals of thoracic surgery, 1997Co-Authors: Paula M. Bokesch, Kenneth G. Warner, James E. Marchand, Dermot P Halpin, William R Ranger, Jonathan J. Drummond-webb, Roderick T. Bronson, Richard M. KreamAbstract:
Abstract Background . Altered gene expression occurs in the brain after global ischemia. We have developed a model to examine the effects of cardiopulmonary bypass and hypothermic circulatory arrest (HCA) on the induction of the immediate-early gene c-fos in the brains of neonatal lambs. We then tested the effects of the noncompetitive N -methyl-d-aspartate antagonist, Aptiganel hydrochloride (Cerestat), on c-fos expression and neuronal injury. Methods . Neonatal lambs (weight, 4 to 6 kg) anesthetized with isoflurane were supported by cardiopulmonary bypass, subjected to 90 or 120 minutes of HCA at 15°C, and rewarmed on bypass to 38°C. One hour after cardiopulmonary bypass was terminated, the brains were perfusion fixed and removed for in situ hybridization and immunohistochemical analysis. Some animals survived 3 days before their brains were removed to examine for neuronal necrosis. One group of lambs (n = 20) received Aptiganel (2.5 mg/kg). A second group (n = 25) received saline vehicle only. Results . Increasing duration of HCA induced a corresponding increase in c-fos messenger RNA expression throughout the hippocampal formation and cortex. However, Fos protein synthesis peaked after 90 minutes of HCA and decreased significantly ( p p c-fos messenger RNA expression and Fos protein synthesis after 90 minutes of HCA and preserved Fos protein synthesis after 120 minutes of HCA. Neuronal necrosis was observed in the brains of vehicle-treated lambs after 120 minutes of HCA but was significantly decreased ( p Conclusions . These experiments indicate that the transcriptional processes of immediate-early genes remain intact, whereas translational processes are impaired after prolonged HCA. The inability to synthesize Fos proteins after 120 minutes of HCA was associated with neuronal degeneration. Aptiganel preserved translational processes and caused a significant improvement in the neurologic outcome.
Richard P. Atkinson – One of the best experts on this subject based on the ideXlab platform.
Glutamate AMPA receptor antagonist treatment for ischaemic stroke.Current Medical Research and Opinion, 2002Co-Authors: Paul T. Akins, Richard P. AtkinsonAbstract:
SUMMARYDuring cerebral ischaemia, glutamate is released in supraphysiological amounts and is toxic to brain tissue. This excitotoxicity is mediated by several glutamate receptor subtypes, including the ionotropic N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. Clinical trials of drugs that block the NMDA receptor in acute ischaemic stroke have been disappointing. No improvement in clinical outcome of stroke has been seen with competitive NMDA antagonists (selfotel) and non-competitive NMDA antagonists (dextrorphan, GV150526, Aptiganel and eliprodil).The AMPA receptor differs in important ways from the NMDA receptor. It is the principal mediator of fast excitatory neurotransmission. This ligand-gated cation channel is primarily permeable to sodium rather than calcium. It is found in grey and white matter.It is expressed by oligodendrocytes. This distribution may provide neuroprotection for both grey and white matter. In a variety of animal models, …
Glutamate AMPA receptor antagonist treatment for ischaemic stroke.Current medical research and opinion, 2002Co-Authors: Paul T. Akins, Richard P. AtkinsonAbstract:
During cerebral ischaemia, glutamate is released in supraphysiological amounts and is toxic to brain tissue. This excitotoxicity is mediated by several glutamate receptor subtypes, including the ionotropic N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. Clinical trials of drugs that block the NMDA receptor in acute ischaemic stroke have been disappointing. No improvement in clinical outcome of stroke has been seen with competitive NMDA antagonists (selfotel) and non-competitive NMDA antagonists (dextrorphan, GV150526, Aptiganel and eliprodil). The AMPA receptor differs in important ways from the NMDA receptor. It is the principal mediator of fast excitatory neurotransmission. This ligand-gated cation channel is primarily permeable to sodium rather than calcium. It is found in grey and white matter. It is expressed by oligodendrocytes. This distribution may provide neuroprotection for both grey and white matter. In a variety of animal models, reduction in infarct volume with AMPA blockade has been demonstrated. AMPA antagonists also show benefit in spinal cord ischaemia and trauma. The clinical development of safe and effective AMPA blockers has been hampered by poor water solubility and associated renal toxicity. A novel, highly water-soluble, competitive AMPA receptor antagonist, YM872 ([2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic acid monohydrate; Yamanouchi), has been identified. Phase I clinical trial data indicate that this agent can be safely administered in young and elderly subjects. Sedation and other CNS associated adverse events determine the ceiling dose and become more problematic with infusion times exceeding 24 h. Phase II studies of YM872 in acute ischaemic stroke are ongoing.