Clinical experience with excitatory amino acid antagonist drugs.

BACKGROUND Excitotoxic damage due to excess release of neuronal glutamate is hypothesized to play a pivotal role in the pathogenesis of focal cerebral ischemia. Drugs that antagonize excitatory amino acid function are consistently neuroprotective in preclinical models of stroke, and many are now entering clinical trials. SUMMARY Antagonists of the N-methyl-D-aspartate (NMDA) receptor are furthest advanced in clinical development for stroke. Both noncompetitive (aptiganel hydrochloride, dextrorphan) and competitive (selfotel, d-CPPene) antagonists have undergone tolerability studies in acute stroke and traumatic brain injury. These agents all cause a similar spectrum of neuropsychological symptoms, and several have important cardiovascular effects. Other modulatory sites on the NMDA receptor complex, notably the polyamine and magnesium ion sites, are also the subject of clinical trials. Glycine site antagonists are in early clinical development. Non-NMDA glutamate receptor antagonists remain in preclinical study. Neuroprotection by agents that block glutamate release in vitro may be due to sodium channel blockade in vivo, but some agents (619C89) exhibit neurological effects similar to NMDA antagonists in stroke. The therapeutic index is unknown for different drugs but may be determined by cardiovascular effects, especially hypotension, which may be detrimental after stroke. CONCLUSIONS Excitatory amino acid antagonists are in advanced development in the treatment of stroke and traumatic brain injury. A similar pattern of side effects is apparent with the majority of agents. However, cardiovascular effects may ultimately define therapeutic index for each drug.

[1]  J. Posner,et al.  The Tolerability, Pharmacokinetics and Pharmacodynamics of Increasing Intravenous Doses of 619C89, a Novel Compound for the Acute Treatment of Stroke, in Healthy Volunteers , 1995, Annals of the New York Academy of Sciences.

[2]  K. Lees,et al.  A Randomized, Double‐Blind, Placebo‐Controlled Ascending Dose Tolerance Study of 619C89 in Acute Stroke , 1995, Annals of the New York Academy of Sciences.

[3]  R. Bullock,et al.  Evidence for Prolonged Release of Excitatory Amino Acids in Severe Human Head Trauma , 1995, Annals of the New York Academy of Sciences.

[4]  K. Lees,et al.  Systemic and Cerebral Hemodynamic Responses to the Noncompetitive N-Methyl-D-Aspartate (NMDA) Antagonist CNS 1102 , 1995, Journal of cardiovascular pharmacology.

[5]  G. Albers,et al.  Safety, Tolerability, and Pharmacokinetics of the N-Methyl-d-Aspartate Antagonist Dextrorphan in Patients With Acute Stroke , 1995 .

[6]  K. Lees,et al.  Pharmacological effects of the non-competitive NMDA antagonist CNS 1102 in normal volunteers. , 1994, British journal of clinical pharmacology.

[7]  N. Wahlgren,et al.  Intravenous Nimodipine West European Stroke Trial (INWEST) of Nimodipine in the Treatment of Acute Ischaemic Stroke , 1994 .

[8]  S. Curry,et al.  Brain uptake and biotransformation of remacemide hydrochloride, a novel anticonvulsant. , 1994, Drug metabolism and disposition: the biological fate of chemicals.

[9]  R. Sacco,et al.  Prophylactic Neuroprotection for Cerebral Ischemia , 1994, Stroke.

[10]  D. Graham,et al.  Neuroprotective Effect of the AMPA Receptor Antagonist LY-293558 in Focal Cerebral Ischemia in the Cat , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  V. Meininger,et al.  A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. , 1994, The New England journal of medicine.

[12]  S. Lipton,et al.  Excitatory amino acids as a final common pathway for neurologic disorders. , 1994, The New England journal of medicine.

[13]  L. Rowland.  Riluzole for the treatment of amyotrophic lateral sclerosis--too soon to tell? , 1994, The New England journal of medicine.

[14]  J. Krystal,et al.  Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. , 1994, Archives of general psychiatry.

[15]  E. Boltshauser,et al.  Drug refractory epilepsy in brain damage: effect of dextromethorphan on EEG in four patients. , 1994, Journal of neurology, neurosurgery, and psychiatry.

[16]  J. Rho,et al.  Mechanism of action of the anticonvulsant felbamate: Opposing effects on N‐methyl‐D‐aspartate and γ‐aminobutyric acidA receptors , 1994, Annals of neurology.

[17]  M. Backonja,et al.  Response of chronic neuropathic pain syndromes to ketamine: a preliminary study , 1994, Pain.

[18]  K. Hossmann.  Glutamate‐Mediated Injury in Focal Cerebral Ischemia: The Excitotoxin Hypothesis Revised , 1994, Brain pathology.

[19]  S. Lipton.  Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide , 1993, Trends in Neurosciences.

[20]  R. Simon,et al.  A study of the dose dependency of a glycine receptor antagonist in focal ischemia. , 1993, The Journal of pharmacology and experimental therapeutics.

[21]  J. Olney,et al.  Neuronal Vacuolization and Necrosis Induced by the Noncompetitive N-methyl-d-aspartate (NMDA) Antagonist MK(+)801 (Dizocilpine Maleate): A Light and Electron Microscopic Evaluation of the Rat Retrosplenial Cortex , 1993, Experimental Neurology.

[22]  B. Meldrum,et al.  The pyrimidine-derivative, BW1003C87, protects CA1 and striatal neurons following transient severe forebrain ischaemia in rats. A microdialysis and histological study , 1993, Neuroscience.

[23]  M. Rigby,et al.  Lack of effect of L‐687,414 ((+)‐cis‐4‐methyl‐HA‐966)5 an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology , 1993, British Journal of Pharmacology.

[24]  R. Porter,et al.  Inhibition of Succinate Dehydrogenase by Malonic Acid Produces an “Excitotoxic” Lesion in Rat Striatum , 1993, Journal of neurochemistry.

[25]  A. Baker,et al.  Excitatory amino acids in cerebrospinal fluid following traumatic brain injury in humans. , 1993, Journal of neurosurgery.

[26]  B L Miller,et al.  Progressive right frontotemporal degeneration: clinical, neuropsychological and SPECT characteristics. , 1993, Dementia.

[27]  M. Jackson.  Cerebral arterial narrowing with nicotine patch , 1993, The Lancet.

[28]  G. Donnan,et al.  Prognostic value of reperfusion during first 48 hours of ischaemic stroke , 1993, The Lancet.

[29]  F. Sharp,et al.  BW619C89, a Glutamate Release Inhibitor, Protects Against Focal Cerebral Ischemic Damage , 1993, Stroke.

[30]  I. Øye,et al.  The effect of CPP in neurogenic pain: inhibition of spinal or cortical NMDA receptors? , 1993, Pain.

[31]  J. Bormann,et al.  Neuroprotective effects of memantine , 1992, Neurology.

[32]  G. Marchal,et al.  PET imaging of cerebral perfusion and oxygen consumption in acute ischaemic stroke: relation to outcome , 1993, The Lancet.

[33]  C. Sotak,et al.  Effects of a novel NMDA antagonist on experimental stroke rapidly and quantitatively assessed by diffusion‐weighted MRI , 1993, Neurology.

[34]  H. Munro,et al.  The cardiovascular response to ketamine: the effects of clonidine and lignocaine , 1993, Acta anaesthesiologica Scandinavica.

[35]  W. Schmidt,et al.  Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats. , 1992, European journal of pharmacology.

[36]  T. Gordh,et al.  The NMDA-receptor antagonist CPP abolishes neurogenic ‘wind-up pain’ after intrathecal administration in humans , 1992, Pain.

[37]  S. Warach,et al.  Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[38]  H. Adams,et al.  [The action of S-(+)-ketamine on serum catecholamine and cortisol. A comparison with ketamine racemate]. , 1992, Der Anaesthesist.

[39]  R. Sachdeo,et al.  Felbamate monotherapy: Controlled trial in patients with partial onset seizures , 1992, Annals of neurology.

[40]  J. Mcculloch,et al.  Excitatory amino acid antagonists and their potential for the treatment of ischaemic brain damage in man. , 1992, British journal of clinical pharmacology.

[41]  R. Görtelmeyer,et al.  Memantine in the treatment of mild to moderate dementia syndrome. A double-blind placebo-controlled study. , 1992, Arzneimittel-Forschung.

[42]  E. Domino.  Chemical dissociation of human awareness: focus on non-competitive NMDA receptor antagonists , 1992, Journal of psychopharmacology.

[43]  R. Albin,et al.  Alternative excitotoxic hypotheses , 1992, Neurology.

[44]  B. Scatton,et al.  SL 82.0715, an NMDA antagonist acting at the polyamine site, does not induce neurotoxic effects on rat cortical neurons , 1992, Neuroscience Letters.

[45]  K Wienhard,et al.  Progressive Derangement of Periinfarct Viable Tissue in Ischemic Stroke , 1992, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[46]  O. Paulsen,et al.  Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors. , 1992, The Journal of pharmacology and experimental therapeutics.

[47]  M. Beal,et al.  Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? , 1992, Annals of neurology.

[48]  J. Olney,et al.  NMDA antagonist neurotoxicity: mechanism and prevention. , 1991, Science.

[49]  L. Noble,et al.  MK‐801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex , 1991, Annals of neurology.

[50]  G. Pledger,et al.  Felbamate for partial seizures , 1991, Neurology.

[51]  J. Mcculloch,et al.  Effects of chronic administration of MK-801 upon local cerebral glucose utilisation and ligand binding to the NMDA receptor complex , 1991, Brain Research.

[52]  D. Soutif,et al.  Sexual disturbances during omeprazole therapy , 1991, The Lancet.

[53]  J. Kornhuber,et al.  Pharmacotoxic psychosis after memantine in Parkinson's disease , 1991, The Lancet.

[54]  E. Kochs,et al.  Concurrent increases in brain electrical activity and intracranial blood flow velocity during low-dose ketamine anaesthesia , 1991, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[55]  D. Javitt,et al.  Recent advances in the phencyclidine model of schizophrenia. , 1991, The American journal of psychiatry.

[56]  R. Bullock,et al.  Evaluation of a competitive NMDA antagonist (D‐CPPene) in feline focal cerebral ischemia , 1991, Annals of neurology.

[57]  E. Aizenman,et al.  Oxygen free radicals regulate NMDA receptor function via a redox modulatory site , 1990, Neuron.

[58]  C. Rossberg,et al.  Neuroprotective effect of memantine demonstrated in vivo and in vitro. , 1990, European journal of pharmacology.

[59]  J. Church.  Dextromethorphan, dysphoria and NMDA receptors. Neuromodulatory effects of dextromethorphan: role of NMDA receptors in responses. , 1990, Trends in pharmacological sciences.

[60]  A. Foster,et al.  Protection Against N‐methyl‐D‐aspartate Receptor‐Mediated Neuronal Degeneration In Rat Brain by 7‐chlorokynurenate and 3‐amino‐1‐hydroxypyrrolid‐2‐one, Antagonists at The Allosteric Site for Glycine , 1990, The European journal of neuroscience.

[61]  D. Lodge,et al.  Noncompetitive excitatory amino acid receptor antagonists. , 1990, Trends in pharmacological sciences.

[62]  F. Tortella,et al.  Dextromethorphan and neuromodulation: old drug coughs up new activities. , 1989, Trends in pharmacological sciences.

[63]  J. Bormann.  Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels. , 1989, European journal of pharmacology.

[64]  J. Olney,et al.  Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. , 1989, Science.

[65]  G. Albers,et al.  N‐methyl‐D‐aspartate antagonists: Ready for clinical trial in brain ischemia? , 1989, Annals of neurology.

[66]  D. Reich,et al.  Ketamine: an update on the first twenty-five years of clinical experience , 1989, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[67]  D. Graham,et al.  Focal Cerebral Ischaemia in the Cat: Treatment with the Glutamate Antagonist MK-801 after Induction of Ischaemia , 1988, Journal of Cerebral Blood Flow and Metabolism.

[68]  J. Mcculloch,et al.  The glutamate antagonist MK‐801 reduces focal ischemic brain damage in the rat , 1988, Annals of neurology.

[69]  D. Graham,et al.  Protective Effect of the Glutamate Antagonist, MK-801 in Focal Cerebral Ischemia in the Cat , 1988, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[70]  D. Greenberg,et al.  Dextromethorphan and dextrorphan as calcium channel antagonists , 1988, Brain Research.

[71]  G. Fagg,et al.  Taking apart NMDA receptors , 1987, Nature.

[72]  P. Ascher,et al.  Glycine potentiates the NMDA response in cultured mouse brain neurons , 1987, Nature.

[73]  W. Fleischhacker,et al.  Memantine in the treatment of senile dementia of the Alzheimer type , 1986, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[74]  M. Gold,et al.  Heart Rate and Blood Pressure Effects of Esmolol after Ketamine Induction and Intubation , 1986, Anesthesiology.

[75]  M. Rock,et al.  Use of ketamine in asthmatic children to treat respiratory failure refractory to conventional therapy , 1986, Critical care medicine.

[76]  G. Thompson,et al.  Differential effects of ketamine isomers on neuronal and extraneuronal catecholamine uptake mechanisms. , 1986, Anesthesiology.

[77]  D. Choi,et al.  Glutamate neurotoxicity in cortical cell culture is calcium dependent , 1985, Neuroscience Letters.

[78]  S. Rothman.  Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[79]  J. Bion.  Infusion analgesia for acute war injuries A comparison of pentazocine and ketamine , 1984, Anaesthesia.

[80]  T. Stefánsson,et al.  Hemodynamic and Metabolic Effects of Ketamine Anesthesia in the Geriatric Patient , 1982, Acta anaesthesiologica Scandinavica.

[81]  P. White,et al.  Ketamine--its pharmacology and therapeutic uses. , 1982, Anesthesiology.

[82]  A. B. Gould,et al.  Development of tolerance to ketamine in an infant undergoing repeated anesthesia. , 1981, Anesthesiology.

[83]  T. Schorn,et al.  Are there long-term effects of ketamine on the central nervous system? , 1980, British journal of anaesthesia.

[84]  U. Hörnchen,et al.  [Investigations on the mechanism of the effects of ketamine (Ketanest) on circulation and respiration (author's transl)]. , 1980, Der Anaesthesist.

[85]  M. Fauman,et al.  Chronic phencyclidine (PCP) abuse: a psychiatric perspective. , 1980, Journal of psychedelic drugs.

[86]  W. Erdmann,et al.  Antagonism of the cardiovascular effects of ketamine by diazepam in volunteers. , 1979, Acta anaesthesiologica Belgica.

[87]  K. Hougaard,et al.  The Effect of Ketamine on Regional Cerebral Blood Flow in Man , 1974, Anesthesiology.

[88]  M. Johnstone,et al.  Sernyl (CI-395) in clinical anaesthesia. , 1959, British journal of anaesthesia.

[89]  G. Rosenbaum,et al.  Study of a new schizophrenomimetic drug; sernyl. , 1959, A.M.A. archives of neurology and psychiatry.

[90]  F. Greifenstein,et al.  A STUDY OF A 1‐ARYL CYCLO HEXYL AMINE FOR ANESTHESIA* , 1958, Anesthesia and analgesia.

[91]  Y. Shinohara,et al.  Aggravated ischemic magnetic resonance imaging findings in patients with chronic cerebrovascular disease without apparent clinical worsening. , 1994, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[92]  M. Iacoboni,et al.  White matter changes and ventricular enlargement on magnetic resonance imaging: Comparison between normal elderly subjects and patients with cerebrovascular disorders. , 1994, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[93]  J. Kemp,et al.  The glycine site of the NMDA receptor--five years on. , 1993, Trends in pharmacological sciences.

[94]  J. Hutchison,et al.  Antiepileptic and neuroprotective potential of remacemide hydrochloride , 1993 .

[95]  W. Pulsinelli,et al.  Antagonism of the NMDA and non-NMDA receptors in global versus focal brain ischemia. , 1993, Progress in brain research.

[96]  E. Domino.  Status of Ketamine in Anesthesiology. , 1992 .

[97]  A. Korczyn,et al.  Efficacy of memantine, an NMDA receptor antagonist, in the treatment of Parkinson's disease , 1992, Journal of neural transmission. Parkinson's disease and dementia section.

[98]  A. Guidotti.  Neurotoxicity of excitatory amino acids , 1990 .

[99]  K. Jansen.  Ketamine--can chronic use impair memory? , 1990, The International journal of the addictions.

[100]  P. Wender,et al.  The use of MK-801, a novel sympathomimetic, in adults with attention deficit disorder, residual type. , 1986, Psychopharmacology bulletin.

[101]  F. Broughton Pipkin,et al.  Ketamine hypertension and the renin-angiotensin system. , 1983, Clinical and experimental hypertension. Part A, Theory and practice.

[102]  T. Pedersen,et al.  [Effect of diazepam on cardio-vascular and psychotomimetic action of ketamine administered as continuous intravenous drip. Double-blind study (author's transl)]. , 1981, Anesthesie, analgesie, reanimation.

[103]  E. Domino.  PCP (phencyclidine), historical and current perspectives , 1981 .

[104]  P. Mcgeer,et al.  Kainic acid as a tool in neurobiology , 1978 .

[105]  J. Mcculloch,et al.  Journal of Cerebral Blood Flow and Metabolism Effects of Mk-801 upon Local Cerebral Glucose Utilisation in Conscious Rats and in Rats Anaesthetised with Halothane , 2022 .