(Stroke. 1995;26:503-513.)
© 1995 American Heart Association, Inc.
Articles |
Clinical Experience With Excitatory Amino Acid Antagonist Drugs
From the University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland.
Correspondence to Keith W. Muir, MRCP, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland G11 6NT.
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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.
Key Words: cerebral ischemia • clinical trials • drug therapy • excitatory amino acids
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Introduction |
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Over the past 10 years the excitatory amino acid (EAA) neurotransmitter glutamate has been hypothesized to have a pivotal role in the pathogenesis of neuronal death due to acute focal or global ischemia of the central nervous system (CNS). There is also increasing evidence that EAA-mediated processes contribute significantly to long-term progressive neuronal loss in conditions such as epilepsy, Huntington's disease, amyotrophic lateral sclerosis (ALS), or AIDS-related dementia.1 A key factor in recognizing the importance of EAAs has been the consistent finding that drugs that antagonize EAA transmission reduce the volume of cerebral infarction resulting from experimental stroke, and many drugs are now entering clinical trials in humans. While the consistent neuroprotection by EAA antagonist drugs holds great promise for the development of viable therapy in humans, there are also concerns over their potential neurotoxicity2 and behavioral side effects,3 particularly if longer-term therapy in chronic CNS diseases is contemplated. This article reviews the available information on the tolerability of compounds that have undergone trials in humans.
Glutamate is the most abundant excitatory neurotransmitter in the human
CNS, being stored in presynaptic vesicles and released in response to
presynaptic neuronal membrane depolarization. Reuptake mechanisms in
presynaptic neurons and glial cells limit the synaptic concentration of
glutamate under physiological conditions. Postsynaptic glutamate
receptors may be divided into two major types, metabotropic and
ionotropic. Metabotropic receptors are coupled to intracellular second
messenger systems, especially the phosphatidylinositol pathways, and
have an as yet incompletely understood physiological role. Their
contribution to CNS ischemic injury appears to be complex. Ionotropic
receptors are ligand-gated ion channels that mediate rapid changes in
postsynaptic membrane permeability to sodium or calcium. Subtypes of
ionotropic receptors are defined by the binding affinity of the
specific synthetic ligands N-methyl-D-aspartate
(NMDA) and 
-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA). The AMPA receptor also mediates the effects of kainic acid (KA)
and is sometimes referred to as the AMPA/KA receptor.
Even transient exposure to excess EAAs is toxic to cultured neurons. Additionally, ischemic neuronal injury in vitro is dependent on synaptic EAA release,4 giving rise to the concept of "excitotoxicity."5 NMDA-mediated elevation of intracellular free calcium appears to be pivotal in the initiation of irreversible cell death.6 Excess synaptic glutamate concentrations result from both excessive presynaptic release and failure of reuptake, due to energy failure of ion exchange systems and resultant membrane depolarization. Elevation of EAA concentrations in in vivo focal ischemia models is only transient, however, and EAA antagonist drugs may have other modes of action beyond blockade of synaptic EAA transmission.7 It has been demonstrated that compromised neuronal energy balance may render even physiological concentrations of EAAs excitotoxic8 (giving rise to the concept of "chronic" or "weak" excitotoxicity9 10 ). In contrast to experimental stroke, many patients with traumatic brain injury (TBI) have been found to have significant elevation of extracellular fluid glutamate for protracted periods,11 12 probably due to prolonged and fluctuating ischemia. These data suggest that acute ischemic processes in humans may progress over a period of hours, presumably relating to the "ischemic penumbra" (a region of reduced perfusion in which neurons remain viable for a period of time after onset of ischemia) around the central core of an infarct. Delayed pharmacological intervention with some agents significantly reduces the volume of infarcted tissue in standard models of stroke,13 but an important unresolved issue remains the duration of the therapeutic window in humans.
Ionotropic glutamate receptors possess a number of modulatory sites amenable to pharmacological intervention.14 There also are agents that may modulate the presynaptic release of glutamate. There is consistent experimental evidence of the efficacy of ionotropic glutamate receptor blockers and of glutamate release inhibitors in reducing the volume of histological cerebral infarction after permanent or transient focal cerebral ischemia.
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Modulatory Sites in Glutamatergic Pathways |
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An outline of excitotoxic pathways and potential sites of therapeutic intervention is shown in Fig 1
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Postsynaptic
The best characterized ionotropic receptor is the NMDA receptor, a
more detailed view of which is presented in Fig 2.
The NMDA receptor complex is a ligand-gated ion channel that increases
membrane conductance of sodium and calcium ions when activated. It
requires combined stimulation by glutamate and the coagonist glycine,
but additionally, membrane depolarization must occur to overcome a
voltage-dependent block of the ion channel by magnesium ions.
Recognized sites for pharmacological action include the glutamate and
glycine recognition sites themselves; a site within the ion channel
distinct from the magnesium site that may be blocked by phencyclidine
(PCP) and related compounds when the ion channel is in an open, active
state; a polyamine site; and a redox site, where a disulfide bond
renders the NMDA receptor proteins amenable to conformational change in
response to different redox states.
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Noncompetitive NMDA Antagonists (Open-Channel Blockers)
Noncompetitive antagonists exert a state-dependent and
use-dependent block: ie, both the ion channel must be open and the
voltage-dependent magnesium block must be overcome by postsynaptic
membrane depolarization for the drug to reach its binding site. For
this reason, they are often known as open-channel blockers: Lipton et
al15 proposed the term "uncompetitive antagonist"
since these drugs do not act at a site that is completely independent
of the endogenous agonist. Because these drugs can bind only in an open
ion channel (ie, the receptor must be activated), drug will tend to
accumulate in regions in which the concentration of glutamate is
highest (ie, the receptor has the greatest likelihood of being
activated), provided that the concentrations of drug and receptor are
approximately equal. Noncompetitive NMDA antagonists exhibit a spectrum
of binding affinities for the ion-channel site but have notionally been
divided into high-affinity and low-affinity blockers (see the
Table). High-affinity blockers bind rapidly and
dissociate slowly from the ion channel (a long "off time"). After
drug administration, therefore, increasing numbers of receptors become
blocked over the course of several hours until steady state is
achieved. Low-affinity blockers in contrast have a much more rapid off
time from the ion-channel site and thus may impede physiological EAA
transmission less. These electrophysiological differences between
noncompetitive antagonists form the basis for the proposal that
low-affinity blockers may be associated with fewer adverse effects than
high-affinity blockers.16
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There is consistent experimental evidence of efficacy for noncompetitive antagonists, which reduce cortical infarct volume by 50% or more17 18 when preadministered in middle cerebral artery occlusion (MCAO) models. NMDA antagonists are not neuroprotective in circumstances of extremely dense ischemia with negligible residual blood flow—for example, the caudate nucleus in MCAO models, MCAO in the spontaneously hypertensive rat, or four-vessel occlusion global ischemia models. This may be due to the primacy of non–receptor-mediated neuronal calcium overload when near absence of blood flow causes energy failure of ion channels (especially the sodium-calcium exchanger).19
Older agents. The archetypal noncompetitive NMDA antagonist is PCP, which was developed in the 1950s as an anesthetic agent but which has subsequently been used mainly in psychiatric research as a chemical model of schizophrenia; it is also encountered as a drug of abuse ("angel dust"). IV administration of PCP in anesthetic doses produces a state of catalepsy, in which consciousness is maintained (eyes remain open), but subjects respond poorly to stimuli, and the majority experience potent analgesia.20 PCP 10 mg IM was noted to induce a state of euphoria and analgesia that was suitable for premedication, and 10 to 20 mg IV as the sole anesthetic was often adequate for major surgery.21 Postanesthesia, however, patients (especially young males) experienced marked agitation, disinhibition, and occasionally violent behavior, accompanied by hallucinations and paranoid ideation.20 21 The dose response to PCP in subjects abusing PCP progresses from subjective feelings of light-headedness, anxiety, agitation, and paranoia at doses of 0.014 mg/kg, through nystagmus and gait ataxia, hypertension, marked confusion, and electroencephalograph (EEG) changes at 0.1 mg/kg, then anesthesia and amnesia at 0.25 mg/kg.22 Higher doses are associated with choreiform movements, severe muscle rigidity, catatonia, seizure activity and, ultimately, respiratory depression. Luby et al23 gave 0.1 mg/kg IV to normal volunteers, who exhibited intellectual impairment, vivid recollection of memories, depersonalization, and dissociation from awareness of time or self. Schizophrenics given PCP generally became more aggressive and difficult to manage, although in at least one instance, catatonia was exacerbated for a period of several days. Single doses of PCP may produce prolonged psychotomimetic reactions.20 PCP remains in use in psychiatry research into schizophrenia, as it uniquely models both negative symptoms of altered perception and withdrawal and positive symptoms of paranoia and hallucinations.24 Changes in the EEG of PCP-treated patients demonstrate dissociation between thalamoneocortical and limbic waveforms, leading to the coining of the term "dissociative anesthetic" for PCP and related drugs.25 Similar effects were evident with the PCP derivatives N-ethyl-1-phenylcyclohexamine (CI-400, PCE) and 1-[1-(2-thienyl)cyclohexyl]piperadine (TCP) when given in doses of 0.25 to 0.35 mg/kg IV, and with the racemic compound (±) N-allylnormetazocine (SKF 10047), which also possesses sigma receptor binding affinity.26
Ketamine, an arylcyclohexylamine analogue of PCP with low affinity for the NMDA ion channel, is a racemic compound widely used for anesthesia. The affinity of the S-enantiomer is two to four times that of the R-enantiomer.27 The clinical effects of ketamine are of identical character to those of PCP but are generally of shorter duration. Anesthetic doses of ketamine produce an identical state of catalepsy, associated in a large series of more than 12 000 anesthetized patients28 with vivid dreams in 7% to 9%, nightmares in 2%, hallucinations in 1% to 2%, and psychotomimetic symptoms in 1% on awaking. Other authors29 have reported psychotomimetic emergence symptoms in up to 30% of anesthetized patients. Subanesthetic doses, either intraveneously or intrathecally, are effective for analgesia,30 possibly by altering pain perception rather than reducing nociceptive stimuli. Ketamine analgesia has been advocated for situations in which cardiovascular stability is crucial, such as hypovolemic states after trauma where maintained consciousness and hypertension may be desirable.31 Subanesthetic doses in normal volunteers produce impaired memory registration,27 altered sensory perception,27 and schizophrenia-like symptoms (both hallucinations and negative symptoms32 ). In normal individuals, ketamine in anesthetic doses causes increased voltage and synchronous slow wave activity on the EEG, associated with increased cerebral blood flow velocity in the middle cerebral artery (MCA) on transcranial Doppler ultrasound (TCD)33 and with increases in regional cerebral blood flow.34
Dose-dependent blood pressure elevation is seen with PCP20 and with ketamine. For ketamine, evidence indicates that central sympathetic nervous system stimulation is responsible, with vasoconstriction mediated by direct neuronal activity.35 36 Circulating catecholamine and cortisol levels are elevated by ketamine administration,37 while the renin-angiotensin system shows changes consistent with secondary responses to hypertension.38 Increased peripheral catecholamine levels may be due primarily to inhibition of reuptake mechanisms by ketamine.39 Elevation of catecholamines contributes to ketamine's potent bronchodilator properties,40 which have led to use in severe acute asthmatic patients refractory to standard therapy.41
In anesthetic practice, ketamine is almost always coadministered with a benzodiazepine, usually midazolam,40 since this has been found to reduce the incidence of both psychotomimetic and cardiovascular effects (including neurohumoral responses).37 42 43 This underacknowledged observation could be of great importance for clinical trials of NMDA antagonists in brain ischemia. Clonidine44 and esmolol45 have also been found to abolish cardiovascular responses to ketamine induction of anesthesia, but their influence on psychotomimetic effects has not been studied.
Clinical development of dizocilpine (MK 801), the agent with the highest affinity for the ion-channel site and the first drug consistently shown to be neuroprotective in vivo,18 46 47 was abandoned after safety concerns were raised over brain histology changes in rats (see below). A small number of clinical studies were performed in humans, mostly with long-term oral administration. Oral doses as add-on therapy in patients with refractory epilepsy48 produced minor improvements in seizure activity in a minority of patients and were associated with transient symptoms of agitation (which many epilepsy patients found preferable to the sedating effects of routine anticonvulsants), especially immediately after dose escalation. Oral doses of 0.025 to 0.15 mg/kg were given to adults with attention deficit disorder in an open study of 10 subjects over 6 weeks,49 with improvement in mood in 5 of 10. Associated symptoms were nonspecific. An open trial in 14 subjects with anxiety disorders49 was discontinued due to exacerbation of symptoms in the majority. Studies of intravenous dizocilpine in normal volunteers covered a limited dose range and remain unreported.
Agents currently in clinical trials. Aptiganel hydrochloride (CNS 1102, Cerestat) is a diarylguanidine with high affinity for the NMDA ion-channel site. In healthy male subjects receiving IV bolus50 or 4-hour infusions (K.W.M. et al, unpublished data, 1994), light-headedness, dizziness, and paresthesia are seen at total doses of 30 µg/kg, progressing to disinhibition, nystagmus, and diplopia at 45 µg/kg. Doses of 60 to 100 µg/kg have been associated with paranoid ideation, hallucinations, peripheral vasoconstriction, and catatonia. Aptiganel also causes dose-dependent hypertension in volunteers with rises of mean arterial pressure of up to 30 mm Hg. The rise occurs rapidly after IV bolus or infusion, peaking by 2 hours, and returning to baseline by 3 to 6 hours. Total cerebral blood flow is unaltered, but MCA flow velocity measured by TCD increases as with ketamine.51 Signs of peripheral vasoconstriction accompany the hemodynamic changes. Interestingly, neither the symptoms nor hemodynamic changes seen in volunteers have been replicated in patients after stroke52 who have received total doses of up to 110 µg/kg. Patients with TBI who are paralyzed and ventilated have received doses of up to 268 µg/kg daily without adverse effects.53 Further trials in stroke and TBI are in progress.
The dextrorotatory opioid derivatives dextrorphan and dextromethorphan have both L-type voltage-sensitive calcium channel (VSCC)54 and NMDA ion-channel blocking properties. Dextromethorphan had been used as an antitussive for many years before its recognition as a low-affinity NMDA ion-channel antagonist. Dextrorphan is the O-methylated metabolite of dextromethorphan and has greater affinity for the NMDA ion-channel site. Dextromethorphan has additional affinity for sigma receptors and for an as yet unidentified "dextromethorphan site."55 Dextromethorphan in doses of 30 to 60 mg daily is an effective antitussive. Doses of 60 mg daily were given to patients considered to be at risk of cerebral ischemia56 without any adverse events. Doses of up to 960 mg daily were given to 11 Huntington's disease patients: all experienced worsening of symptoms, and drowsiness and incoordination necessitated drug withdrawal in 6 of 11.57 Oral doses of 60 to 360 mg four times daily begun 6 hours preoperatively and stopped 24 hours postoperatively in 194 neurosurgical patients with vascular lesions or tumors achieved theoretical neuroprotective cerebrospinal fluid levels with transient dizziness in 29%, gait ataxia in 12%, and dysarthria in 4% of those receiving doses of more than 250 mg four times daily.58 Overdose has been associated with psychotomimetic features and dysphoria.59 High doses of dextromethorphan (20 to 42 mg/kg per day) were given to 4 children with resistant epileptic seizure activity with favorable effects on EEG and abolition of seizures in 3 of the 4, but uniformly poor clinical outcome (death in 3 and severe neurological deficit in the 1 survivor).60
Dextrorphan caused dizziness, nystagmus, ataxia, hypokinesia, alterations in mood, paresthesia, flushing, nausea, and vomiting in normal volunteers in doses up to 120 mg/h. Dizziness and tiredness were encountered at doses of 10 mg but became more universal as features of CNS excitation developed. A multicenter ascending dose phase 2 trial of dextrorphan in 67 patients (including 16 placebo subjects) within 48 hours of stroke61 used loading doses of 60 to 260 mg/h over 1 hour followed by ascending maintenance doses for 11 or 23 hours. Total cumulative doses were 475 to 1280 mg over 12 hours or 945 to 2140 mg over 24 hours. Dextrorphan was associated with nystagmus (53% of patients), somnolence (45%), agitation (53%), hallucinations (43%), confusion (51%), and nausea or vomiting (28%). Urticarial reactions at the infusion site were reported in 39%. Transient but highly significant and clinically concerning hypotension occurred in 11 of 51 patients during bolus infusion (decrease in blood pressure of up to 50 mm Hg) and was the dose-limiting effect. During maintenance infusion over 11 or 23 hours, hypertension was recorded in more than 40% of patients. The dose-response relation of initial hypotension has not been defined, and the absence of clinically reportable hypotension does not necessarily equate with absence of an effect. Further development of dextrorphan has been abandoned.
Low-affinity noncompetitive NMDA antagonists. Memantine is the dimethyl derivative of the anti-parkinsonian agent amantidine; it has been used in Germany since the early 1980s as both an anti-parkinsonian agent and an antispastic agent in a variety of chronic neurological diseases including multiple sclerosis. Electrophysiological work well after its introduction to clinical practice revealed its NMDA ion-channel blocking properties62 and neuroprotective efficacy.63 While there is substantial experience with long-term oral administration, there is a lack of placebo-controlled trials, and there are no reports of the effects of short-term IV administration. Side effects of long-term oral administration include vertigo, agitation, and fatigue.64 Short-term oral administration of 10 to 30 mg daily to patients with Parkinson's disease has been associated with psychotic symptoms without improvement of akinesia,65 but amantidine was coadministered. A small open trial66 of memantine 30 mg daily in 14 patients with refractory Parkinson's disease found improvement in bradykinesia in 6 individuals but no effect on other symptoms: 2 patients withdrew with acute confusion and 1 with psychomotor agitation. A double-blind study in 88 patients67 with dementia found functional improvement on memantine 20 mg and commented that the drug was "well tolerated" over a period of 42 days. A single-blind trial68 of daily memantine 20 to 30 mg IV in 10 demented patients found no significant improvement and transient deterioration in 2 of the 10 during drug administration.
Remacemide hydrochloride was developed as an anticonvulsant, and there is substantial clinical experience with long-term oral dosing for epilepsy.69 Remacemide hydrochloride itself has little affinity for the NMDA receptor, but a principal metabolite, remacemide desglycine (FPL 12495), is a low-affinity NMDA antagonist. Both parent compound and metabolite also block VSCCs, which may confer an important non-NMDA–mediated neuroprotective effect. The precise contribution of the parent compound to clinical effect is unknown, but it is hydrolyzed rapidly in the brain or blood-brain barrier to FPL 12495.70
Remacemide hydrochloride has been administered to normal volunteers in single IV doses up to 300 mg69 and multiple oral doses up to 150 mg every 6 hours for 28 days. Dose-related dizziness and gastrointestinal upset were the most commonly reported adverse effects. In humans, remacemide and its active metabolite have elimination half-lives of around 4 and 12 hours, respectively. In a phase 2 trial in 36 cardiopulmonary bypass patients, a prophylactic dose of 150 mg every 6 hours was tolerated without specific adverse effects. A larger study in this group is under way. To date, more than 400 patients with medically refractory epilepsy have been exposed to remacemide hydrochloride69 in doses up to 400 mg every 6 hours, some of whom have received the drug for more than 2 years. Diplopia and somnolence have been observed in some patients also on maintenance carbamazepine therapy, with which remacemide hydrochloride has some pharmacokinetic interaction. Phase 2 trials using IV and oral doses of up to 400 mg every 12 hours are ongoing in stroke patients71 and have, as yet, identified no specific side effects.
Safety of noncompetitive NMDA antagonists. Safety concerns arose after the finding of neuronal vacuolation in the cingulate gyrus and retrosplenial cortex in rats treated acutely with dizocilpine and other high-affinity noncompetitive NMDA antagonists,2 apparently due to a drug-induced increase in neuronal metabolic activity and glucose utilization.72 Vacuoles appear to be enlarged neuronal ultrastructural elements,73 whose demonstration may depend on the method of tissue preparation.73 Only specific neuronal populations are affected.74 At low drug doses, vacuolation is temporary,69 and no functional significance has been demonstrated. The changes resolve spontaneously even with continued drug administration75 and are not seen with preischemic treatment69 even in doses that cause vacuolation acutely. Low-affinity antagonists69 also produce vacuolation, although only in supraneuroprotective doses. High doses of dizocilpine may cause necrosis76 in cultured neurons.
While these changes have been thought to be a class-specific effect of noncompetitive antagonists, identical abnormalities have been observed after administration of competitive NMDA antagonists.77 Polyamine78 or glycine site antagonists79 have not been reported to cause vacuolation.
The increased regional cerebral blood flow seen in humans after ketamine administration may reflect an equivalent process. Ketamine has been used for 30 years, however, and no significant long-term CNS toxicity has been identified,40 80 despite occasional case reports of sequelae.81 Neuronal vacuolation caused by PCP and ketamine is prevented by coadministration of benzodiazepines.82
Magnesium
The magnesium ion blocks the NMDA ion channel in a
voltage-dependent fashion, but electrophysiologically, extracellular
magnesium behaves as a noncompetitive NMDA antagonist. Neuroprotection
in permanent MCAO models and global ischemia models has been
demonstrated with both chloride and sulfate salts. It has the
attraction of being cheap, widely available, and with an established
safety profile, having been used for many years as standard therapy for
preeclampsia in North America. Two preliminary trials of magnesium as
IV magnesium sulfate infused over 24 hours have been conducted with no
evidence of adverse effects.83 84 The optimal dose has yet
to be defined. Phase 3 trials are in planning stages.
Competitive NMDA Antagonists
The original competitive antagonists of the glutamate binding site
were water-soluble compounds that did not cross the blood-brain
barrier, rendering them unsuitable for clinical use. More lipophilic
drugs have subsequently been developed, the prototype compound being
3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP, usually
administered as the dextrorotary stereoisomer), with its derivatives
d-CPPene and CGS 19755. Reported use of CPP in humans has
been limited to intrathecal doses for a patient with chronic pain.
Maximal analgesia was evident after 100 nmol of CPP, and delayed CNS
side effects were evident with severe anxiety, agitation, hyperacusis,
and nightmares for several nights.85 The basis of the
analgesic effect may be inhibition of spinal NMDA receptors or a
central dissociation of nociception from perception of
pain.86
CPPene has been administered orally in patients with refractory epilepsy in two small trials.87 A dosage of 500 mg every 12 hours for 7 days produced mood changes, impaired concentration, and restlessness. Eight patients with refractory complex partial seizures given 250 to 500 mg every 12 hours all reported sedation, ataxia, and confusion. A trial of CPPene in traumatic brain injury in humans has recently been completed.
Selfotel (CGS 19755) has been extensively investigated in normal subjects, patients with stroke or head injury, and those undergoing neurosurgical procedures. Normal subjects experienced light-headedness, anxiety, decreased consciousness level, altered sensory perception, vertigo, ataxia visual distortion, disorientation, and sedation at doses of 2 mg/kg and 3 mg/kg IV bolus. Lower doses were well tolerated. Doses of 6 to 12 mg/kg have been given to sedated head-injured patients without significant drug-related toxicity. By contrast, over half of a group of patients undergoing elective neurosurgical procedures (12 of 21) experienced agitation, dizziness, hallucinations, confusion, ataxia, and paranoia after 2 mg/kg.88 Similar adverse events were evident after doses of 1 or 1.5 mg/kg. A phase 2 trial in 127 acute stroke patients has recently been completed.89 Doses of 2 mg/kg IV every 12 hours resulted in confusion, dysarthria, ataxia, acute paranoid psychosis, and hallucinations in all patients at this dose. Milder symptoms of similar character were seen at lower doses and were deemed to be clinically acceptable at 1.5 mg/kg. Side effects were evident 1 to 3 hours after drug administration in the majority and persisted for up to 60 hours.
Glycine Site Antagonists
Simultaneous binding of glycine to a specific recognition site on
the glutamate receptor protein is required for NMDA channel
activation.90 Endogenous glycine concentrations are
sufficiently high that the site is fully saturated under normal
conditions.91 Partial agonists, such as HA
966,92 L687414, and 1-aminocyclopropanecarboxylic acid
(ACPC), or full antagonists, such as 7-chlorokynurenic
acid92 and its derivatives93 or ACEA 1021,
are efficacious in stroke models. Many experimental compounds cross the
blood-brain barrier only poorly after systemic
administration,91 but compounds with enhanced CNS
penetration (eg, ACPC) are now entering phase 1 volunteer trials in
humans.
The anticonvulsant felbamate has several potential sites of action that
may contribute to its experimental neuroprotective efficacy. It is a
competitive glycine site antagonist at the NMDA receptor and
potentiates 
-amino butyric acid A (GABA-A) receptor–mediated
events.94 GABA-A mediated increased chloride ion
conductance, and consequent membrane hyperpolarization may confer
neuroprotective efficacy. Use of felbamate as an anticonvulsant has
been associated with aplastic anemia, and prescribing has therefore
been restricted to patients with severe refractory epilepsy in whom
therapeutic benefit has been shown. Long-term oral dosing up to 3.6 g
daily has been associated with anorexia, insomnia, and altered
taste95 after substitution of felbamate for standard
anticonvulsant monotherapy, and with headache, ataxia, diplopia,
dizziness, nausea, and vomiting96 when compared with
placebo.
Polyamine Site Antagonists
The endogenous polyamines spermine and spermidine, produced during
amino acid biosynthesis, impede glutamate-mediated neurotoxicity and
appear to bind to a site associated with the NMDA receptor complex that
is distinct from the ion channel. Ifenprodil and eliprodil (SL82.0715)
are synthetic agents that bind to the polyamine site and have
preclinical neuroprotective efficacy. Eliprodil additionally possesses
significant voltage-sensitive calcium antagonist properties and is a
high-affinity ligand for the sigma receptor, whose function remains
unknown. Eliprodil is now in early phase 3 trials in stroke
patients.
In normal volunteers, eliprodil97 in doses of up to 60 mg orally was associated with dose-dependent prolongation of the corrected QT (QTc) interval, vertigo, and drowsiness. Stroke patients have received IV doses of 1.5 and 3 mg twice daily for 3 days, with oral doses of 5 to 10 mg twice daily for 11 days. No psychological effects, cardiovascular changes, or cardiac repolarization abnormalities have been encountered with this dosing regimen.
Redox Site Modulators
Altering the redox state of the disulfide bond of the NMDA
receptor complex modulates ion-channel permeability, such that reducing
states enhance permeability to calcium and sodium and oxidation reduces
transmembrane ion flux.98 This may represent an
endogenous mechanism to reduce free oxygen radical potentiation of
excitotoxicity during reperfusion.99 The oxidizing NO
donor compounds nitroglycerin and sodium nitroprusside are
neuroprotective in vitro. However, the effects of NO on experimental
ischemic injury are complex due to the different effects on endothelial
function (where increased NO tends to attenuate injury) and on neuronal
function (where increased NO tends to exacerbate neuronal injury). The
net effect of exogenous NO in stroke is uncertain. Neither compound is
well suited for clinical use since they each cause profound falls in
blood pressure.
Non-NMDA EAA Antagonists
Experimental characterization of AMPA antagonists is most
advanced, and quinoxaline dione derivatives such as the competitive
AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline
(NBQX) or the noncompetitive antagonist GYKI 52466 are neuroprotective
in both focal and global ischemia models. Poor water solubility and the
brightly colored nature (which prevents study blinding) of the
quinoxaline diones have impeded clinical development, and more recently
developed compounds with improved physicochemical characteristics such
as the competitive antagonist S 17625100 or LY
293558101 are more likely to undergo further development.
AMPA antagonists have exhibited dose-dependent respiratory depression,
associated with a general depression of cerebral
metabolism,101 within the neuroprotective range in
animals, and whether these effects will be separable with further
pharmacological development remains to be seen.
Presynaptic
Glutamate Release Inhibitors
Drugs that block veratrine-induced glutamate release probably do
so by blocking presynaptic voltage-sensitive sodium channels to prevent
membrane depolarization. Wellcome's series of folate-antagonist
derivatives, lamotrigine (clinically used as an anticonvulsant),
1003C87, and 619C89,102 103 104 and the benzothiazole riluzole
are referred to as glutamate release inhibitors on this
basis.104 Lubeluzole (R 87926), the
S-enantiomer of a related benzothiazole, inhibits
glutamate-induced rises in intracellular cyclic guanosine monophosphate
but does not appear to inhibit glutamate release. Drugs that block
sodium channels (eg, phenytoin, carbamazepine, lidoflazine, lifarizine)
have preclinical efficacy in both focal ischemia and white-matter
ischemia models that is independent of EAA antagonism. It has been
cogently argued that the efficacy of glutamate release inhibitors is in
fact due to sodium channel blockade, since neuroprotection is evident
for 619C89 (and for lubeluzole) administered up to 6 hours postischemic
onset, while glutamate release occurs only in the first minutes after
onset of ischemia.105
619C89 is currently in phase 2 trials in stroke and TBI. Volunteer studies in both young and elderly individuals encountered only light-headedness as a side effect at single IV doses up to 1 mg/kg,106 and 619C89 was observed to reduce EEG alpha wave amplitude in a dose-dependent manner. Doses up to 2.0 mg/kg loading dose + 1.0 mg/kg every 8 hours as repeated bolus or continuous infusion over 72 hours have been well tolerated after acute stroke.107 Visual hallucinations were commonly encountered at doses of 2.5 mg/kg + 1.25 mg/kg every 8 hours.
Riluzole has been administered to normal volunteers in short-term oral dosing studies and to patients with ALS in a multicenter efficacy trial.108 Apparent improved outcome due to riluzole treatment in a post hoc subgroup analysis after 12 months is almost undoubtedly an artifact of study randomization.109 Only increased blood pressure and elevated transaminases were reported more frequently in the riluzole-treated group compared with placebo. Riluzole is not being developed for stroke therapy.
Lubeluzole is neuroprotective up to 6 hours after photochemically induced stroke in rats. A phase 2 trial in 232 stroke patients over age 50 using IV infusion of either 15 mg over 1 hour followed by 20 mg/d for 5 days or half of these doses has recently been completed in Europe and Canada. The 7.5 mg + 10 mg/d regime was reported to be well tolerated and has been selected for phase 3 trials.
Kappa opioid agonists (eg, CI 977) and adenosine agonists limit glutamate release in preclinical models. Adenosine agonists limit presynaptic calcium-mediated EAA release and promote postsynaptic membrane hyperpolarization by increasing potassium conductance via A1 receptors. Adenosine A2 receptor–mediated hypotension and cardiac effects are likely to prove dose-limiting in humans, however, unless more subtype-specific drugs are developed.
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Discussion |
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Blockade of the NMDA receptor consistently reduces infarct volume in vivo in focal ischemia models, and optimal pharmacological NMDA blockade is therefore the favored neuroprotective strategy in human stroke trials. Noncompetitive open-channel blockers are pharmacologically attractive since they may be concentrated in ischemic regions where pathological activation of glutamate receptors is greatest. High-affinity blockers may have advantages over low-affinity blockers since their long off time effectively reduces the number of available NMDA receptors. Competitive antagonists may theoretically be outcompeted by very high synaptic glutamate concentrations, and CNS levels may therefore have to be very high to achieve neuroprotection. Low-affinity ion-channel blockers similarly must be present in greater concentration to effectively reduce available receptor numbers, but their receptor binding kinetics may render them preferable for long-term administration, for instance, in epilepsy. Endogenous glycine is present in concentrations sufficient to render the glycine site permanently saturated, and this represents a potential problem of glycine site blocking drugs, which may have to achieve extremely high synaptic concentrations to prevent NMDA receptor activation.
All competitive and noncompetitive NMDA receptor antagonists appear to cause similar symptoms and signs in humans regardless of their pharmacology, if given in large-enough doses. Low doses are associated with altered sensory perception, dysphoria, hypertension, nystagmus, and disorientation, with progression to agitation, paranoia, hallucinations, severe motor retardation, and ultimately catatonia at higher doses. While it has been proposed that low-affinity antagonists will be better tolerated, clinical experience with ketamine does not support this. The possible attenuation of pharmacological effects (including neuronal vacuolation) by benzodiazepines is an inadequately explored area of considerable potential clinical importance. The benzodiazepines may also have advantages over other drugs that have been used to control psychotomimetic effects, such as phenothiazines, since phenothiazines and related antipsychotics may cause hypotension, potentiation of seizures, and irreversible prolonged sedation. While the primary neuroprotective mechanism of 619C89 and its related compounds in vivo may be sodium channel blockade rather than EAA release inhibition, the hallucinogenic effects of high doses of 619C89 are reminiscent of NMDA antagonists and suggest that inhibition of physiological EAA transmission in nonischemic brain regions could cause symptoms. This could also explain the high incidence of adverse effects associated with competitive antagonists: since they do not exert a use-dependent block, no accumulation in regions of high EAA concentrations will occur, and uniformly high brain levels must be achieved to outcompete pathologically elevated synaptic glutamate. If the symptoms associated with NMDA blockade thus reflect impaired physiological EAA transmission, then the lack of symptoms seen so far with polyamine and glycine site antagonists cannot be accounted for, except by invoking non-NMDA–based actions or inadequate dose.
An issue of major clinical importance is whether there are significant
differences in therapeutic index (TI) (the ratio of neuroprotective
dose to doses causing significant toxicity) between EAA antagonist
compounds. Animal data have been advanced to suggest differences in TI
both within the noncompetitive antagonists110 and between
different drug classes.111 Behavioral changes are not
evident with glycine or polyamine site antagonists or the putative
glutamate release inhibitors; however, similar behavioral paradigms
indicated a 10-fold difference in TI of competitive antagonists
compared with noncompetitive antagonists, an observation not borne out
by clinical experience. The adjustment of dose on the basis of symptoms
may be critical since the dose-response curve for neuroprotection in
focal ischemia models (eg, d-CPPene112 ) may be
extremely steep: maximal neuroprotection is separated from no
neuroprotection by only a half-log dose increment, representing
only a 3-fold difference in dose. Fig 3 shows the dose
range between onset of CNS symptoms and the maximal tolerable dose
based on currently available data.
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In humans, TI is likely to be determined by non-EAA antagonist drug properties, principally, their cardiovascular effects. Many sodium channel blocking compounds have significant cardiac effects, particularly prolongation of the QTc interval of the ECG (eg, lifarizine, lubeluzole) with the associated risk of arrhythmogenesis, which may limit dosing or restrict clinical use. Drug-induced hypotension early after stroke appears to reduce critically cerebral perfusion. The Intravenous Nimodipine West European Stroke Trial (INWEST)113 was abandoned due to hypotension-associated worsening of outcome in nimodipine-treated groups compared with placebo. Similar trends were noted in a trial of lifarizine (I.B. Squire et al, unpublished data, 1994). Significant hypotension induced by dextrorphan may relate to VSCC blockade. Cardiovascular toxicity may therefore produce a bell-shaped response, with reduced efficacy at higher doses. Clinical trials designed to administer the maximal tolerable dose as determined by phase 2 studies assume that the dose-response curve for neuroprotection is linear or sigmoid: in some cases, this may be a false assumption.
Conversely, use of agents with multiple neuroprotective actions may be associated with fewer NMDA blockade–mediated side effects while achieving equal neuroprotective efficacy. Felbamate is unlikely to be studied, but other drugs remain in development, notably remacemide (sodium blocking and prodrug NMDA antagonist properties) and lifarizine (sodium and calcium antagonist properties).
Comparison of drugs in humans will require stroke trials larger than are currently feasible unless the sensitivity of outcome measures improves. Clinical development of neuroprotective drugs is likely to be influenced critically by the choice of dose and therapeutic regimen for efficacy trials. Since large multicenter efficacy trials are expensive, optimization of the dosing regimen based on adequate phase 2 studies is essential. Pharmacokinetic data for the elderly and in disease states will influence method and duration of drug administration and therefore both toxicity and efficacy. Ideally, dose schedules should be simple (eg, avoiding the need for calculation of weight-adjusted doses; initial administration as a single IV injection rather than infusion) and designed both to achieve maximal CNS levels very rapidly and to maintain levels constant for the duration of ongoing ischemia. The safety and tolerability of relatively large loading IV doses ideally should be determined in phase 1 and 2 studies. Animal studies have not addressed the duration of therapy required and have yet to explore adequately the influence of reperfusion, which appears to be crucial to outcome in human stroke.114 115 Positron emission tomography studies in humans have identified a penumbral region persisting for 48 hours after stroke,116 and this must be assumed at present to be the minimal duration of therapy.
Prophylactic administration of neuroprotective drugs to patients at high risk of cerebral ischemia (eg, those undergoing cardiopulmonary bypass or carotid endarterectomy) represents both a fertile area for trials and a potentially major clinical application.117 Pharmacokinetic data may indicate suitability for prophylaxis: for example, remacemide hydrochloride (as a prodrug NMDA antagonist) or lamotrigine (orally active glutamate release inhibition). A caveat to long-term NMDA receptor antagonist administration is the evidence of tachyphylaxis with dizocilpine in epilepsy48 and with ketamine in patients undergoing repeated anesthetics.118 Prophylactic use of open-channel blockers may therefore be best confined to the perioperative period. Additionally, the "weak excitotoxicity" hypothesized for neurodegenerative diseases requires only physiological EAA concentrations, and EAA antagonists must therefore inhibit physiological EAA transmission—presumably with both short-term effects as noted above and long-term effects such as learning and perceptual problems—to be effective.
Ongoing clinical trials will furnish answers to many of these questions but will doubtless raise issues as yet unanticipated. The therapeutic prospects for stroke, head injury, and many chronic disorders appear more favorable now than at any time previously.
Received November 7, 1994; revision received December 15, 1994; accepted December 16, 1994.
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