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PubMed2002

Measuring cognition in advanced Alzheimer's disease for clinical trials.

Measurement of cognitive dysfunction and treatment response in the early stages of Alzheimer's disease (AD) has used such scales as the Mini-Mental State Examination (MMSE) and the AD Assessment Scale (ADAS). With the exception of clinical rating scales, however, there are only a few objective measures of cognition for tracking progression in advanced AD. Given renewed interest in potential therapies for advanced AD, objective measures of cognition are important for the adequate evaluation of change due to AD progression or therapy. Several cognitive measures for advanced AD are reviewed. One measure, the Severe Impairment Battery (SIB) is reviewed in detail. Preliminary analyses from a trial of memantine show significant change on the SIB in memory (p < 0.001) and visuospatial functions (p < 0.02) over six-months with a trend for language and praxis. Data from a donepezil trial also highlight the importance of accurate assessment in advanced AD.

Aged↗
PubMed1979

In vitro studies on the possible effects of 1-aminoadamantanes on the serotonergic system in M. Parkinson.

Synaptosomes, synaptic vesicles, and membranes were isolated from rat brain homogenates by differential and density gradient centrifugation in sucrose. Synaptosomes incorporated serotonin (5-HT) with two different uptake mechanisms, high affinity: Kt1 = 47 nM and low affinity: Kt2 = 660 nM. Both uptake mechanisms are non-competitively inhibited by the potential antiparkinson drugs 1-aminoadamantane (amantadine, D 1: Ki1 = 57 microM, Ki2 = 96 microM) and 1-amino-3,5-dimethyladamantane (memantine, D 145: Ki1 = 97 microM, Ki2 = 150 microM). The incorporated 5-HT is released from synaptosomes on incubation with high concentrations (0.5--5 mM) of the drugs or on electrical stimulation with rectangular pulses of alternating polarity. Subthreshold concentrations of these drugs (5--50 microM) which are too low to liberate 5-HT increase the electrically stimulated release of 5-HT.--The effect of D 1, D 145, and electrical stimulation on DA release parallels the results observed with 5-HT. The uptake of 5-HT into isolated synaptic vesicles and the binding to isolated nerve ending membranes is non-competitively inhibited by 1-aminoadamantanes. D 145 inhibits the binding of 5-HT to membranes more effectively (Ki = 0.95 mM) than its uptake into vesicles (Ki = 1.2 mM) contrasting with D 1 which is a weaker inhibitor affecting vesicular uptake (Ki = 2.5 mM) slightly more than membrane binding (Ki = 3.1 mM). The results obtained suggest that, in addition to other mechanisms like receptor stimulation, 1-aminoadamantanes may act in parkinsonian patients by enriching the transmitter content in the synaptic cleft.

Adamantane↗
PubMed1998

Effects of glutamate antagonists on the activity of aromatic L-amino acid decarboxylase.

This study examines the hypothesis that glutamate tonically suppresses the activity of the enzyme aromatic L-amino acid decarboxylase (AADC), and hence the biosynthesis of dopamine, to explain how antagonists of glutamate receptors might potentiale the motor actions of L-DOPA in animal models of Parkinson's disease. A variety of glutamate antagonists were therefore administered acutely to normal rats, which were sacrificed 30-60 min later and AADC activity assayed in the substantia nigra pars reticulata (SNr) and corpus striatum (CS). The NMDA receptor-ion channel antagonists MK 801, budipine, amantadine, memantine and dextromethorphan all caused a pronounced in creased in AADC activity, more especially in the SNr than CS. The NMDA glycine site antagonist (R)-HA 966 produced a modest increase in AADC activity in the CS but not SNr, whilst the NMDA polyamine site antagonist eliprodil, the NMDA competitive antagonist CGP 40116 and the AMPA antagonist NBQX were without effect. The results suggest that an increase in dopamine synthesis might contribute to the L-DOPA-facilitating actions of some glutamate antagonists.

Animals↗
PubMed1996

Interactions of excitatory amino acid antagonists with conventional antiepileptic drugs.

Excitatory amino acid antagonists possess anticonvulsant properties in many experimental models of epilepsy and were shown to potentiate the protective activity of conventional antiepileptics against maximal electroshock-induced seizures in mice. Combined treatments of valproate with either D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid or dizocilpine (NMDA antagonists), which provided a 50% protection against maximal electroshock, produced no side-effects, as measured in the chimney test (motor coordination) or passive avoidance task (long-term memory). Valproate alone at its ED50 against maximal electroshock, induced severe adverse effects. The NMDA antagonists, D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid, memantine, procyclidine, and trihexyphenidyl also potentiated the protective activity of conventional antiepileptics but these treatments were associated with considerable side-effects. The non-NMDA receptor antagonists, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline and 1-(amino-phenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine, also enhanced the anticonvulsive action of antiepileptic drugs against maximal electroshock, and these combinations generally resulted in no adverse effects. The potential clinical importance of some combinations of common antiepileptics with excitatory amino acid antagonists is postulated.

Animals↗
PubMed1993

Glutamate receptor antagonists for neuroleptic malignant syndrome and akinetic hyperthermic parkinsonian crisis.

Schizophrenia and Parkinson's disease have been considered inversely related neuropsychiatric disorders since the former has been attributed to increased dopaminergic transmission while the latter is thought to result from loss of dopaminergic neurons. It is in line with this concept that the classical neuroleptic (anti-schizophrenic) drugs cause as a side effect a drug-induced type of Parkinsonism. Most etiopathogenetic models hold that the "neuroleptic malignant syndrome" may result from "over-therapy" of schizophrenia, causing too widespread a block of dopaminergic transmission. The same clinical condition can be triggered by rapid discontinuation of dopaminergic medication in Parkinson's disease. Further, neuroleptic malignant syndrome shares key clinical features such as extrapyramidal motor disturbances and hyperthermia with a severe form of clinical deterioration in Parkinson's disease patients, the akinetic Parkinsonian crisis. Both conditions, neuroleptic malignant syndrome and Parkinsonian crisis, are resistant to anticholinergic treatment but may well respond to drugs with N-methyl-D-aspartate (NMDA) antagonistic properties such as amantadine and memantine. We advocate the use of NMDA receptor antagonists in these medical emergencies and link their clinical efficacy to the common pathophysiological pathway of increased excitatory amino acid neurotransmitter activity in neuroleptic malignant syndrome, Parkinsonian crisis, and dopamine agonist withdrawal states.

Antipsychotic Agents↗
PubMedDate not supplied

Anticonvulsants for soman-induced seizure activity.

This report describes studies of anticonvulsants for the organophosphorus (OP) nerve agent soman: a basic research effort to understand how different pharmacological classes of compounds influence the expression of seizure produced by soman in rats, and a drug screening effort to determine whether clinically useful antiepileptics can modulate soman-induced seizures in rats. Electroencephalographic (EEG) recordings were used in these studies. Basic studies were conducted in rats pretreated with HI-6 and challenged with 1.6 x LD50 soman. Antimuscarinic compounds were extremely effective in blocking (pretreatment) or terminating soman seizures when given 5 min after seizure onset. However, significantly higher doses were required when treatment was delayed for more than 10 min, and some antimuscarinic compounds lost anticonvulsant efficacy when treatment was delayed for more than 40 min. Diazepam blocked seizure onset, yet seizures could recur after an initial period of anticonvulsant effect at doses </=2.5 mg/kg. Diazepam could terminate ongoing seizures when given 5 min after seizure onset, but doses up to 20 mg/kg were ineffective when treatment was delayed for 40 min. The GABA uptake inhibitor, tiagabine, was ineffective in blocking or terminating soman motor convulsions or seizures. The glutamate receptor antagonists, NBQX, GYKI 52466, and memantine, had weak or minimal antiseizure activity, even at doses that virtually eliminated signs of motor convulsions. The antinicotinic, mecamylamine, was ineffective in blocking or stopping seizure activity. Pretreatment with a narrow range of doses of alpha2-adrenergic agonist, clonidine, produced variable protection (40-60%) against seizure onset; treatment after seizure onset with clonidine was not effective. Screening studies in rats, using HI-6 pretreatment, showed that benzodiazepines (diazepam, midazolam and lorazepam) were quite effective when given 5 min after seizure onset, but lost their efficacy when given 40 min after onset. The barbiturate, pentobarbital, was modestly effective in terminating seizures when given 5 or 40 min after seizure onset, while other clinically effective antiepileptic drugs, trimethadione and valproic acid, were only slightly effective when given 5 min after onset. In contrast, phenytoin, carbamazepine, ethosuximide, magnesium sulfate, lamotrigine, primidone, felbamate, acetazolamide, and ketamine were ineffective.

Animals↗
PubMed2000

Restoration and putative protection in Parkinsonism.

Synergistic antiparkinsonian actions of different classes of putative therapeutic agents co-administered with a subthreshold dose of L-3,4-dihydroxyphenylalanine (L-Dopa) (5 mg/kg) in drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice as well as the restorative actions of those compounds in suprathreshold L-Dopa-tolerant MPTP-treated mice subjected to "wearing-off" of L-Dopa efficacy were assessed in a series of experiments. The classes of compounds studied included the noncompetitive NMDA antagonists, memantine, amantadine and MK-801, the anticonvulsive and putative anticonvulsive agents, lamotrigine, FCE 26743, phenytoin, the monoamine oxidase inhibitors, L-Deprenyl, amiflamine, alpha-ethyltryptamine, clorgyline and guanfacine. In this final case, the restorative effects of clonidine and guanfacine were antagonized by the alpha(2)-adrenoceptor antagonist, yohimbine, but not the alpha(1)-adrenoceptor antagonist, prazosin. Within each class of potentially therapeutic agents a differential restorative efficacy was obtained, but the combination of different doses of apomorphine with clonidine failed to restore motor activity. Finally, the neuroprotective actions of acute and subchronic administration of the nitrone spin-trapping compound, alpha-phenyl-tert-butyl nitrone upon the spontaneous motor behaviour and striatal dopamine concentrations of MPTP-treated mice was examined.

Journal Article↗
PubMed2005

Lamotrigine has an anxiolytic-like profile in the rat conditioned emotional response test of anxiety: a potential role for sodium channels?

RATIONALE: Many anticonvulsants are used in disorders other than epilepsy. For example, lamotrigine is reported to be effective in post-traumatic stress disorder and mania. OBJECTIVE: We assessed the effects of the anticonvulsants lamotrigine, valproate and carbamazepine in an animal model of anxiety. We assessed a wide range of pharmacological tools to delineate the mechanism of lamotrigine's anxiolytic effect. METHODS: We assessed these compounds in the rat conditioned emotional response (CER) test of anxiety. RESULTS: Lamotrigine (30-80 mg/kg) dose-dependently and reproducibly engendered an anxiolytic response in this test, with similar efficacy to benzodiazepines. Carbamazepine (20-40 mg/kg) and riluzole (10 mg/kg), which block Na+ channels by a similar mechanism as lamotrigine, were also anxiolytic. By contrast, valproate (100-600 mg/kg) was inactive and appears to differ in its interaction with Na+ channels. The SSRI paroxetine, the GABA(A) receptor positive modulator propofol, the NMDA antagonists memantine and (+)MK-801, and the Ca2+ channel antagonist nifedipine were all inactive in the CER test, suggesting these mechanisms may not mediate the anxiolytic effect of lamotrigine. More directly, we showed that the anxiolytic effect of lamotrigine could be blocked by co-administering rats with the Na+ channel activator veratrine (0.1 mg/kg). By contrast, neither the Ca2+ channel agonist BAYK8644 (0.5 mg/kg) nor the 5-HT1A or 5-HT(1/2) antagonists WAY100635 (0.3 mg/kg) and metergoline (3 mg/kg), respectively, were able to block the effect. CONCLUSION: Lamotrigine's anxiolytic effect in the CER test may be mediated via block of Na+ channels, and this may represent a target for the development of novel anxiolytics.

Animals↗
PubMed2000

Pharmacological reversal of behavioral and cellular indices of cocaine sensitization in the rat.

RATIONALE AND OBJECTIVES: Behavioral sensitization has been proposed as an animal model for the intensification of drug craving in cocaine addiction. Interactions between dopamine and glutamate systems are important for the induction and maintenance of sensitization. The goal of this study was to determine if established cocaine sensitization could be reversed by pharmacological manipulation of these transmitter systems. METHODS: Rats received 15 mg/kg cocaine (IP) on days 1-10 and were challenged with cocaine (10 mg/kg) on day 13 to verify that sensitization had occurred. On days 14-20, separate groups of sensitized rats received daily injections of dopamine D1- or D2-class agonists, an NMDA receptor antagonist, or a dopamine agonist with an NMDA antagonist. Three days or 2 weeks later, all rats were again tested for their response to cocaine to determine if sensitization had been reversed. RESULTS: Reversal of sensitization was produced by repeated administration of either a D1-class agonist (SKF 81297) or the combination of an NMDA receptor antagonist and a D2-class agonist. Effective combinations were cocaine+MK-801, quinpirole+MK-801, quinpirole+CGS 19755, and pergolide+memantine. The latter drugs are approved for human use. Reversal of sensitization persisted for at least 2 weeks after cessation of drug treatment. Electrophysiological studies revealed that these drug treatments also reversed dopamine D1 receptor supersensitivity in the nucleus accumbens, a cellular correlate of sensitization. CONCLUSIONS: These results demonstrate that pharmacotherapy can reverse behavioral and cellular adaptations associated with repeated cocaine administration, and may do so without the need for continued medication.

Animals↗
PubMed1998

Ethanol and N-methyl-D-aspartate receptor complex interactions: a detailed drug discrimination study in the rat.

The discriminative stimulus properties of compounds that interact with the NMDA receptor complex were investigated in rats trained to discriminate ethanol from saline. Male Wistar rats were trained in a two-lever operant drug discrimination paradigm to make differential responses [fixed ratio 10 (FR10)] for food after ethanol (1 g/kg i.p.; 12% v/v ethanol solution) and saline vehicle injections. Drug effects were assessed by means of generalization and antagonism tests. In the generalization tests, the noncompetitive NMDA antagonists acting at the ion channel dizocilpine, memantine, phencyclidine (PCP) and the sigma1 receptor agonists (+)-pentazocine and (+)-N-allyl-normetazocine (NANM) dose-dependently generalized for ethanol, whereas the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) antagonist GYKI 52466, the glycine antagonists L-701,324 and MRZ 2/502, the polyamine site antagonist arcaine and the polyamine site ligand spermidine, did not. Our results show that the noncompetitive NMDA antagonists fully substitute dose-dependently for ethanol in a drug-discrimination task. The ethanol-like discriminative stimulus effects of PCP, pentazocine and NANM, which are also sigma receptor ligands, are likely to be attributed to their activity at NMDA receptors. We therefore assume that some of the acute effects of ethanol are mediated via NMDA receptor antagonism at the PCP binding site.

Animals↗
PubMed2003

Efficacy, safety and cost of new drugs acting on the central nervous system.

OBJECTIVE: To examine the degree of innovation of the products with indications for CNS diseases approved for the European market through the centralized procedure. METHODS: This paper examines the documentation available on nine products approved by the European Medicines Evaluation Agency in its first years of activity. RESULTS: The Committee for Proprietary Medicinal Products approved only five products by consensus (levacetylmethadol, levetiracetam, olanzapine, pramipexole, riluzole). Four were approved by majority (entacapone, memantine, rivastigmine, zaleplon). One product received a negative opinion, and five had the application withdrawn before reaching the Committee decision. CONCLUSIONS: An analysis of the efficacy and safety profile of these products indicates that few minor therapeutic advances have been achieved in this area. Most approved products cover needs already met, at higher cost, without substantial improvement.

Central Nervous System Agents↗
PubMed2006

From benefit to damage. Glutamate and advanced glycation end products in Alzheimer brain.

The glutamatergic system is the most widespread neurotransmitter system in the mammalian brain. It is connected to the acetylcholinergic neurotransmitter system to form the glutamatergic/aspartatergic-acetylcholinergic circuit, which is the morphobiochemical basis of learning, memory and cognition assisted by the glutamatergic N-methyl-D-aspartate receptor, which mediates long-term potentiation as the fundamental molecular mechanisms of these mental capacities. Glutamate and acetylcholine as ligands of the two neurotransmitter systems are products of the neuronal glucose metabolism as holds true also for advanced glycation end products (AGEs), which are markers of damaged and/or aged proteins. During normal aging, both the neurotransmitters glutamate and acetylcholine undergo strong functional variations. Their synthesis was found to be reduced as a common feature. In contrast, basal release of acetylcholine and receptor number decrease, whereas basal release of glutamate and receptor number increase. AGEs increase during aging obviously preferentially in glutamatergic pyramidal neurons in cerebral cortical layers prone to neurodegeneration. In sporadic Alzheimer disease (SAD), glutamate concentration was shown to fall since it may serve as a substitute for lacking glucose in the beginning of the disease. In contrast, glutamate receptor density was found to be much less involved indicating an excessive activation of the glutamatergic neurotransmitter system particularly via the NMDA receptor, mediating endogenous excitotoxicity. The morphological hallmarks of SAD neuritic plaques and neurofibrillary tangles have been demonstrated to crosslink with AGEs causing an increased rate of free radical production. First data from animal studies and investigations on human beings may indicate that the NMDA receptor antagonist memantine may have beneficial effects on the course of SAD and its clinical symptoms.

Acetylcholine↗
PubMed2006

Medical management of patients with brain tumors.

The most common medical problems in brain tumor patients include the management of seizures, peritumoral edema, medication side effects, venous thromboembolism (VTE), fatigue and cognitive dysfunction. Despite their importance, there are relatively few studies specifically addressing these issues. There is increasing evidence that brain tumor patients who have not had a seizure do not benefit from prophylactic antiepileptic medications. Patients on corticosteroids are at greater risk of Pneumocystis jerovecii pneumonia and may benefit from prophylactic therapy. There is also growing evidence suggesting that anticoagulation may be more effective than inferior vena cava IVC) filtration devices for treating VTE in brain tumor patients and the risk of hemorrhage with anticoagulation is relatively small. Low-molecular weight heparin may be more effective than coumadin. Medications such as modafinil and methylphenidate have assumed an increasing role in the treatment of fatigue, while donepezil and memantine may be helpful with memory loss.

Adrenal Cortex Hormones↗
PubMed2006

Current treatment of mild cognitive impairment and Alzheimer's disease.

Current therapy for Alzheimer's disease (AD) consists of two classes of drugs: the cholinesterase inhibitors, of which there are three currently available medications; and the glutamate modulators, of which there is one. There has been no new information regarding efficacy of the cholinesterase inhibitors or memantine in AD over the past year, but a large, randomized trial concerning mild cognitive impairment was reported. Donepezil delayed conversion to dementia for 12 months but not longer in that trial, whereas vitamin E had no impact on outcomes. The results of the first immunization therapy for AD were released in 2005. Adverse events forced the premature discontinuation of the trial, but there were some grounds for optimism about the basic approach. Several new agents targeted directly at amyloid beta peptide production are currently in clinical trials, but no large studies have been reported over the past year.

Alzheimer Disease↗
PubMed2005

Current Treatment of Nystagmus.

Acquired and congenital nystagmus often causes decreased visual acuity as a direct result of the inability to maintain stable foveal vision. In addition, acquired nystagmus causes a disabling subjective sensation of movement of the visual world called oscillopsia. The eye movements themselves do not require treatment if the patient is asymptomatic. However, therapy is necessary if visual disability is present. Treatments based in pharmacologic mechanisms are preferred. There are few controlled treatment trials and therapeutic efficacy generally is sought in a trial and error approach, depending on the type of nystagmus present. Treatment with 3,4-diaminopyridine and 4-aminopyridine recently have been shown to be effective for downbeat nystagmus. Gabapentin, baclofen, and clonazepam also are useful in some patients with downbeat nystagmus. Baclofen is the therapy of choice for periodic alternating nystagmus. Gabapentin often is effective for acquired pendular nystagmus. Clonazepam and valproate also may be effective for acquired pendular nystagmus. Memantine now is available in the United States and is promising in the treatment of pendular nystagmus. Optical devices that negate the negative effects of nystagmus continue to undergo development research. These and other medical, surgical, and optical devices are potentially useful alone or in combination with other therapies.

Journal Article↗
PubMed1999

Acquired Nystagmus.

Patients with acquired forms of nystagmus may suffer from oscillopsia and blurred vision; abolishing or reducing nystagmus ameliorates these symptoms. Ideally, treatment of nystagmus should be directed against the pathophysiologic mechanism responsible. Identification of nystagmus pattern is important in directing therapy and occasionally requires electronic eye movement recording for precise characterization. Patients with acquired pendular nystagmus, particularly those with multiple sclerosis, often benefit from gabapentin, a drug with few side effects. Scopolamine, clonazepam, and valproate are also useful in some patients. A new drug, memantine, was effective in treating pendular nystagmus in one study, but it has not yet been approved for use in the United States. Periodic alternating nystagmus usually responds to baclofen. Central vestibular nystagmus, including downbeating and upbeating forms, can be treated with baclofen or clonazepam. In some patients, treatment of an underlying condition, such as periodic ataxia, Whipple's disease, and Chiari malformation, abolishes nystagmus and improves vision. If pharmacologic therapy fails, optical devices can be considered in selected patients. Injections of botulinum toxin and surgery to weaken extraocular muscles are prone to induce diplopia and may precipitate plastic-adaptive ocular motor changes that eventually negate the beneficial effect.

Journal Article↗
PubMed1993

Neurotoxic effect of the anti-HIV drug D-aspartate beta-hydroxamate for rat primary neuronal cultures: attenuation by N-methyl-D-aspartate (NMDA) antagonists.

The anti-tumor drug D-aspartate beta-hydroxamate (D-A beta H), selectively destroys HIV-1 infected peripheral blood mononuclear cells, but produces anorexia and nausea during prolonged treatment to AIDS patients. Consequently, based on the structural similarity between D-A beta H and the excitotoxins L-aspartate and NMDA, we have investigated the potential neurotoxic action and pharmacology of D-A beta H and of a series of chemically related anti-tumor drugs on rat primary neuronal/glial cultures. In this aim, after a 30 min exposure to D-A beta H (1-2 mM), cortical neurons were selectively destroyed within 24 h. The stereoisomer L-A beta H (0.5-2 mM) was highly neurotoxic for both glial and neuronal cells in mixed cultures but demonstrated no toxicity in glial cell cultures alone. Furthermore, for a series of D-A beta H analogues, VHS.121 and VHS.122 demonstrated a reduced but significant neurotoxicity, whereas VHS.124 and VHS.125 showed no significant neurotoxic effect, and in the case of VHS.125 also prevented D-A beta H and glutamate-mediated neurotoxicity. The related anti-tumor drugs L- or D-glutamate gamma-monohydroxamate or keto-glutamate gamma-monohydroxamate (< or = 2 mM) were not neurotoxic for cortical neurons. The neurotoxic effect of D-A beta H and L-A beta H was attenuated by the NMDA antagonists MK-801, TCP, memantine, ifenprodil, pentamidine and CGS-19755. alpha-Difluoromethylornithine, an inhibitor of polyamine biosynthesis, also protected cultures against the neurotoxicity of L-A beta H and D-A beta H.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Pharmacological changes in dopaminergic systems induced by long-term administration of amantadine.

The pharmacological effects of 6 weeks administration of amantadine was evaluated in the mouse. Motor stimulation induced by amphetamine or the amantadine analog memantine was reduced while that of apomorphine was enhanced by the long-term amantadine treatment. This was accompanied by an increase in the binding of spiroperidol to putative striatal dopamine receptors, without a change in amantadine-induced inhibition of dopamine uptake in the striatum. The possible significance of changes in pre- and postsynaptic dopamine mechanisms is discussed in relation to the anti-parkinson activity of the drug.

Amantadine↗