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PubMed2000

Reducing conditions significantly attenuate the neuroprotective efficacy of competitive, but not other NMDA receptor antagonists in vitro.

Inappropriate activation of NMDA receptors during a period of cerebral ischaemia is a crucial event in the pathway leading to neuronal degeneration. However, significant research has failed to deliver a clinically active NMDA receptor antagonist, and competitive NMDA antagonists are ineffective in many experimental models of ischaemia. The NMDA receptor itself has a number of modulatory sites which may affect receptor function under ischaemic conditions. Using rat organotypic hippocampal slice cultures we have investigated whether the redox modulatory site affects the neuroprotective efficacy of NMDA receptor antagonists against excitotoxicity and experimental ischaemia (OGD). NMDA toxicity was significantly enhanced in cultures pretreated with a reducing agent. The noncompetitive antagonist MK-801 and a glycine-site blocker were equally neuroprotective in both normal and reduced conditions, but there was a significant rightward shift in the dose-response curves of the competitive antagonists APV and CPP and the uncompetitive antagonist memantine. OGD produced neuronal damage predominantly in the CA1 region, which was prevented by MK-801 and memantine, but not by APV or CPP. Inclusion of an oxidizing agent during the period of OGD had no effect alone, but significantly enhanced the neuroprotective potency of the competitive antagonists. These data clearly demonstrate that chemical reduction of the redox modulatory site of the NMDA receptor decreases the ability of competitive antagonists to block NMDA receptor-mediated neuronal damage, and that the reducing conditions which occur during simulated ischaemia are sufficient to produce a similar effect. This may have important implications for the design of future neuroprotective agents.

2-Amino-5-phosphonovalerate↗
PubMed2003

NMDA receptor activity and the transmission of sensory input into motor output in introverts and extraverts.

Recent research suggests that individual differences in brain dopamine functioning may be related to the personality dimension of extraversion. The major goal of the present study was to answer the question of whether a pharmacologically induced change in glutamatergic NMDA receptor activity would also differentially affect the transmission of sensory input into motor out-put in introverts and extraverts. Therefore, in a double-blind within-subjects design, either 30 mg of the NMDA receptor antagonist memantine or placebo were administered to 48 healthy male volunteers before performing a choice reaction-time task. In introverts, memantine caused a pronounced increase in lift-off time (i.e., the time required to lift the finger from a home button) compared to that in extraverts, whereas movement time (i.e., the time required to move the finger from the home button to a response button) was decreased in both groups. The pattern of results suggests that extraversion-related differential sensitivity to pharmacologically induced changes in NMDA receptor activity is limited to functions that involve an interaction between the glutamatergic and dopaminergic systems.

Adult↗
PubMed2001

Effect of drugs used for neuropathic pain management on tetrodotoxin-resistant Na(+) currents in rat sensory neurons.

BACKGROUND: Tetrodotoxin-resistant Na(+) channels play an important role in generation and conduction of nociceptive discharges in peripheral endings of small-diameter axons of the peripheral nervous system. Pathophysiologically, these channels may produce ectopic discharges in damaged nociceptive fibers, leading to neuropathic pain syndromes. Systemically applied Na(+) channel--blocking drugs can alleviate pain, the mechanism of which is rather unresolved. The authors investigated the effects of some commonly used drugs, i.e., lidocaine, mexiletine, carbamazepine, amitriptyline, memantine, and gabapentin, on tetrodotoxin-resistant Na+ channels in rat dorsal root ganglia. METHODS: Tetrodotoxin-resistant Na(+) currents were recorded in the whole-cell configuration of the patch-clamp method in enzymatically dissociated dorsal root ganglion neurons of adult rats. Half-maximal blocking concentrations were derived from concentration-inhibition curves at different holding potentials (-90, -70, and -60 mV). RESULTS: Lidocaine, mexiletine, and amitriptyline reversibly blocked tetrodotoxin-resistant Na(+) currents in a concentration- and use-dependent manner. Block by carbamazepine and memantine was not use-dependent at 2 Hz. Gabapentin had no effect at concentrations of up to 3 mm. Depolarizing the membrane potential from -90 mV to -60 mV reduced the available Na(+) current only by 23% but increased the sensitivity of the channels to the use-dependent blockers approximately fivefold. The availability curve of the current was shifted by 5.3 mV to the left in 300 microm lidocaine. CONCLUSIONS: Less negative membrane potential and repetitive firing have little effect on tetrodotoxin-resistant Na(+) current amplitude but increase their sensitivity to lidocaine, mexiletine, and amitriptyline so that concentrations after intravenous administration of these drugs can impair channel function. This may explain alleviation from pain by reducing firing frequency in ectopic sites without depressing central nervous or cardiac excitability.

Amitriptyline↗
PubMed2002

Ketamine, an N-methyl-D-aspartate receptor antagonist, inhibits the spinal neuronal responses to distension of the rat urinary bladder.

BACKGROUND: The effect of ketamine as a treatment of visceral pain is not known. The current study investigated the effect of ketamine on spinal dorsal horn neurons excited by urinary bladder distension (UBD). The effect of other clinically available N-methyl-D-aspartate receptor antagonists on these responses was also studied. METHODS: Extracellular recordings of neurons located in the L6-S2 spinal dorsal horn of cervical spinal cord-transected, decerebrate female rats were obtained. Cutaneous receptive fields of neuronal units excited by UBD were characterized for responses to segmental noxious and nonnoxious stimuli. Nonsegmental noxious stimuli were also applied, and neurons were classified as type I (inhibited) and type II (noninhibited) by the stimulus. The effect of intravenous ketamine (1, 3, and 10 mg/kg), dextromethorphan (5 mg/kg), and memantine (16 mg/kg) on neuronal responses of these units was measured. RESULTS: Spontaneous and evoked neuronal activity to UBD was reduced in a dose-dependent fashion by ketamine. Responses to nonnoxious cutaneous stimuli were also significantly reduced after treatment. Dextromethorphan inhibited neuronal activity evoked by UBD in type I neurons. A similar selective effect of treatment on type I versus type II neurons was observed after intravenous ketamine and memantine. CONCLUSIONS: Intravenous ketamine produces dose-dependent inhibition of the spinal cord neuronal responses evoked by UBD. All three N-methyl-D-aspartate receptor antagonists showed selective effects on spinal cord neurons subject to counterirritation. This neurophysiologic evidence supports a spinally mediated analgesic effect of ketamine in this model of urinary bladder nociception, an effect likely caused by N-methyl-D-aspartate receptor antagonism.

Animals↗
PubMedDate not supplied

Current treatment for Alzheimer disease and future prospects.

A cascade of pathophysiological events is triggered in Alzheimer disease (AD) that ultimately involves common cellular signaling pathways and leads to cellular and network dysfunction, failure of neurotransmission, cell death, and a common clinical outcome. The process is asynchronous, meaning that viable neurons remain as targets for therapy even in the diseased state, and each stage of the cascade affords the possibility for therapeutic intervention. Cholinesterase inhibitors are the only available treatment in the United States for patients with mild to moderate AD, helping maintain cognitive and functional abilities in most patients and conferring beneficial behavioral effects in some. Memantine is an NMDA receptor antagonist that has recently been approved in Europe for treatment of moderately severe to severe AD and is under investigation in the United States. Its mechanism of action may include enhanced neurotransmission in several systems as well as antiexcitotoxic effects. There are data regarding the effectiveness of the combination of memantine with cholinesterase inhibitors that will be useful for the practicing clinician. Other agents have shown some benefit in clinical trials, including the antioxidants vitamin E, selegiline, and Ginkgo biloba extracts, although the weight of evidence regarding their effects is not sufficient to define clinical practice. Potential future therapies currently are in development that target multiple aspects of the illness cascade, including aberrant inflammation, neurotrophic function, and processing of beta amyloid and tau proteins. These newer approaches hold promise for disease modification but are as yet unproven. Whether or not disease-modifying or preventive therapies become a reality, clinicians will be faced with AD patients who require treatment at all stages of illness for the indefinite future. Cholinergic and emerging noncholinergic medications will likely prevail as the standards of treatment for years to come.

Alzheimer Disease↗
PubMed2006

Treatment of dementia: anything new?

PURPOSE OF REVIEW: The aim of this article is to discuss new data on presently approved drugs for dementia, such as cholinesterase inhibitors and memantine, and concerns regarding the use of antipsychotics for treating neuropsychiatric symptoms, as well as to summarize some relevant studies recently published on emerging therapies with potential disease-modifying effects. RECENT FINDINGS: The main focuses of recent studies of cholinesterase inhibitors and memantine have been on efficacy and safety aspects in extended clinical trials, combined treatments or comparative analysis between agents, and also on potential neuroprotective effects and new indications. Other publications have assessed the evidence of efficacy and the increased risk of cerebrovascular events, rapid cognitive decline, and mortality with the use of antipsychotics in dementia, providing important information in relation to the controversy surrounding its use. Although more studies are warranted, a sizable literature on novel treatment options under investigation is currently available as a result of a better understanding of pathogenesis of dementia. SUMMARY: So far, there is no established method to predict better responders or long-term benefits with currently approved drugs for treatment of dementia. Recent systematic reviews and new research on current treatment, however, provide valuable information for clinicians, and novel drugs under investigation reveal promising new therapeutic strategies.

Alzheimer Disease↗
PubMedDate not supplied

Effects of pharmacologically induced changes in NMDA-receptor activity on long-term memory in humans.

In a double-blind crossover design, either 30 mg of the noncompetitive NMDA-receptor antagonist memantine or a placebo was administered to 40 healthy male volunteers. Twenty line drawings of objects and 20 photographs of unfamiliar faces were presented on a computer screen. After a retention interval of 80 min, the participants' task was to select the original objects and faces from a set of 80 items. Results were analyzed applying a signal-detection-theory approach. Recognition performance for objects was significantly impaired under memantine as compared to placebo, whereas performance on face recognition was not affected. Findings support the notion of differential effects of NMDA-receptor antagonists on memory functions in humans.

Adult↗
PubMed1998

Open-channel blockers at the human alpha4beta2 neuronal nicotinic acetylcholine receptor.

To extend our knowledge of the pharmacological profile of human alpha4beta2 neuronal nicotinic receptors, we investigated the action of hexamethonium on the major brain human nicotinic acetylcholine receptor (nAChR) stably expressed in human embryonic kidney 293 cells. This compound displays all of the characteristics of an open-channel blocker at the human alpha4beta2 nAChR: a voltage-dependent inhibition (more pronounced at hyperpolarized potentials), absence of competition, and use dependence. Moreover, we observed that classic N-methyl-D-aspartate open-channel blockers amantadine, 3,5-dimethyl-1-adamantanamine (memantine), and dizocilpine [(+)-MK-801] and the calcium channel antagonist 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate are powerful inhibitors of the human alpha4beta2 nAChR. Dose-inhibition curves yield, at -100 mV, IC50 values in the micromolar range for all of compounds and Hill coefficients below unity. Whole-cell current-voltage relationships display a strong rectification profile at hyperpolarized potentials, and current blockades are fitted adequately by a mathematical model that describes the mechanism of an ion channel block. We conclude that these molecules are powerful human alpha4beta2 open-channel blockers ranking in the following order of potency: amantadine > memantine = hexamethonium > 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate approximately (+)-MK-801.

Dizocilpine Maleate↗
PubMed2005

Health utilities in Alzheimer's disease and implications for cost-effectiveness analysis.

The National Institute for Health and Clinical Excellence (NICE) provisional decision against memantine and other medications for Alzheimer's disease (AD) has generated much discussion. In its decision, NICE expressed concern about the data source used for the utility scores in the industry submission of the memantine model. NICE therefore turned to an alternative data source. However, in doing so, it made the key assumption that moderate-to-severe AD patients living in the community were independent. Furthermore, the NICE data source also had its limitations. There are numerous limitations in inferring from available data how utilities vary between dependent and non-dependent patients with AD. Most importantly, we lack direct evidence from primary data. Nonetheless, it seems reasonable to assume that patients with severe AD, and likely those with moderate AD as well, have full-time care needs, regardless of their setting. The NICE assumption that they do not results in a difference in utilities between dependent and non-dependent AD individuals of only 0.06. This seems to be at the low end of what one would consider a reasonable estimate.

Alzheimer Disease↗
PubMed2002

Non-cholinergic strategies for treating and preventing Alzheimer's disease.

The pathophysiology of Alzheimer's disease is complex and involves several different biochemical pathways. These include defective beta-amyloid (Abeta) protein metabolism, abnormalities of glutamatergic, adrenergic, serotonergic and dopaminergic neurotransmission, and the potential involvement of inflammatory, oxidative and hormonal pathways. Consequently, these pathways are all potential targets for Alzheimer's disease treatment and prevention strategies. Currently, the mainstay treatments for Alzheimer's disease are the cholinesterase inhibitors, which increase the availability of acetylcholine at cholinergic synapses. Since the cholinesterase inhibitors confer only modest benefits, additional non-cholinergic Alzheimer's disease therapies are urgently needed. Several non-cholinergic agents are currently under development for the treatment and/or prevention of Alzheimer's disease. These include anti-amyloid strategies (e.g. immunisation, aggregation inhibitors, secretase inhibitors), transition metal chelators (e.g. clioquinol), growth factors, hormones (e.g. estradiol), herbs (e.g. Ginkgo biloba), nonsteroidal anti-inflammatory drugs (NSAIDs, e.g. indomethacin), antioxidants, lipid-lowering agents, antihypertensives, selective phosphodiesterase inhibitors, vitamins (E, B12, B6, folic acid) and agents that target neurotransmitter or neuropeptide alterations. Neurotransmitter receptor-based approaches include agents that modulate certain receptors (e.g. nicotinic, muscarinic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid [AMPA], gamma-aminobutyric acid [GABA], N-methyl-D-aspartate [NMDA]) and agents that increase the availability of neurotransmitters (e.g. noradrenergic reuptake inhibitors). Of these strategies, the NMDA receptor antagonist memantine is in the most advanced stage of development in the US and is already approved in Europe as the first treatment for moderately severe to severe Alzheimer's disease. Memantine is proposed to counteract cellular damage due to pathological activation of NMDA receptors by glutamate. Results with Ginkgo biloba have been mixed. Data for neurotrophic therapies and vitamin E (tocopherol) appear promising but require confirmation. NSAIDs and conjugated estrogens have not proven to be of value to date for the treatment of Alzheimer's disease. Statins may have a potential role in reducing the risk or delaying the onset of Alzheimer's disease, although this has yet to be confirmed in randomised trials. There are currently no data to support the use of statins as a treatment for dementia. This article provides an update on the current status of selected agents, focusing primarily on those agents with the most extensive clinical evidence at present.

Alzheimer Disease↗
PubMed2004

What are the treatment options for patients with severe Alzheimer's disease?

By some estimates moderate-to-severe Alzheimer's disease accounts for 50% of all patients with Alzheimer's disease. However, there are numerous issues that remain to be resolved in the management of patients with more advanced Alzheimer's disease. The first prospective, randomised, controlled trial of the cholinesterase inhibitor donepezil in more advanced Alzheimer's disease has reported quite encouraging results, with further studies being undertaken. Post-hoc analyses of rivastigmine and galantamine in patients with more advanced Alzheimer's disease have supported the hypothesis that acetylcholinesterase inhibitors are likely be efficacious in this subgroup. Memantine, a glutamate NMDA receptor antagonist, is newly licensed in Europe for the treatment of more advanced Alzheimer's disease and will provide the first non-cholinesterase inhibitor option for the treatment of Alzheimer's disease. The combination of donepezil and memantine has been shown to have superior efficacy than donepezil alone in this severe Alzheimer's disease subgroup, potentially supporting a role for dual treatment in more advanced Alzheimer's disease. Further studies of all aspects of more advanced Alzheimer's disease are clearly needed. The problems of translating clinical trial results to routine clinical practice are even more complex and challenging in this patient group, with the true impact of any one given treatment ranging over a spectrum of clinical domains from improved cognition to reduced caregiver burden. Increased attentiveness by clinicians to treatment response across this multidisciplinary spectrum in more advanced Alzheimer's disease is warranted.

Alzheimer Disease↗
PubMedDate not supplied

NMDA antagonists inhibit the development of ethanol dependence in rats.

The influence of non-competitive NMDA receptor antagonist, 1-amino-3,5-dimethyl-adamantane (memantine), and glycineB site antagonist, 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolone (L-701,324), on the development of ethanol dependence was investigated in Wistar rats. The development of ethanol dependence was induced by intragastric administration of 20% w/v ethanol, three times a day at increasing doses. The results were quantified using withdrawal audiogenic seizures, 12 h after the last ethanol administration. Memantine (3.75 or 7.5 mg/kg) and L-701,324 (2.5 or 5 mg/kg), given before ethanol administration, prevented the development of ethanol dependence. Our results support the data that NMDA receptors are involved in the development of ethanol dependence.

2-Amino-5-phosphonovalerate↗
PubMed2005

Combination drug therapy for Alzheimer's disease: what is evidence-based, and what is not?

Although FDA-approved Alzheimer's disease (AD) treatment strategies (cholinesterase inhibitors and memantine) offer proven benefits, providers recognize unmet needs beyond what is currently available. Consequently there is a significant use of anecdotal yet unproven combinations for treating AD in practice. Based on the best evidence, combination drug therapy is the standard of care for treating other medical conditions such as malignancies, human immunodeficiency virus (HIV), and hypertension. We review recent combination drug therapy studies in AD. To date, the best evidence-based combination strategy is for moderate-to-severe AD, in which the addition of memantine to stable donepezil therapy was found to benefit cognition, behavior, and function. In milder stages of AD, the benefit of combination drug therapy has not been demonstrated. This review highlights the urgent need to systematically test additional rational drug combinations and the need for future trials to enroll adequate sample sizes and utilize relevant and sensitive outcome measures.

Alzheimer Disease↗
PubMed2005

Pharmacologic treatment options in Alzheimer's disease: optimizing disease management.

Cholinesterase inhibitors and memantine have been shown to improve symptoms associated with AD. Mechanisms of action and the pathophysiologic targets are distinct for the 2 classes, but clinical outcomes demonstrate both medications improve patient symptomatology. In addition, memantine and a ChEI appear to produce an additive effect resulting in a well-tolerated, effective treatment strategy.

Acetylcholine↗
PubMed2005

[Effects of blockade of ionotropic glutamate receptors on the development of pentylenetetrazole kindling in mice].

Effects of mono- and dicationic derivatives of adamantane and phenylcyclohexyl on the petyleneterazole-induced (35 mg/kg i. p.) kindling were studied in the experiments on mice. Monocationic derivative of phenylcyclohexyl IEM-1921, effectively retarded the development of kindling beginning the dose 0.0001 microM/kg. Memantine: derivative of adamantane (derivative of adamatane) produced the same effect with 100-fold increased dose. Dicationic derivative ofphenylcyclohexyl: IEM-1925, is able to block equally the open channels of both NMDA and subtype of Ca-permeable AMPA receptors. Its effect on kindling differed markedly from selective NMDA antagonists (IEM-1921 and memantine) in more complicated dose-dependence. The retardation of kindling IEM-1925 was induced at 0.001 microM/kg. On the contrary, a 10-time lower dose: 0.0001 microM/kg, facilitated the development of kindling. The observed difference in the activity of selective NMDA antagonists and the drugs combining anti-NMDA and anti-AMPA potency indicates that both types of ionotropic glutamate receptors are involved in the mechanism of petyleneterazole-induced kindling. The integral effect of channel blockade evoked by drugs seems to be dependent not only upon the ratio of the receptor types but on the kinetics of drug action, too.

Animals↗
PubMed2006

[The practice guideline 'Diagnosis and pharmaceutical treatment of dementia'].

The practice guideline 'Diagnosis and pharmaceutical treatment of dementia' emphasizes that a nosological diagnosis should be made and that it is important to assess the extent of need for care. The guideline recommends the use of diagnostic criteria for the various conditions that can cause dementia. With respect to ancillary investigations, the burden to the patient should be weighed against the benefits of increasing diagnostic confidence. Observation of the course of the disease, laboratory and cerebrospinal-fluid investigations, neuropsychological and EEG examinations, and neuroimaging all increase diagnostic confidence. Treatment with a cholinesterase inhibitor or memantine should always be embedded in a comprehensive-treatment protocol that includes explicit discussion of treatment goals and expectations at baseline, in combination with criteria for starting and stopping treatment. Guidelines for evaluating the effects of treatment with cholinesterase inhibitors or memantine are specified. If psychosis, depression or behavioural disturbances occur in patients with dementia, antidepressants, antipsychotics or anticonvulsants may be indicated.

Antipsychotic Agents↗
PubMed2006

[Pharmacotherapy for Alzheimer's disease].

BACKGROUND: So far no causal therapies are available for the treatment of Alzheimer's disease. However, four drugs, namely donepezil, rivastigmine, galantamine and memantine, have been licensed for treating the symptoms of the disease. AIM: To systematically review the efficacy and side-effects of these drugs. METHOD: With the help of Pubmed, Medline and the Cochrane Library the literature was searched systematically. RESULTS: Cholinesterase-inhibitors and memantine do have a beneficial effect on cognition and daily functioning. The effect, however, is limited and the cholinesterase-inhibitors in particular frequently have side-effects. CONCLUSION: Treatment with the new anti-Alzheimer drugs demands a careful and realistic approach. The drugs should not be prescribed in isolation but the treatment needs to be embedded in the entire set of currently available psychosocial intervention techniques.

Alzheimer Disease↗
PubMed2006

[Medical treatment of Alzheimer's disease].

In Denmark, Alzheimer drugs have been registered since 1997. Three cholinesterase inhibitors (donepezil, rivastigmin og galantamin) are approved mild to moderate Alzheimer's disease and one partial NMDA receptor antagonist (memantin) with the indication moderate to severe Alzheimer's disease. The treatment is symptomatic with a parallel shift of the course. The life expectancy does not seem to be altered. There is documented effect on the cholinesterase inhibitors of up to two years and for memantine for 6 months. New disease modifying agents are under clinical development.

Activities of Daily Living↗