Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:281-23-2 (adamantane)
 1,467 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efficacy and tolerability of memantine (1-amino-3,5-dimethyl-adamantane hydrochloride, Akatinol Memantine; CAS 41100-52-1) was investigated in a double-blind, randomized clinical study versus placebo in 66 patients aged between 65 and 80 years predominantly suffering from mild to moderate vascular dementia. The target variables assessed were the baseline differences of the Sandoz Clinical Assessment Geriatric scale (SCAG) and Syndrom-Kurz-Test (SKT) total scores and the total time required in the subtests of Activity of Daily Living tests (ADL). Additional parameters assessed were the physician's global impression, the Mini Mental State Evaluation (MMSE), the Tapping and Trace tests for fine motor rating and the quality in performing the ADL tests. Adverse drug effects were recorded by DOTES/TWIS. 59 of the 66 patients included in the study terminated the trial (29 in the placebo and 30 in the memantine group). For the baseline differences of the SCAG total score a statistically significant improvement was observed already after 14 days of memantine treatment as compared to placebo. After 42 days this difference was still more pronounced and highly significant. Significant improvements after 14 and 42 days of memantine treatment could also be demonstrated for the SCAG subscales cognitive disturbances, lack of drive, emotional disturbances, social behaviour and somatic disturbances. Additionally, the efficacy of the drug could be confirmed by the SKT and ADL tests. Particularly striking in the ADL tests was the considerable improvement achieved in the quality of performing the tasks under memantine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Efficacy and tolerability of memantine in patients with dementia syndrome. A double-blind, placebo controlled trial. 178 96

Memantine (1-amino-3,5-dimethyl-adamantane) has therapeutic potential in Parkinson's disease and dementia. However, its effect on dopaminergic activity in the central nervous system is still unclear. Therefore, we studied the effect of memantine on dopamine release in prefrontal cortex and striatum, using in vivo microdialysis. Memantine (5, 10 and 20 mg/kg i.p.) caused a dose-dependent increase in dopamine release up to nearly 50% over basal levels. The output of the metabolites was of later onset and longer duration in prefrontal cortex and in striatum. After administration of 10 and 20 mg/kg, in both brain areas memantine levels could be detected over the investigated period of 160 min. The maximal concentrations (Cmax) differed dose dependently, whereas the time to reach this maximum (tmax) was almost identical (68.5 +/- 3.4 min). From the flat elimination profile a half-life of 2.8 +/- 0.5 h (range 2-3.4 h) was calculated. These data demonstrate enhanced dopamine release and metabolism after memantine treatment and support the assumption of an interaction between noncompetitive NMDA-receptor antagonists and dopaminergic systems.
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PMID:Memantine-induced dopamine release in the prefrontal cortex and striatum of the rat--a pharmacokinetic microdialysis study. 781 74

The 1-aminoadamantanes memantine (1-amino-3,5-dimethyl-adamantane) and amantadine (1-amino-adamantane) are clinically used as anti-parkinsonian, anti-spasticity, anti-dementia and antiviral drugs. In the present investigation we have tested a series of 1-aminoadamantane derivatives including memantine and amantadine for their ability to compete with [3H](+)-pentazocine in homogenates of post-mortem human frontal cortex. The Ki values ranged from 0.237 +/- 0.019 microM for 1-N-dimethyl-amino-3,5-dimethyl-adamantane to 20.25 +/- 16.48 microM for amantadine. The Ki value of memantine was 19.98 +/- 3.08 microM and was thus very similar to that of amantadine. Memantine, at therapeutic concentrations, probably does not interact with the sigma binding site. Amantadine, at therapeutic concentrations, probably binds both to the sigma site and to the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor.
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PMID:Affinity of 1-aminoadamantanes for the sigma binding site in post-mortem human frontal cortex. 830 17

The amino-adamantane derivatives memantine (1-amino-3,5-dimethyladamantane) and amantadine (1-amino-adamantane) are relatively low affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists which have been used clinically in the treatment of dementia and Parkinson's disease respectively for several years without serious side effects. The aim of this study was to test whether memantine, amantadine and other low affinity uncompetitive NMDA receptor antagonists also have better therapeutic indices than high affinity antagonists in preclinical models of epilepsy by assessing the potency, kinetics and voltage-dependency of open channel blockade for a series antagonists in vitro and comparing these effects to anticonvulsive and motor impairment activity in vivo. The compounds tested were memantine, amantadine, 14 other amino-adamantanes, (+)-MK-801, ketamine, dextrorphan, dextromethorphan and phencyclidine. The offset kinetics of open-channel blockade assessed with whole cell patch clamp recordings from cultured superior colliculus neurones were highly correlated to potency i.e. the less potent antagonists showed faster unblocking kinetics (Koff, r = 0.904). Although, onset kinetics as assessed by Kon were not correlated to potency (r = 0.023), tau on estimated at IC50 is perhaps a more meaningful measure of onset kinetics at equieffective concentrations and was also well correlated to potency (r = -0.863). All amino-adamantanes tested were strongly voltage-dependent. There was also a good correlation between the in vitro potencies of uncompetitive NMDA receptor antagonists assessed with patch clamp recordings and displacement of equilibrium [3H](+)-MK-801 binding and their in vivo activity against maximal electroshock (MES) and pentylenetetrazol (PTZ) induced tonic convulsions and NMDA-induced lethality in mice. Memantine and four other amino-adamantanes with somewhat lower potency and faster blocking kinetics had better therapeutic indices (ED50 rotarod and traction reflex over ED50 in MES-induced convulsions; TI = 2-4) than substances with higher affinity such as ketamine, dextrorphan and (+)-MK-801 (TI < 2). However, amantadine and several other amino-adamantanes with lower potency than memantine actually had poorer therapeutic indices (TI < or = 0.5) which may have been due to additional actions at other ion channels or receptors at the doses necessary to protect against seizures. In fact, ED50 in the MES test was negatively-correlated to therapeutic indices (traction r = -0.790, rotarod r = -0.797) i.e. the less potent uncompetitive antagonists had worse therapeutic indices. The data from the present study do not lend support to the idea that low affinity, open channel NMDA receptor blockers are also effective in models of epilepsy at doses having little effect on physiological processes. It should be stressed that these data do not contradict the known therapeutic safety of memantine and amantadine in dementia and Parkinson's disease respectively. Thus the good clinical profile of memantine in dementia has been attributed not only to its fast blocking/unblocking kinetics but also to its strong voltage-dependency. These biophysical properties may allow therapeutically-relevant concentrations to block chronic, low level pathological activation of NMDA receptors whilst leaving their synaptic activation intact. Precisely these properties may also underlie the poor therapeutic indices seen in the present study on antiepileptic activity due to the synaptic nature of both seizures and normal glutamatergic transmission.
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PMID:Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo. 857 22

Glaucoma is a neurodegenerative disease typified by progressive loss of retinal ganglion cells (RGCs). Mild excitotoxicity has been implicated as one of the factors contributing to RGC death during the glaucomatous process. This type of excitotoxic cell death is due, at least in part, to somewhat excessive activation of N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA-receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA-receptor activity will have unacceptable clinical side effects. Studies in our laboratory have shown that the adamantane derivative, memantine, blocks only excessive NMDA-receptor activity without disrupting normal activity. Past clinical use has demonstrated that memantine is safe, and it has recently been approved in Europe for the treatment of Alzheimer's disease and vascular dementia. Clinical studies of the safety and efficacy of memantine in glaucoma are currently underway. A series of second-generation memantine derivatives called nitro-memantines are currently in development and may prove to have even greater neuroprotective properties than does memantine.
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PMID:Possible role for memantine in protecting retinal ganglion cells from glaucomatous damage. 1285 33

Alzheimer's disease is the fourth largest cause of death for people over 65 years of age. Dementia of Alzheimer's type is the commonest form of dementia, the other two forms being vascular dementia and mixed dementia. At present, the therapy of Alzheimer's disease is aimed at improving both, cognitive and behavioural symptoms and thereby, quality of life for the patients. Since the discovery of Alzheimer's disease by Alois Alzheimer, many pathological mechanisms have been proposed which led to the testing of various new treatments. Until recently the available drugs for the treatment of Alzheimer's disease are cholinesterase inhibitors, which have limited success because these drugs improve cognitive functions only in mild dementia and cannot stop the process of neurodegeneration. Moreover, drugs of this category show gastrointestinal side effects. As the cells of central and peripheral nervous system cannot regenerate, newer strategies are aimed at preserving the surviving neurons by preventing their degeneration. NMDA-receptor-mediated glutamate excitotoxicity plays a major role in Abeta-induced neuronal death. Hence, it was thought that NMDA receptors could be a promising target for preventing the progression of Alzheimer's disease. All the compounds synthesized initially in this category showed toxicity mainly because of their high affinity for NMDA receptors. Memantine (1-amino adamantane derivative), NMDA-receptor antagonist was reported to be effective therapeutically in Alzheimer's disease. It was available in Germany as well as European Union and has been approved for moderate to severe dementia in United States of America recently. It is an uncompetitive, moderate affinity antagonist of NMDA receptors that inhibits the pathological functions of NMDA receptors while physiological processes in learning and memory are unaffected. Memantine is also reported to have beneficial effects in other CNS disorders viz., Parkinson's disease (PD), stroke, epilepsy, CNS trauma, amyotrophic lateral sclerosis (ALS), drug dependence and chronic pain. Mechanisms of neuroprotection, preclinical and clinical evidence for effectiveness of memantine have been provided. Pharmacology and pharmacokinetics of memantine and other NMDA-receptor antagonists in comparison with currently approved drugs for dementia treatment have been discussed. The focus is on 'glutamate excitotoxicity' and glutamate receptors as drug target. Various other novel strategies for the treatment of dementia of neurodegenerative disorders have also been discussed.
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PMID:Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope. 1551 30

Alzheimer's disease (AD) is the most common form of dementia, as least in western countries. It has been estimated that the cost to society for caring for AD patients will consume the entire gross national product of the U.S.A. by the middle of this century if left unabated. Until recently, the only available drugs for this condition were cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. In fact, many potential neuroprotective drugs tested in clinical trials failed because they were poorly tolerated. However, after our discovery of its clinically-tolerated mechanism of action, one neuroprotective drug, memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. Recent phase 3 clinical trials have shown that memantine is effective in the treatment of moderate-to-severe Alzheimer's disease and possibly vascular dementia (multi-infarct dementia). Here we review the molecular mechanism of memantine's action and also the basis for the drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell death is mediated in part by overactivation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, which results in excessive Ca(2+) influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of neurodegenerative disorders. In contrast, studies in our laboratory have shown that the adamantane derivative, memantine, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Clinical use has corroborated the prediction that memantine is thus well tolerated. Besides Alzheimer's disease, memantine is currently in trials for additional neurological disorders, including other forms of dementia, depression, glaucoma, and severe neuropathic pain. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites in addition to its ion channel that potentially could also be used for safe but effective clinical intervention.
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PMID:Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer's disease and other neurologic disorders. 1566 16

Excitotoxicity, defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, has been implicated as one of the key factors contributing to neuronal injury and death in a wide range of both acute and chronic neurologic disorders. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-D-aspartate (NMDA)-type glutamate receptors and hence excessive Ca2+ influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function; potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of diseases including stroke and neurodegenerative disorders such as Huntington's disease. In contrast, studies in my laboratory were the first to show that memantine, an adamantane derivative, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Past clinical use for other indications has demonstrated that memantine is well tolerated, and it has recently been approved in both Europe and the USA for the treatment of dementia of the Alzheimer's type. Clinical studies of the safety and efficacy of memantine for other neurological disorders, including glaucoma and other forms of dementia, are currently underway. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than does memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites, in addition to its ion channel, that could potentially be used for safe but effective clinical intervention.
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PMID:Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. 1571 10

In western countries, Alzheimer's disease (AD) is the most common form of dementia. In fact, if left uncurbed, the economic cost of caring for AD patients could consume the entire gross national product of the USA by the middle of this century. Until recently, the only available drugs for this condition were cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. In fact, many potential neuroprotective drugs tested in clinical trials failed because they were poorly tolerated. However, after our discovery of its clinically-tolerated mechanism of action, one neuroprotective drug, memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. Recent phase 3 clinical trials have shown that memantine is effective in the treatment of both mild and moderate-to-severe Alzheimer's disease and possibly vascular dementia (multi-infarct dementia). Here we review the molecular mechanism of memantine's action and also the basis for the drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell death is mediated in part by overactivation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, which results in excessive Ca2+ influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of neurodegenerative disorders. In contrast, studies in our laboratory have shown that the adamantane derivative, memantine, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Clinical use has corroborated the prediction that memantine is thus well tolerated. Besides Alzheimer's disease, memantine is currently in trials for additional neurological disorders, including other forms of dementia, depression, glaucoma, and severe neuropathic pain. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites in addition to its ion channel that potentially could also be used for safe but effective clinical intervention.
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PMID:The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity, uncompetitive antagonism. 1597 13

Alzheimer's disease (AD) is the most common form of dementia in industrialized nations. If more effective therapies are not developed that either prevent AD or block progression of the disease in its very early stages, the economic and societal cost of caring for AD patients will be devastating. Only two types of drugs are currently approved for the treatment of AD: inhibitors of acetyl cholinesterase, which symptomatically enhance cognitive state to some degree but are not disease modifying; and the adamantane derivative, memantine. Memantine preferentially blocks excessive NMDA receptor activity without disrupting normal receptor activity and is thought to be a neuroprotective agent that blocks excitotoxicty. Memantine therefore may have a potentially disease modifying effect in multiple neurodegenerative conditions. An improved understanding of the pathogeneses of AD has now led to the identification of numerous therapeutic targets designed to alter amyloid beta protein (Abeta) or tau accumulation. Therapies that alter Abeta and tau through these various targets are likely to have significant disease modifying effects. Many of these targets have been validated in proof of concept studies in preclinical animal models, and some potentially disease modifying therapies targeting Abeta or tau are being tested in the clinic. This review will highlight both the promise of and the obstacles to developing such disease modifying AD therapies.
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PMID:Disease modifying therapy for AD? 1707 54


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