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PubMed1994

Memantine, amantadine, and L-deprenyl potentiate the action of L-dopa in monoamine-depleted rats.

Some treatments used for Parkinson's disease attenuate locomotor depression in rats treated with reserpine and alpha-methyl-p-tyrosine. In the present study memantine (2.5, 5.0 mg/kg), amantadine (10, 20 mg/kg) (both uncompetitive NMDA antagonists), and L-deprenyl (1.0, 5.0 mg/kg; MAO-B inhibitor) were tested for possible synergistic interactions with the dopamine agonists: bromocriptine (2.5, 5.0 mg/kg) and L-dopa (50, 100 mg/kg, +benserazide, 100 mg/kg). At higher doses, memantine (10 mg/kg), amantadine (40 mg/kg), bromocriptine (5 and 10 mg/kg) and L-dopa (100, 200 mg/kg) but not L-deprenyl (up to 10 mg/kg) produced a pronounced increase in locomotor activity when given alone. The combination of memantine, amantadine and L-deprenyl with bromocriptine did not result in synergism of action and, at best, an additive effect was seen. On the other hand the combination of these agents with L-dopa produced a pronounced synergistic effect. Hence, the clinical observation that coadministration of L-dopa with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl.

Amantadine↗

PubMed1994

Are NMDA antagonistic properties relevant for antiparkinsonian-like activity in rats?--case of amantadine and memantine.

Amantadine (25, 50, 100 mg/kg), memantine (5, 10, 20 mg/kg) and MK-801 (0.05, 0.1, 0.2 mg/kg), all having NMDA channel blocking properties, were compared in three tests used for screening of antiparkinsonian agents in rats, namely: haloperidol-induced catalepsy, locomotor activity in monoamine depleted rats and rotation in rats with a unilateral substantia nigra lesion. Additionally, plasma levels of amantadine and memantine were assessed to gain an insight into the concentration ranges achieved at behaviorally active doses. Amantadine and (+)-MK-801 produced dose-dependent inhibition of haloperidol-induced catalepsy while memantine was less efficacious producing clear-cut anticataleptic action at a dose of 10 mg/kg only but failing at 20 mg/kg due to myorelaxant activity. All agents attenuated sedation in monoamine depleted rats with amantadine being the least and MK-801 being the most effective. The same rank order of efficacy was seen in inducing ipsilateral rotations in rats after a substantia nigra lesion. On the basis of the present study and published data, it can be assumed that the doses of amantadine, memantine and MK-801 showing antiparkinsonian-like activity in animals result in plasma levels leading to NMDA antagonism. However, in the haloperidol-induced catalepsy test the efficacy of amantadine was higher than memantine, while the opposite was true for rotation and reserpine-induced sedation indicating pharmacodynamic differences between both agents.

Amantadine↗

PubMed2003

No nerve growth factor response to treatment with memantine in adult rats.

Nerve growth factor (NGF) is the most widely examined neurotrophin in the experimental models of Alzheimer's disease (AD) and has been shown to prevent the retrograde degeneration of cholinergic neurons. In this study we examined NGF and cholineacetyltransferase (ChAT) changes in several rat brain regions after excitotoxic lesion of the entorhinal cortex with quinolinic acid and tested the effect of memantine on spatial learning in the radial maze after lesion. We observed a significant increase (+26%, p=0.02) of NGF concentrations in the hippocampus of the lesioned rats when compared to sham-lesioned rats. Chronic treatment with memantine showed no significant effect on the NGF increase in the hippocampus (p=0.72). The ChAT activity was significantly increased in the lesioned rats when compared to controls (+16%, p<0.05) and did not depend on treatment with memantine. In spite of this, memantine improved performance of the radial maze. This indicates that memory improving effects of memantine observed in experimental animals and in clinical studies are probably not related to changes in brain NGF content, whereas the observed NGF increase in the denervated hippocampus is probably trauma-related reflecting impaired retrograde transport of hippocampal NGF.

Animals↗

PubMed2001

Co-administration of memantine and amantadine with sub/suprathreshold doses of L-Dopa restores motor behaviour of MPTP-treated mice.

The antiparkinsonian effects of the uncompetitive NMDA antagonists, memantine, amantadine and MK-801, in combination with an acute subthreshold dose of L-Dopa (5 mg/kg) in drug-naive MPTP-treated mice or a suprathreshold dose (20 mg/kg) in L-Dopa tolerant MPTP-treated mice were investigated. In the former case, memantine (locomotion: 3 mg/kg; rearing: 1 mg/kg) and amantadine (locomotion and rearing: 10 mg/kg) injected 60 min before the subthreshold dose of L-Dopa (5 mg/kg), each induced an antiparkinsonian action in hypokinesic MPTP-treated mice that consisted of dose-specific, as opposed to dose-related, elevations of locomotion and rearing behaviour. At the same time, higher doses of memantine reduced further the rearing (10 and 30 mg/kg) and locomotor (30mg/kg) behaviour of the MPTP-treated mice. MK-801 plus L-Dopa elevated locomotion (0.1 mg/kg) but reduced rearing at the 0.3 mg/kg dose. In control, saline-treated mice, memantine (3, 10 and 30 mg/kg) and MK-801 (0.1 and 0.3 mg/kg) increased locomotor behaviour but decreased rearing behaviour, while amantadine produced no effects. Memantine increased locomotor (1 and 3 mg/kg, s.c.; 1 mg/kg dose restored activity) and rearing (0.3 and 3 mg/kg) activity in the L-Dopa tolerant MPTP-treated mice, whereas amantadine (3 and 10 mg/kg) restored both locomotor (30 mg/kg significantly increased locomotion but did not restore the activity level) and rearing (3 mg/kg only) activity. MK-801 (0.1 and 0.3 mg/kg, s.c.) also increased significantly locomotor activity of L-Dopa-tolerant MPTP mice although the antikinetic action was not reversed, thereby precluding a restorative effect of the compound. These results, demonstrating both a synergistic and a restorative effect of the NMDA antagonists in coadministration with L-Dopa, demonstrate a putative antiparkinson action by these compounds in a functional animal model that incorporates the "wearing-off" complications of L-Dopa administration in the disorder.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1986

Effects of memantine on the frog neuromuscular junction.

The effects of memantine, an adamantane derivative, on neuromuscular transmission in the frog sartorius muscle preparation were studied by measuring the endplate current (EPC) by the voltage clamp method. Memantine (0.5-50 microM) reduced the peak amplitude and shortened the duration of the EPC, and the membrane voltage-peak EPC relationship became non-linear. Since it decreased the quantal height of the EPC without affecting the mean quantal content, the effects were considered to be mainly postsynaptic. Noise analysis revealed that memantine decreased the mean lifetime of the ACh-activated channel. In addition, lineweaver-Burk analysis of the response to ionophoretically applied carbamylcholine showed that memantine acted essentially as a linear mixed-type inhibitor. Thus memantine seems to block neuromuscular transmission by reacting with the ACh receptor-ion channel complex in both the open and closed states.

Acetylcholine↗

PubMed1992

Memantine prevents quinolinic acid-induced hippocampal damage.

Memantine, used as a drug for treatment of spasticity and other extrapyramidal disorders as well as dementia, was shown to prevent brain damage caused by the glutamate (N-methyl-D-aspartate, NMDA) receptor agonist, quinolinic acid. Studies were focused on the hippocampal formation which is known to be highly vulnerable to quinolinate. Pretreatment of animals with memantine added to the food led to a reliable protection of hippocampal neurons when the drug was administered chronically for a period of 10 days prior to quinolinate exposure (i.c.v. injected). Additional i.p. administration of memantine (simultaneously with quinolinic acid or up to 24 h later) did not substantially add to the protective potency of the memantine diet. Our findings indicate that memantine may have beneficial effects in the treatment of brain disorders which are mediated by excitotoxic effects of glutamate.

Animals↗

PubMed1994

Memantine-induced dopamine release in the prefrontal cortex and striatum of the rat--a pharmacokinetic microdialysis study.

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.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2005

Cost-effectiveness of memantine for moderate to severe Alzheimer's disease in Sweden.

BACKGROUND: Alzheimer's disease entails enormous costs for society and impairs quality of life for patients and caregivers. OBJECTIVE: This study estimated the cost-effectiveness of memantine in the treatment of patients with moderately severe to severe cognitive impairment from Alzheimer's disease in Sweden. METHODS: The study was based on published data from several sources, including a randomized controlled trial of memantine versus placebo and a longitudinal observational study of Alzheimer's disease patients in Sweden. Costs were estimated from the public payer's perspective, including direct costs but excluding costs of informal care, and resource utilization data were taken from the observational study. Cost-effectiveness was quantified as quality-adjusted life-years (QALYs) gained from treatment with the use of previously published utility weights. A Markov simulation model was constructed, incorporating the effect of treatment on cognitive function, physical dependence related to activities of daily living, and institutionalization. Costs and effects for treated and untreated patients were estimated for 5 years (10 cycles). In the base-case analysis, treatment costs were added for 2 years, but the effect on transition probabilities was applied only for the first year of treatment. RESULTS: Compared with no treatment, memantine treatment was predicted to be associated with lower costs of care, longer time to dependence and institutionalization, and gains in QALYs. Treatment was estimated to decrease formal care costs by 123,600 Swedish kronor (SEK) and, after taking into account the cost of memantine, to lead to net cost savings of 100,528 SEK per patient. Treated patients gained 0.148 QALY over the 5-year simulation. CONCLUSIONS: From a public payer's perspective, the observed effect of memantine on cognitive and physical function is predicted to translate into economic benefits that offset the added treatment cost. Treatment is also predicted to delay institutionalization, improve independence, and increase QALYs.

Activities of Daily Living↗

PubMed2005

Memantine attenuates staurosporine-induced activation of caspase-3 and LDH release in mouse primary neuronal cultures.

Developmental aspects of pro- and antiapoptotic action of some NMDA receptor antagonists in the central nervous system have been postulated. In order to further elucidate this problem, we investigated effect of memantine, an uncompetitive NMDA receptor antagonist and staurosporine alone and in combination on caspase-3 activity and lactate dehydrogenase (LDH) release in primary hippocampal, neocortical and striatal cell cultures on 7 and 12 days in vitro. The data showed that the vulnerability of neuronal cells to induction of caspase-3 activity by staurosporine was higher on 7 DIV than on 12 DIV, whereas staurosporine-mediated LDH release increased with days in vitro in striatal culture only. A specific inhibitor of caspase-3, AcDEVDCHO (60 microM), completely abolished the effect of staurosporine on this enzyme's activity, but only partially attenuated staurosporine-induced LDH release in hippocampal cells. Memantine alone (0.05-2.0 microM) did not induce any cytotoxic effect but attenuated the staurosporine-induced caspase-3 activity and LDH release in hippocampal cultured neurons on each investigated day in vitro. In striatal culture, memantine had a moderate inhibitory effect on staurosporine-evoked LDH release only on 7 DIV with no significant influence on caspase-3 activity. As for neocortical cultures, memantine partially inhibited staurosporine-induced neuronal injury only on 7 DIV. These data showed that the induction of caspase-3 activity by staurosporine was more profound in immature cells, however, the staurosporine neurotoxicity, as reflected by LDH release, only partially depended on caspase-3 activation and stage of cell development. Furthermore, memantine attenuated staurosporine-induced apoptosis more efficiently in hippocampal cultures than in neocortical and striatal ones, which points to tissue specificity of effects of this neuroprotectant.

Analysis of Variance↗

PubMed2005

Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study.

Cholinesterase inhibitors including donepezil, rivastigmine, and galantamine and the N-methyl-D-aspartate (NMDA) antagonist, memantine are the medications currently approved for the treatment of Alzheimer's disease (AD). In addition to their beneficial effects on cognitive and functional domains typically disrupted in AD, these agents have also been shown to slow down the emergence of behavioral and psychotic symptoms associated with this disease. However, the underlying mechanisms for these therapeutic effects remain poorly understood and could involve effects of these medications on non-cholinergic or non-glutamatergic neurotransmitter systems respectively. These considerations prompted us to initiate a series of investigations to examine the acute and chronic effects of donepezil (Aricept (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-1 hydrochloride and memantine (1-amino-3,5-dimethyladamantane hydrochloride C12H21N.HCl)). The present study focuses on the acute effects of donepezil and memantine on brain extracellular levels of acetylcholine, dopamine, serotonin, norepinephrine and their metabolites. We assayed changes in the ventral and dorsal hippocampus and the prefrontal and medial temporal cortex by microdialysis. Memantine resulted in significant increases in extracellular dopamine (DA), norepinephrine (NE), and their metabolites, in the cortical regions, and in a reduction of DA in the hippocampus. Donepezil produced an increase in extracellular DA in the cortex and in the dorsal hippocampus. Norepinephrine increased in the cortex; with donepezil it increased in the dorsal hippocampus and the medial temporal cortex, and decreased in the ventral hippocampus. Interestingly both compounds decreased extracellular serotonin (5HT) levels. The metabolites of the neurotransmitters were increased in most areas. We also found an increase in extracellular acetylcholine (ACh) by memantine in the nucleus accumbens and the ventral tegmental area. Our results suggest both region and drug specific neurotransmitter effects of these agents as well as some similarities. We conclude that drugs influencing cognitive mechanisms induce changes in a number of neurotransmitters with the changes being both region and drug specific. Release and metabolism are altered and extracellular neurotransmitter levels can be increased or decreased by the drugs. Other studies are in progress to determine the pharmacological effects associated with chronic treatment with these compounds, which may be more pertinent to the clinical situation in which patients take these medications for months or years.

Acetylcholine↗

PubMed2005

An evaluation of the reinforcing effects of memantine in cocaine-dependent humans.

The purpose of this double-blind, outpatient study was to evaluate the reinforcing and subjective effects of the uncompetitive N-methyl-d-aspartate (NMDA) antagonist memantine in cocaine-dependent humans. Eight participants (two females, six males) completed this study which consisted of three blocks of seven sessions; each block tested a different dose of memantine. During the first two sessions of each block, participants "sampled" the memantine capsule (10, 20, or 30 mg) and the placebo capsule that were available for the next five sessions. During the five subsequent sessions, participants had an opportunity to self-administer either the active or placebo capsule. Memantine was not reinforcing and subjective-effects ratings were not altered as a function of dose. Results suggest that these doses of memantine do not have abuse liability in cocaine-dependent individuals.

Adult↗

PubMed2005

Comparison of donepezil and memantine for protective effect against amyloid-beta(1-42) toxicity in rat septal neurons.

Donepezil, a potent acetylcholinesterase (AChE) inhibitor and memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, have been used for the treatment of Alzheimer's disease (AD), and both of them have been shown to have neuroprotective action against glutamate excitotoxicity. However, it is not known whether donepezil and memantine similarly exert neuroprotective effects against amyloid-beta peptide(1-42) [Abeta(1-42)] toxicity in cholinergic neurons. Therefore, in the present study we compared the neuroprotective effects of donepezil and memantine against Abeta(1-42) toxicity in rat cultured septal cholinergic neurons, because deficit in cholinergic neurotransmission is a major feature in AD, and medial septal cholinergic neurons are known to degenerate in AD patients. Septal neuronal cells were cultured for 7 days and then 5 micromol/L of Abeta(1-42) was added to the medium for 48 h. Measurement of the efflux of lactate dehydrogenase (LDH) indicated that septal neuronal cells were highly susceptible to Abeta toxicity and relatively resistant to NMDA toxicity. Donepezil concentration-dependently reduced the LDH efflux induced by Abeta(1-42), and the effect was significant at 1 micromol/L and above. NMDA receptor antagonists, memantine and MK-801, did not show a significant neuroprotective effect against Abeta(1-42) toxicity. It is concluded that the neuroprotective effect of donepezil against Abeta(1-42) toxicity is not mediated by interference with the NMDA-mediated excitotoxic process, and that donepezil may be more effective than memantine against cholinergic neuronal damage induced by Abeta(1-42) exposure.

Acetylcholinesterase↗

PubMed2006

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain.

The NMDA antagonist, memantine (Namenda), and the cholinesterase inhibitor, donepezil (Aricept), are currently being used widely, either individually or in combination, for treatment of Alzheimer's disease (AD). NMDA antagonists have both neuroprotective and neurotoxic properties; the latter is augmented by drugs, such as pilocarpine, that increase cholinergic activity. Whether donepezil, by increasing cholinergic activity, might augment memantine's neurotoxic potential has not been investigated. In the present study, we determined that a dose of memantine (20mg/kg, i.p.), considered to be in the therapeutic (neuroprotective) range for rats, causes a mild neurotoxic reaction in the adult rat brain. Co-administration of memantine (20 or 30 mg/kg) with donepezil (2.5-10mg/kg) markedly potentiated this neurotoxic reaction, causing neuronal injury at lower doses of memantine, and causing the toxic reaction to become disseminated and lethal to neurons throughout many brain regions. These findings raise questions about using this drug combination in AD, especially in the absence of evidence that the combination is beneficial, or that either drug arrests or reverses the disease process.

Animals↗

PubMed2006

Enhancement of long-term spatial memory in adult rats by the noncompetitive NMDA receptor antagonists, memantine and neramexane.

Memantine and neramexane are noncompetitive NMDA receptor antagonists which have been investigated for their promising effects in aiding memory in people with dementia. Memantine is approved for the treatment of Alzheimer's disease, and neramexane is currently under development for this indication. Therefore, the present study provided a comparative assessment of the effects of equimolar doses of memantine and neramexane on spatial (hippocampus-dependent) memory. Adult male rats were given only 3 training trials to learn the location of a hidden platform in a water maze. In control (vehicle-injected) rats, this minimal amount of training produced intact short-term (15 min), but poor long-term (24 h), memory. Pre-training administration of memantine or neramexane produced a dose-dependent enhancement of long-term memory. Pharmacokinetic experiments with equimolar doses of both agents indicated that lower plasma levels of neramexane were more effective than memantine at enhancing memory. The effective doses of both agents in the current study produced plasma levels (and extrapolated brain CSF levels) within a range of activity at NMDA receptors and plasma levels seen in patients with Alzheimer's disease. These findings provide support for the use of neramexane as a pharmacological intervention in the treatment of dementia.

Alzheimer Disease↗

PubMed2004

Effects of NMDA receptor antagonists (MK-801 and memantine) on the acquisition of morphine-induced conditioned place preference in mice.

Several studies have shown that the systemic administration of a variety of N-methyl-D-aspartate (NMDA) receptor antagonists can block the development or expression of conditioned place preference (CPP) induced by rewarding drugs such as morphine. In the present study, we examined the effects of different doses of two non-competitive NMDA receptor antagonists, MK-801 (0.1, 0.2 and 0.3 mg/kg) and memantine (2.5, 5, 10, 20 and 40 mg/kg), in CPP induced by 40 mg/kg of morphine in male mice. The CPP was carried out with an unbiased procedure in terms of initial spontaneous preference. Animals received the different doses of drugs in the conditioning sessions. MK-801 and memantine, at all doses used, produced neither place preference nor place aversion, but the higher doses of memantine (20 and 40 mg/kg) were able to completely block morphine-induced CPP. The present data show that the NMDA receptor antagonists MK-801 and memantine have no reinforcing properties but memantine is capable of preventing the acquisition of morphine-induced CPP. These results suggest that the development of morphine-induced CPP may be closely related to NMDA receptors and that the glutamatergic system can modulate opiate reward.

Analysis of Variance↗

PubMed1998

Investigation on possible antioxidative properties of the NMDA-receptor antagonists ketamine, memantine, and amantadine in comparison to nicanartine in vitro.

Possible antioxidative properties of three N-methyl-D-aspartate (NMDA)-receptor antagonists, the anesthetic ketamine and the antiparkinson drugs memantine and amantadine were investigated in vitro on the microsomal cytochrome P450 (P450) system of rat livers and on rat whole blood chemiluminescence in comparison to nicanartine, a substance with known antiatherosclerotic, hypolipemic and antioxidative capacity. For this purpose, the effects on NADPH- and iron-stimulated lipid peroxidation (LPO), hydrogen peroxide (H2O2) production, and NADPH- and iron-stimulated lucigenin (LC) and luminol (LM) amplified chemiluminescence (CL) were examined using rat liver microsomes. Additionally, the influence on LM amplified whole blood chemiluminescence after zymosan activation of polymorphonuclear leukocytes (WB-CL) was investigated. Furthermore, binding to P450 and effects on P450 mediated monooxygenase function, as measured by the model reactions ethoxyresorufin O-deethylation (EROD), ethoxycoumarin O-deethylation (ECOD), and ethylmorphine N-demethylation (END), were assessed. Nicanartine concentration dependently reduced LPO and H2O2 production already at a concentration of 1 microM, whereas LC and LM amplified CL and WB-CL were not affected. EROD and END were concentration dependently diminished starting at 1 microM, and ECOD already at 0.1 microM. Ketamine decreased LPO, H2O2 production and LM and LC amplified CL, starting at 100 microM. WB-CL was significantly diminished already at 10 microM. EROD and ECOD were inhibited at 10 and 100 microM and END at 100 microM. With memantine a concentration dependent inhibition of LPO and WB-CL was seen at 100 and 1000 microM and a reduction of LC and LM amplified CL only at 1000 microM. H2O2 production was not affected. EROD and ECOD were significantly diminished by a concentration of 100 microM. No effect was observed on END. Amantadine significantly reduced LPO and WB-CL, but only at 1000 microM. H2O2 production and LC and LM amplified CL were not affected. EROD was significantly diminished at 100 microM, whereas no influence was seen on ECOD and END. Nicanartine displayed type II or reverse type I, ketamine, memantine and amantadine type I substrate binding to P450. The highest binding affinity to P450 was seen with nicanartine, followed by ketamine, memantine and then amantadine. These results demonstrate, that all four substances seem to act as radical scavengers and/or as inhibitors of the oxidative function of P450. All four substances seem to interfere with the monooxygenase function of P450. This may result in a possible influence on the biotransformation of endogenous as well as of foreign compounds. The effects of nicanartine were much more pronounced than those of ketamine, memantine, and amantadine.

7-Alkoxycoumarin O-Dealkylase↗

PubMed2003

Memantine in vascular dementia.

The uncompetitive N-methyl-D-aspartate (NMDA) antagonist memantine was tested against placebo in two randomized controlled trials. In total, 900 patients suffering from mild-to-moderate "probable" VaD (according to NINDS-AIREN criteria) were included. In these prospective, 2-arm parallel, multicenter trials conducted in the United Kingdom (MMM500) and in France (MMM300), patients suffering from "probable" vascular dementia (according to NINDS-AIREN criteria) were recruited. Active treatment in both trials was memantine at the standard daily dose of 10 mg b.i.d. The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) was a primary endpoint in both trials, and in both trials a statistically significant difference was seen between treatment groups after 28 weeks. In a pooled analysis of the data, various subgroups were examined. In a first analysis, patients were stratified by their severity of dementia (measured by the MMSE total scores at baseline). In this analysis, memantine was superior to placebo in all subgroups, but the magnitude of effect was clearly more pronounced in the more severely demented patients. A second analysis stratified the patients by the neuroradiological findings at baseline ("small vessel" versus "large vessel" type of VaD). The cognitive benefit by memantine treatment was larger for the small vessel group and, interestingly, also the decline in the placebo group was faster in the small vessel patients. In these trials, memantine at a dose of 10 mg b.i.d. was safe and very well tolerated with a frequency of dropouts due to adverse events that was close to placebo.

Aged↗

PubMed2003

Binding of memantine to melanin: influence of type of melanin and characteristics.

PURPOSE: The objectives of this study were to characterize sepia, synthetic, and bovine melanin and to determine their binding characteristics to the drug memantine. METHODS: Physical methods were used to characterize sepia, synthetic, and bovine melanin. Their binding properties toward memantine were determined in deionized water and phosphate-buffered saline (PBS) at 37 degrees C. Melanin-memantine binding was measured indirectly by determining the unbound fraction of memantine. Curve fitting according to the Langmuir binding isotherm for one binding site was used for the determination of binding capacity (BLmax) and dissociation constant (KD). RESULTS: Synthetic and sepia melanin had comparable Gaussian particle size distributions, whereas bovine melanin showed a heterogeneous distribution profile. The suspension medium had a small effect on the particle size distribution of synthetic and bovine melanin. There were characteristic differences in the infrared spectra of the melanins. The rank order for BLmax in deionized water was sepia > bovine > synthetic melanin. However, when the melanins were suspended in PBS, the BLmax values were lower, and the rank order was bovine > sepia > synthetic. Whereas the KD values for sepia and synthetic melanin remained largely the same in deionized water and PBS, the KD value for bovine melanin in PBS was more than twice than in deionized water. CONCLUSIONS: This study showed that the physical characteristics of the melanins investigated differ markedly. The binding of memantine to melanin is thought to be determined by the different chemistries of the melanins, particle size, and buffer electrolytes.

Animals↗