Dementia of Alzheimer’s disease and other neurodegenerative disorders—memantine, a new hope

Pharmacological Research 51 (2005) 1–17

Dementia of Alzheimer’s disease and other neurodegenerative disorders—memantine, a new hope S.K. Sonkusare, C.L. Kaul, P. Ramarao∗ Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali 160 062, India Accepted 19 May 2004

Abstract 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 A␤-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. © 2004 Elsevier Ltd. All rights reserved. Keywords: Dementia; Memantine; Neuroprotection; NMDA-receptor antagonist; Preclinical and clinical studies

1. Alzheimer’s disease—pathology and therapeutic options 1.1. Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by irreversible, progressive loss of memory followed by complete dementia [1]. The cognitive decline is accompanied by impaired performance of daily activities, behavior, speech and visual-spatial perception [2]. The disease, along with vascular and mixed dementia, is the ∗ Corresponding

author. Tel.: +91 172 2214683; fax: +91 172 2214692. E-mail address: [email protected] (P. Ramarao).

1043-6618/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2004.05.005

commonest form of dementia affecting older people and accounts for 60–65% of dementia cases whereas vascular dementia and mixed dementia account for 15–20% of the cases each [3]. Neuritic plaques (consisting of a core of ␤-amyloid aggregates covered by dead neurons, microglia and apolipoprotein E) and neurofibrillary tangles (paired helical filaments of microtubules and hyperphosphorylated tau proteins) are the major pathological lesions in an AD brain [4]. Differential diagnosis of the disease is difficult and AD can be confirmed only when autopsy reveals characteristic pathological changes in brain morphology and histology. Various hypotheses have been proposed for the pathogenesis of AD. These include glutamate excitotoxicity as a result of blockade of glutamate uptake into the astrocytes

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by A␤ aggregates, oxidative stress and membrane lipid peroxidation induced by A␤-aggregates, membrane lipid peroxidation due to C-terminal fragment of amyloid precursor protein (APP), microglial activation by A␤-aggregates and molecular pathways activated by A␤-induced stimulation of various kinases including MAP kinases and JNK (Jun amino-terminal kinase) [5]. Cognitive impairment in AD is caused mainly by death of cholinergic neurons in basal forebrain area, though other neurotransmitter systems could well be involved. A deficit of acetylcholine (ACh) in an Alzheimer’s disease brain is well known. At the same time, extent of dementia correlates well with the extent of neuronal death caused by excess of glutamate, the most prevalent excitatory neurotransmitter in the brain [6] (Fig. 1).

1.2. Therapeutic options for treatment of Alzheimer’s disease Alzheimer’s disease is the fourth largest cause of death for people over the age of 65 years. Prevalence of the disease is shown by the United Nations Population Projections estimate, which states that more than 100 million people will be affected by the disease in coming 50 years [7]. Since the last decade or so, AD patients are being treated with replacement of neurotransmitters that are deficient in AD brain, based on ‘cholinergic hypothesis’ of AD. Currently approved drugs for AD treatment are cholinesterase inhibitors that include tacrine (Cognex® ), rivastigmine (Exelon® ), donepezil (Aricept® ) and galantamine (Reminyl® ) (Tables 1

Fig. 1. (A) Steps involved in neurodegeneration of AD and targets therein for novel treatment strategies; (B) glutamate excitotoxicity in AD and its prevention by memantine. GSK: glycogen synthase kinase; CTF: C-terminal fragment; APP: amyloid precursor protein; MAPK: mitogen activated protein kinase, JNK: Jun amino-terminal kinase, NFT: neurofibrillary tangles; NSAID: non-steroidal anti-inflammatory agents; KA: kainic acid (A: calcium channel; B: membrane ion pore).

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Fig. 1. (Continued ).

and 2). The approach is to inactivate acetyl cholinesterase (AChE), the enzyme that cleaves synaptic ACh and terminates neuronal signaling. These drugs have limited success as they only improve memory in mild dementia but cannot stop the process of neurodegeneration. The magnitude of response to AChE inhibitors depends on integrity of presynaptic neurons. Obviously, effectiveness of these agents will decrease with increase in severity of AD. Moreover, their use is associated with gastro-intestinal side effects [8]. First generation of cholinesterase inhibitors includes tacrine, physostigmine and NIK-247. These agents were non-selective and inhibited butyryl cholinesterase (plasma cholinesterase) as well. NIK-247 and tacrine also block potassium channels. Tacrine is known to cause hepatotoxicity and sedation. Selective inhibition of AChE markedly reduces peripheral adverse effects [9]. Second generation anticholinesterases were developed using this principle and include donepezil (Pfizer and Eisai) [10], galantamine (Janssen) [11] and eptastigmine (Mediolanum) [12]. Another approach is to develop prodrugs, which release the active component slowly in the blood giving long-term inhibition of cholinesterase. Metrifonate (Bayer) is one such drug that releases dimethyl-2,2-dichlorvinylphosphate. Huperazine A, a plant alkaloid having both, AChE as well as

antioxidant activity, is under investigation as a potential therapeutic option for treatment of AD [13]. As depression is commonly seen in AD patients, dual inhibitors of AChE-SERT (serotonin transporters) would be a better therapeutic option. Inhibition of serotonin transporters may also reduce dose-related side effects of AChE inhibitors. Such dual inhibitors were designed by hybridization of rivastigmine and fluoxetine [14]. 1.3. Novel therapeutic approaches for treatment of Alzheimer’s disease As the cells of central and peripheral nervous system cannot regenerate, newer strategies are aimed at preserving the surviving neurons by reducing their degeneration [15]. Some of these potentially disease modifying treatments include NMDA-receptor blockade, use of ␤-sheet breakers, antioxidant strategies, amyloid-␤-peptide vaccination, secretase inhibitors, cholesterol-lowering drugs, metal chelators, anti-inflammatory agents [16], inhibitors of tau phosphorylation, activators of phosphatases, neuroregeneration by neurotrophic factors and immunophylline ligands, supply of neuronal cells by gene therapy and human embryonic stem cells [17]. A brief description of these newer therapeutic strategies has been given below.

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Table 1 Comparative pharmacology of currently approved drugs Drug Tacrine

(Cognex® )

Donepezil (Aricept® )

Rivastigmine (Exelon® )

Galantamine (Reminyl® ) Memantine (Ebixa® , Axura® , Akatinol® , Namenda® )

Mechanism

Adverse effects

Special comments

Non-selective cholinesterase inhibitor, more affinity towards synaptic G4 form of AChE than G1 form Selective AChE inhibitor affinity for G1 and G4 forms varies from region to region Non-selective inhibitor of cholinesterases, has higher affinity for cytoplasmic G1 Form of AChE Specifically inhibits AChE

Hepatotoxicity and gastro-intestinal symptoms such as nausea, anorexia, diarrhoea

Monitoring of liver transaminase levels is required; also inhibits K+ -channels weakly

Diarrhoea, nausea, anorexia, vomiting, muscle cramps, fatigue in some cases Nausea, vomiting and diarrhoea

Reversible inhibitor, high oral bioavailability and no hepatotoxicity Pseudo-irreversible inhibitor inactivated by enzymatic cleavage at the active site of enzyme and not by metabolism Also binds to presynaptic nicotinic receptors, stimulating ACh release Inhibits pathological but not physiological functions of NMDA receptors, also has antioxidant action and increases BDNF production

Moderate affinity, non-competitive inhibitor of NMDA receptors

Nausea, vomiting, anorexia, weight loss acutely at higher doses Mild and not common, constipation, confusion, headache, dizziness, tiredness

BDNF: brain-derived neurotrophic factor; G1 and G4 forms: isoforms of AChE; G1 form is a cytoplasmic whereas G4 form is synaptic.

• Inhibition of ␤- and ␥-secretase reduces A␤ levels in brain. Activation of ␣-secretase stimulates non-amyloidogenic pathway of APP proteolysis that forms harmless p3, thereby decreasing A␤ levels. Inhibition of ␥-secretase inhibits cleavage of APP and Notch. Inhibition of notch cleavage affects embryogenesis, haematopoiesis, and thymocyte maturation. Partial inhibition of ␥-secretase does not inhibit its physiological functions [18]. • A␤ fragments are cleared by phagocytosis and intra- and extracellular proteolysis. Insulin degrading enzyme and neprilysin [19] degrade A␤-fragments extracellularly. Activation of these enzymes or administration of exogenous enzymes can be beneficial. Delivery of genes that express neprilysin into neurons of frontal cortex and hippocampus reduces A␤-levels and neuronal death [20] in transgenic mouse model expressing human form of A␤.

• In AD brain, presence of oxidative stress is well known [21]. A␤-aggregates can directly insert into cell membrane and cause membrane lipid peroxidation. After internalization into the cell, A␤-aggregates damage mitochondrial membrane leading to electron leakage from mitochondrial electron transport system. This results into formation of intracellular free radicals. C-terminal fragment of APP also results into intracellular free radical formation in a similar way. These free radicals cause membrane lipid peroxidation and disturb the integrity of neuronal membrane. This finally results in neuronal death. Free radical formation also couples with calcium excitotoxicity and both these factors act synergistically to cause neuronal death. In this regard, antioxidants, particularly those, which can cross cell membrane, can prove beneficial in AD patients [5].

Table 2 Comparative clinical pharmacology of currently available drugs Characteristic

Tacrine

Rivastigmine

Donepezil

Galantamine

Memantine

Introduced Chemical class Maximum dose (mg per day) Times per day Initial dose (mg) tmax (h) Plasma protein binding (%) Elimination t1/2 (h) Metabolism by CYP450 system Interaction with food Drug–drug interactions Metabolites Bioavailability (%)

1993 Aminoacridine 160 4 40 1–2 55 2–3 Yes (CYP1A2) Not observed Yes Active 10–30

2000 Phenylcarbamate 12 2 3 1 40 1.5 No To be taken with mealsb None known Inactive 40

1996 Piperidine 10 1 5 3–4 96 70 Yes (CYP3A4) Not observed Yes Active 99

2001 Phenanthrene Alkaloid 24 2 8 1 18 7 Yes (CYP3A4) To be taken with mealsb Yes, some Active 90

2002a Amino Adamantine 20 1 10 3–8 45 60–80 No Not observed No Inactive 100

a The drug is being used over 10 years in Germany for the treatment of dementia but was approved for this purpose by the European Medicines Evaluation Agency in February 2002. b Food delays absorption, lowers C max and reduces adverse effects.

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• Only insoluble aggregates of A␤ are neurotoxic. ␤-folded oligomeric forms of A␤ are responsible for formation of insoluble A␤-fibrils. Compounds that prevent the formation of ␤-folded forms (␤-sheet breakers) will be an obvious choice. Many such agents, e.g. laminin derivatives, rifampicin, daunomycin, etc. are being worked upon [22]. • A clinical study has shown that log-term treatment with NSAIDS decreases the risk of AD. Their effectiveness is mainly because of reduced generation of A␤1–42 which is more amyloidogenic. Anti-inflammatory activity plays a little role (by preventing microglial activation and release of neurotoxins) [23], as all anti-inflammatory agents do not show benefit in AD [24]. Unfortunately, results from clinical trials with NSAIDs are not encouraging [7,25]. • High blood cholesterol is a risk factor for AD. High cholesterol levels favour APP processing by ␤-secretase pathway that is amyloidogenic, whereas low cholesterol favours processing by non-amyloidogenic ␣-secretase pathway [26]. Cholesterol depletion inhibits A␤-formation in brain hippocampus [27]. Moreover, cholesterol-lowering statins reduce A␤-levels in vitro and in vivo [28]. Statins also block interferon-␥-induced T-cell activation, thus reduces inflammation and has neuroprotective effect [29]. • Antibodies against A␤ may enhance its excretion as observed in animal model of peripheral amyloidosis [30]. Antibodies can cross blood–brain barrier and trigger microglia to phagocytose A␤ [24]. Such passive vaccination reduces the extent of amyloid plaque formation in transgenic mouse model of AD. • Active immunisation with A␤-peptide was well tolerated in phase I trials, but many patients developed meningoencephalitis in phase II. These trials confirmed the production of antibodies to A␤ in humans, though the trials were halted [31–33]. • A␤ in brain exists as membrane associated, soluble and aggregated forms. In AD, later two fractions are aggravated [34]. Zn2+ precipitates soluble A␤ to form insoluble aggregate. Cu2+ and Fe3+ induce A␤-aggregation at acidic pH. All these ions are constitutively present in neocortex, which is the area most susceptible to AD. Depletion of biometal causes A␤-deposits to dissolve. Clioquinol prevents metal ions from binding to A␤ and prevents A␤-deposition in transgenic mouse model for AD [35]. Metal ions catalyze H2 O2 production by A␤. Metal chelator act by preventing this process [36]. • Neuronal growth factor can prevent death due to excitotoxin and oxidative stress, but its delivery to brain is a problem as it cannot cross blood–brain barrier [37]. Induction of neurotrophic factors is another option. Nerve growth factor has a survival and growth promoting effect on basal forebrain neurons. • Co-localization of tau with microtubules is required for transport of essential nutrients and organelles and neurotransmitters along the microtubules. When tau protein is hyperphosphorylated, as in AD brain, co-localisation of tau and microtubules cannot take place and the transport

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is hampered. GSK (glycogen synthase kinase)-3␤ and CDK5 (cyclin-dependent kinases) are implicated in tau-phosphorylation at sites that are phosphorylated in neurofibrillary tangles. These enzymes also accumulate in neurons with NFTs. Overexpression of GSK-3␤ results into tau-hyperphosphorylation. This indicates that inhibition of GSK-3 could be beneficial in AD [38]. • Oestrogen protects against risk of AD in ageing women by enhancing the outgrowth of nerve processes and formation of synaptic connections. It prevents neuronal death caused by oxidative stress and excitotoxicity and upregulates cholinergic and monoamine neurotransmitter transport system. In controlled trials, estrogen replacement therapy was protective against decline in verbal memory [39]. • Some of the disease modifying agents that are under phase II trials include phenserine of Axonyx (AChEI and A␤ formation inhibitor), clioquinol of Prana Biotechnology (A␤ aggregation inhibitor) and Alzhemed of Neurochem (A␤ aggregation inhibitor) [40]. • Finally, if selective antagonists at NMDA receptors are used, death of cholinergic neurons in basal forebrain can be prevented [41].

2. Memantine—a new hope 2.1. Memantine vis-à-vis other NMDA-receptor antagonists NMDA-receptor-mediated glutamate excitotoxicity is a major factor responsible for A␤-induced neuronal death. NMDA receptors therefore appear promising target for preventing progression of neurodegeneration. Theoretically, any disorder of central nervous system characterized by glutamate excitotoxicity-induced neuronal death, should be cured with treatment of NMDA-receptor antagonists. These include diseases like Alzheimer’s disease (in which glutamate excitotoxicity is one of the causative factors for neuronal death), cerebral ischemia (dying neurons at the core release glutamate to overstimulate the neurons nearby), Parkinson’s and Huntington’s disease (in which compromised neurons are sensitized to glutamate excitotoxicity, though excess of glutamate is not seen). However, clinical trials with NMDA antagonists, before introduction of memantine, have failed, the reason being side effects of these drugs that occur because of high binding affinity towards NMDA receptors, differential actions on neurons from various regions of brain and interaction with neurotransmitter receptors other than NMDA receptors [42]. Mechanism-based side effects of these agents on central nervous system include hallucination, agitation, catatonia, centrally mediated increase in blood pressure and anaesthesia. In fact, NMDA antagonists like ketamine and phencyclidine were developed as anaesthetics only. Competitive NMDA-receptor antagonists bind to the same receptor site as glutamate and include midafotel and selfotel,

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whose development has been discontinued because of their dose-related psychotomimetic side effects. Uncompetitive NMDA-receptor antagonists block the NMDA-receptor channel and prevent excessive flux of calcium inside the cell. The agents have been categorized on the basis of their in vitro binding affinities as low to moderate affinity antagonists (memantine, dextromethorphan and amantadine) and high-affinity antagonists (dizocilpine or MK-801, phencyclidine, ketamine). Uncompetitive antagonism is a type of non-competitive block i.e. it can not be overcome by increasing the concentration of glutamate [43]. High-affinity blockers like PCP and MK-801 block open ion channels and get trapped when the ion channels close, which means there is no unblocking. NMDA receptors (NR) are composed of an NR1 subunit in combination with NR2 subunit/s and a less common NR3 subunit. NR1 subunit is invariably present whereas NR2A, -B, -C or -D subunits determine the kinetics of channel opening and effect of various antagonists [44]. Subunit selective compounds therefore provide a better option for neuroprotection. Ifenprodil, an NR2B antagonist, has a less affinity for NMDA receptors and leaves non-activated receptors. Moreover, it acts mainly at persistently activated receptor ion-channels, sparing the transiently activated receptors (Table 3). Several subtypes selective NMDA antagonists have been studied that produce minimal adverse effects at neuroprotective doses. Agents selective for NR2B have shown their effectiveness in animal and primate models of Parkinson’s disease [45]. One such agent, traxoprodil is devoid of the side effects of non-selective NMDA antagonists in humans and clinical trials with traxoprodil in traumatic brain injury have shown some promise [46]. However, development of Gavestinel, a glycine-site antagonist, has been halted. Amantadine, a low-affinity NMDA-receptor blocker, is used in the treatment of Parkinson’s disease. Dextromethorphan (known for decades as a non-opioid cough suppressant),

another low-affinity NMDA antagonist, has been demonstrated to reduce epileptiform discharges reversibly in mouse cortical slices [47] and is neuroprotective in glutamate-induced excitotoxicity in retina [48]. It also has an analgesic effect in patients with diabetic neuropathy and neuropathic pain of traumatic origin [49]. Dextromethorphan reduces the amount of analgesics required perioperatively by 50% without serious side effects [50,51]. Low-affinity NMDA-receptor ion channels therefore may have upper hand over the high-affinity blockers in disorders like AD. Main reason behind this is a transient blockade of activated NMDA receptors by low-affinity agents, inhibiting their pathological functions only, leaving physiological functions unaltered. Memantine is one such agent that has been approved in European Union and Australia, whereas, US-FDA has approved it very recently in October, 2003. Above all, this agent does not show the side effects typically associated with high-affinity NMDA-blockers and its usefulness has been proved in several clinical trials across the globe. The drug has regenerated the interest in this category of drugs when NMDA antagonists were being thought of as “too toxic to be used therapeutically” in humans. Therapeutic goals in AD should be to improve the cellular energy status and the membrane functioning [52]. Memantine meets both these goals and is the first drug that can be used for the treatment of more advanced AD. 2.2. Development of memantine as a treatment for dementia Memantine is the first drug to be licensed in UK for treatment of severe AD [53] and the only treatment approved for more advanced AD [54]. Synthesized for the first time by Lilly (USA) in 1963 as a postulated hypoglycaemic agent, this drug was disappointing, as it did not have any blood sugar lowering activity. Merz Co. (Germany) was the first to identify the potential of this compound as a moderate

Table 3 NMDA antagonists at different stages of development Name of drug Agmatine Eliprodil Amantadine Amisulpiride Aptiganel Dizocilpine (MK-801) Fanapanel Ifenprodil Ketamine HCl Methoxy idazoxan Neramexane HCl Phencyclidine HCl Remacemide HCl Safinamide mesilate Selfotel a b

Ki . IC50 value.

Licensee Harvard University Pharmacia, Sanofi-Synth DuPont Pharmaceuticals Sanofi-Synth,Labo Cambridge NeuroScience Merck Sharp and Dohme Novo Nordisk, Schering AG Sanofi-Synth, Labo Pfizer, Bristol-Myer’s Squibb Pierre Fabre, Reckitt & Colman Forest, Merz Pfizer Astra Zeneca Newron Novartis

Developmental Stage

Ki or IC50

Preclinical Phase III Launched Launched Phase II Phase II Phase I Launched in 1973 Launched in 1966 Phase I Phase II Unspecified phase Phase III Phase II Phase III

219 ␮M in rat cerebral 0.277 ± 0.103 in hippocampusb 219 ␮M in cortexa >10 ␮M in cortexb 0.029 ± 0.005 ␮M in cortexa 0.0086 ␮M in cortexa 11 ± 2.1 ␮M in cortexb 10 ␮M in cortexb 3.9 ± 0.5 ␮M in entorhinal cortexb 190 ␮M cortexa 1.47 ± 0.13 ␮M in cortex a 1.06 ± 0.07 ␮M in hippocampusb 968 ± 45 ␮M in hippocampusb >100 ␮M in hippocampusb 22.4 ␮M in rat brainb

Reference cortexa

[142] [143] [142] [144] [145] [146] [147] [148] [124] [142] [60] [124] [124] [149] [150]

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affinity non-competitive antagonist at NMDA receptors in 1972. It launched the drug in 1989 for the treatment of dementia. Merz and Lundbeck submitted an NDA for memantine in AD in November 2000. The compound was in phase II trials in the US for the treatment of AIDS-related dementia and pain by August 1996 and phase III trials for glaucoma and neuroprotection by 1999. Analysts at Merrill Lynch predicted in October 2001 that Allergan would make regulatory filings in the US for memantine in glaucoma and ocular hypertension in 2005 [55]. At the same time, the drug is under development by Lundbeck, Neurobiological Technologies Inc. (NTI), Suntory for the treatment of AD, AIDS-related dementia, pain in patients with neuropathy and by Allergan for the treatment of ocular diseases. Memantine was also found beneficial in patients with vascular dementia [56,57] and in Wernicke–Korsakoff syndrome [58]. This well-tolerated drug (as shown by several clinical trials) is being used over 10 years in Germany where it is being marketed by Merz Co. under the trade name of Axura® for the treatment of dementia and was approved for this purpose by the European Medicines Evaluation Agency in February 2002. Namenda® of Forest Laboratories was approved by US-FDA in October 2003 for use in moderate to severe AD. Compared with acetylcholine-esterase inhibitors, memantine can be beneficial not only for mild but advanced dementia as well. Before the approval of memantine by US-FDA, it was predicted that the approval would make it a blockbuster drug. After US-FDA approval, memantine looks all set to cross US$ 1 billion mark in annual sales by the year 2005 [59]. Ebixa® , launched by Lundbeck Ltd. in October 2002, has been licensed for the treatment of moderately severe to severe AD. Memantine treatment leads to reduction in overall cost for management of AD patients by reducing utilization of resources. 2.3. Chemical structure of memantine Memantine (1-amino-3,5-dimethyladamantane), an amino-alkyl cyclohexane derivative (1-amino adamantine series), is a white bitter solid that is soluble in DMSO (Fig. 2). Aminoadamantanes are atypical drug compounds with non-planar, three dimensional tricyclic structure [46]. Memantine hydrochloride is readily soluble in water. The NH 3+ Cl-

R6

R5

R1

H 3C CH 3

(A)

R4

R2

R3

(B)

Fig. 2. Structure of memantine hydrochloride (A) and basic structure of aminoalkyl cyclohexane (B).

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aminoadamantanes represent a class of drugs, which may be largely free of side effects of other NMDA antagonists, and which have already been used clinically as antiviral and antiparkinsonian agents. It has been predicted that amino-alkyl-cyclohexanes having methyl substitutions at R1, R2, and R5, at least one methyl or ethyl at R3 or R4 and a charged amino-containing substitution at R6 (given in the diagram below), could be useful therapeutics in a wide range of CNS disorders involving disturbances in glutamatergic neurotransmission [60]. Kinetic analysis of the molecule shows that amino adamantane-induced block of open NMDA channels is mediated by two distinct blocking sites. These sites are located in the depth of the channel pore and can be simultaneously occupied by two blocking molecules [61]. Memantine has a log P value of 3.28 and pKa of 10.27 which make this drug suitable for oral drug delivery. • Molecular formula of memantine: C12 H21 N, • Molecular weight of memantine: 179.30, • CAS registry number: 41100-52-1.

3. Neuroprotection by memantine 3.1. Mechanisms involved in neuroprotection About 70% of all excitatory synapses in the central nervous system are stimulated by glutamate. Glutamate release from the vesicles in presynaptic neuron occurs via a calcium-dependent mechanism that involves N- and P/Q-type calcium channels. Glutamate concentration in a vesicle is around 100 mmol/L. Glutamate acts at three types of ionotropic receptors on post-synaptic membrane. These receptors have been named after their agonists as N-methyl-d-aspartate (NMDA), ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptors. NMDA receptors are present mainly in neurons and their activation results into Ca2+ influx [62] whereas AMPA- and kainate receptors are present in neurons as well as in glia and cause Na+ -influx and K+ -efflux on activation [44]. In the last decade, molecular biology of NMDA receptors has also been explored. It is now known that NMDA receptors have an NR1 subunit [63] along with one or more NR2 subunits and less commonly, NR3 subunit [64]. Four NR2 subunits (A–D) determine the biophysical and pharmacological characteristics of NMDA receptors though alternative splicing of NR1, especially in exon 5 also plays some role [45]. Glutamate is the most potent agonist at NMDA receptors in hippocampus, its EC50 being 2.3 ␮mol/L. Two special features of NMDA receptors are voltage-dependent blockade by Mg2+ ions at physiological concentrations [65] and requirement of glycine as a coagonist [44]. Each receptor unit has two binding sites for glutamate and two for glycine. Opening of NMDA receptor ion channel and calcium entry

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is a complex process, which requires binding of both, glutamate and glycine. Glutamate is released from the presynaptic terminal whereas glycine is present constitutively in the extracellular fluid at a constant level. Schaffer-collateral pathway between CA1 and CA3 regions of hippocampus plays a major role in storage of learning and memory. Long-term potentiation (LTP), which can be defined as long lasting enhancement of post-synaptic potential in response to a brief stimulus of high frequency, is responsible for long-term memory and changes in synaptic structure and strength in the hippocampus. Glutamate is the most important neurotransmitter involved in expression of LTP. Glutamate receptors could be ionotropic as well as metabotropic, but ionotropic NMDA receptors are more important for LTP. Metabotropic glutamate receptors are broadly divided into three groups—group I receptors act via stimulation of phospholipase C and production of diacylglycerol and inositol triphosphate as second messengers whereas groups II and III receptors inhibit adenyl cyclase. Transient release of high concentration of glutamate in synaptic cleft activates AMPA-receptors on post-synaptic membrane, leading to membrane depolarization that removes voltage-dependent Mg2+ -block of NMDA receptors [66]. This results into Ca2+ -influx inside the neuron. Ca2+ -calmodulin dependent kinases then induce long-term activation of neighbouring AMPA and kainate receptors. Sustained activation of NMDA receptors results into activation of MAP kinases (mitogen activated protein kinases), which translocate to the nucleus and phosphorylate CREB (cyclic AMP response element binding protein). This leads to rapid induction of several immediate early genes that give way to late response genes. This is the mechanism underlying synaptic plasticity and increased synaptic strength [45]. In short, long-term memory involves orderly activation of genes. Calcium is required in the brain for synaptic transmission, neuronal development, synaptic plasticity and several metabolic processes, but improper regulation of intracellular calcium ions is associated with pathological features of AD i.e. neuritic plaques and neurofibrillary tangles. Glutamate excitotoxicity cannot be an initiating factor for neurodegeneration, but plays an important role in events triggered by some other processes like aggregates of ␤-amyloid (A␤) and reduced energy metabolism in the neurons [67]. Chronic excess of glutamate causes overactivation of NMDA receptors and excess of intracellular calcium ions and leads to excitotoxicity (the mechanism responsible for neuronal death because of glutamate excitotoxicity in neurodegenerative disorders). Recently, it has been proposed that increased calcium influx into the cytoplasm results into accumulation of calcium inside mitochondria [68]. This leads to generation of reactive oxygen species that destroy Ca2+ -ATPase and hence to reduced ability of cell membrane to expel Ca2+ -ions. This causes further increase in mitochondrial calcium ions and when a threshold is reached, mitochondrial permeability transition pores (a way out for both calcium ions and com-

pounds with a molecular weight <1.5 kDa) open irreversibly. This is followed by exit of Ca2+ -ions and macromolecular compounds that predetermine the cell death like cyt c (amplifier for apoptotic signal), Apaf-1 (trigger for apoptosis) and caspase activators from the mitochondria [69]. This explains the role played by glutamate excitotoxicity in apoptotic cell death. Overloading of a cell with calcium ions also results into overactivation of calcium-calmodulin-dependent nitric oxide synthase (NOS). NO formed by this enzyme then combines with superoxide radicals to form peroxynitrite, which may cause DNA-fragmentation. Lastly, excess of calcium ions inside the cell overactivates various kinases, including those responsible for tau-phosphorylation and JNK (Jun amino-terminal kinase). NMDA receptors are, therefore, promising targets for neuroprotective drugs as high permeability of these receptors for Ca2+ ions is responsible for their neurotoxic potential [70,71]. Radioligand binding studies have proved selective interaction of A␤ with recognition sites for glutamate and glycine on NMDA receptors. Glutamate transporters on the glial membrane are Na+ -dependent and transmembrane gradient of Na+ and K+ is the driving force for the transport. A␤-induced elevation of cytosolic Ca2+ causes further Ca2+ release from endoplasmic reticulum by IP3 -signalling. These changes in glial membrane conductance reduces glial glutamate uptake by blockade of Na+ -dependent glutamate transporters [72]. This increases glutamate concentration in synaptic cleft beyond physiological levels [73,74] causing calcium excitotoxicity-induced neuronal death by activating NMDA receptors on post-synaptic neuronal membrane. Calcium overload may result in protein hyperphosphorylation such as that of tau proteins [75], activation of proteolytic enzymes and even DNA breakdown leading to apoptotic cell death. A␤ has also been found to increase the voltage-dependant release of glutamate in vitro [76]. This glutamate then exerts its excitotoxicity by acting on glutamate receptors (docking sites) on the cell surface resulting into calcium influx into the neurons [77]. Sustained elevation of glutamate leads to overloading of the cell with calcium and even after the transient release of glutamate that occurs during learning and memory process, the signal is not detected because of already elevated Ca2+ inside the cells. This results into impairment of learning and memory and symptoms of dementia. Though NMDA receptors are involved in long-term potentiation, continuous activation of NMDA receptors increases noise and probability of arriving signal to be detected is reduced. This couples with neuronal damage caused by Ca2+ excitotoxicity and ultimately produces neuronal dysfunction. Memantine blocks NMDA receptors non-competitively in use-dependent manner i.e. only when the channels are open. Memantine blocks NMDA receptor when there is sustained release of low glutamate concentrations. The influx of calcium is prevented (neuroprotection) [78]. The intracellular calcium pool is reduced. During learning and memory processes (i.e. transient high glutamate release), meman-

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tine—the fast, voltage-dependent NMDA-receptor antagonist—leaves the NMDA receptor for a short time and a signal is produced that can be recognized and processed (symptomatic improvement in dementia symptoms). Thus, memantine blocks the neurotoxicity of glutamate without interfering with its physiological actions required for learning and memory [3]. Memantine was found to have antioxidant property which is useful since calcium excitotoxicity is associated with oxidative stress. Moreover, only non-competitive NMDA-receptor blockers showed such property [79]. Brain-derived neurotrophic factor (BDNF) is a neurotrophin, which also enhances hippocampal synaptic transmission by increasing NMDA receptor activity [80]. Memantine increases the levels of BDNF mRNA in the limbic cortex and this effect increases with increase in dose. Effects of memantine on BDNF mRNA result in increased production of BDNF. At the same time, memantine induces isoforms of the BDNF receptor trkB. Both these factors may also mediate the neuroprotective and memory enhancing effect of memantine [81]. The N-methyl-d-aspartate (NMDA) receptors are involved in long-term potentiation (LTP) and are phosphorylated by several tyrosine kinases including Src-family tyrosine kinases Fyn. Fyn links the BDNF receptor trkB with NMDA receptors, which play an important role in spatial memory formation [82]. BDNF activates hippocampal extracellular signal-regulated kinase (ERK) and Ras-signalling, both of which are responsible for synaptic plasticity in hippocampus [83]. Calcium ions inside the cells have been found to increase BDNF expression [84]. Other actions of memantine include non-competitive, voltage-independent inhibition of 5HT3 receptor currents with an IC50 value of 2 ␮m by inducing receptor desensitization [85]. Memantine was found to reduce the peak amplitude and duration of endplate current in frog sartorious muscle preparation and it was postulated that it reacts with ACh receptor ion channel complex (IC50 value of 10 ␮m) in open and closed state and inhibits neuromuscular transmission [86]. It has also been shown to block human neuronal nicotinic cholinergic receptors (IC50 = 6.6 ␮m) [87]. Redox-modulatory sites consisting of cystein residues are present on NMDA-receptor ion channel complex. These sites act in a manner similar to memantine by blocking NMDA-receptor ion channel when it is open for an excessively longer period (pathological activation). Redox-related forms of NO act with these cystein residues by a reaction called S-nitrosylation and this reaction protects neurons against excitotoxic damage. [88,89]. Nitroglycerin supplies NO group in the form of nitrosonium ion (NO+ ), which acts with critical sulphydryl groups at the redox modulatory site and facilitates the formation of disulphide bonds. This reduces the activity of NMDA-receptor ion channel. Long-term use of nitroglycerin produces tolerance to its effects on cardiovascular system, but not to its effect on NMDA-receptor-mediated neurotoxicity in brain [90]. Clinically safer NMDA antagonists such as memantine and

9

nitroglycerin and the combination drug nitro-memantine are promising as drugs in treating neurodegenerative diseases [91]. There are several other agents acting on glutamate system, apart from memantine, in the pipeline. Sabeluzole is one such agent known to block glutamate-induced calcium influx and to stabilize neuronal cytoskeleton [22]. Taurine also protects against glutamate excitotoxicity by stabilizing calcium homeostasis and energy metabolism [92]. Dimebon, an antihistaminic agent, shows dual activity, as an NMDA antagonist (ED50 = 42 mg kg−1 , i.p.) and an AChE and BuChE inhibitor (IC50 values of 42 and 7.9 ␮M, respectively). 3.2. Memantine in neurological disorders other than dementia Besides dementias, memantine can be an effective alternative for treatment of numerous CNS disorders that include stroke, CNS trauma, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence, glaucoma and chronic pain [55]. Glaucoma is a neurodegenerative disease showing progressive loss of retinal ganglion cells (RGCs). It is a leading cause of blindness and second leading cause of irreversible blindness worldwide [93]. Safety and efficacy of memantine in glaucoma is being tested in clinical trials. Mild excitotoxicity is one of the factors contributing to RGC death. This type of excitotoxic cell death is, in part, due to overactivation of N-methyl-d-aspartate (NMDA)-type glutamate receptors. In glaucoma, glutamate levels are increased in the vitreous humour [94]. Memantine may be beneficial as it acts by blocking excessive activity of NMDA receptors without interfering with physiological activity [95,96]. NMDA-receptor excitotoxicity contributes towards neurodegeneration of Parkinson’s disease. Memantine shows antiparkinsonian activity in animal models and patients of Parkinson’s disease [97]. It also prevents MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neuronal excitotoxicity and death [98]. Neuroprotective activity of memantine has also been seen in neonatal as well as adult stroke models [91,99]. Since there is evidence that NMDA-excitotoxicity may play an important role in epilepsy, NMDA-receptor antagonists have become the compounds of interest. Memantine might be a lead for therapeutically promising compounds for symptomatic treatment of epilepsy [53,100]. Memantine was found to be effective and safe in amyotrophic sclerosis as well [59,101], suggesting NMDA receptors as a target for future treatment of multiple sclerosis. Drug dependence on exposure to opiates relates to neuronal plasticity and NMDA receptors are implicated in this. Memantine administration prevented the development of morphine dependence in rats. Memantine has also been found to be effective in the treatment of addiction [102–104]. Memantine showed antinociceptive effect in experimental models of inflammatory and neuropathic pain. It prevented carageenan-induced mechanical

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Table 4 Memantine—preclinical evidence Experimental model

Parameter

Effect of memantine

Reference

Adult (9–12 months) male F-344 rats

(a) LTP or field excitatory post-synaptic potential (f-EPSP) (b) Morris water maze task

[109]

Injection of antigen or lipoplysaccharides in NBM NMDA-receptor overactivation by an agonist or reduced Mg2+ concentration Systemic NMDA-administration (25 mg kg−1 ) Incubation of hippocampal slices with NMDA (10 ␮M) Lesioning of entorhinal cortex in rats by quinolinic acid AF64A-induced lesions to cholinergic neurons A␤-injection in hippocampal fissure

Inflammation, neuronal death

Increased maintenance of LTP of f-EPSP at 30 mg kg−1 Increased tendency towards selective spatial search 1 ␮M memantine provided neuroprotection Attenuated NMDA-induced deficit in passive avoidance and LTP Antagonized the impairment produced by NMDA Antagonized NMDA-induced decrease in expression of LTP Decreased lesion-induced impairment

Incubation of rat cortical cell culture with human HIV type 1 coat protein gp120

Passive avoidance in vivo and LTP in CA1 in vitro LTP in vitro and passive avoidance LTP expression, AMPA-mediated field potential in CA1 Radial Arm Maze performance Active avoidance and Morris water maze Neuronal death, astrocytic and microglial activation, spatial discrimination DNA fragmentation, percentage of viable cells

and thermal analgesia and reduced nociception during late phase of formalin test [105,106]. Memantine exhibited an antinociceptive effect in diabetic neuropathy in rats [107]. 3.3. Memantine in experimental models for Alzheimer’s disease and dementia—preclinical evidence Memantine inhibits binding of (3 H)MK-801 to both rat and human cortical neuronal membranes with an affinity that is less than MK-801. Unblocking kinetics of memantine (Koff =0.2 s−1 ) is 40 times faster than that of MK-801 (Koff = 0.005 s−1 ) [108]. Memantine improves memory and spatial learning in aged rats and increases the expression of hippocampal LTP. Memantine-treated rats showed more selective spatial search patterns in the training quadrant of the Morris water maze. Electrophysiological studies have shown the ability of memantine to increase the durability of synaptic plasticity in moderately aged rats and improved performance in Morris water maze task [109,110]. Incubation of rat hippocampal slices with exogenous NMDA decreased AMPA-receptor-mediated currents and impaired LTP in CA1 region. This latter effect was prevented by co-incubation with memantine but not by MK-801 [111] indicating a basic difference in mode of action. It also improves reference memory based learning in rats with lesions in entorhinal cortex, the area that is affected in early stages of AD [112]. Memantine cured the memory impairment caused by AF64A-induced lesion of cholinergic system [113]. Memantine protected neurons from glutamate-induced neurotoxicity (EC50 of 1.1–1.4 ␮m) [60] and reduced A␤-induced apoptotic death and neuroinflammation in the hippocampus [114]. It also exerted antiapoptotic effects against DNA fragmentation induced by the HIV type I coat

Attenuated the deficit in memory due to the lesion Protected against A␤-induced neuronal death Prevented apoptosis caused by gp120

[110] [110] [111] [111] [112] [113] [114] [115]

protein gp 120 [115]. Apoptosis induced by gp120 may contribute to the neurological complications associated with the immunodeficiency syndrome. The cytoprotective effect of memantine as observed in cortical cell cultures may help in the treatment of AIDS-related dementia. There was no evidence of carcinogenicity, genotoxicity and impairment of fertility with memantine in animal toxicity studies. Table 4 summarizes the preclinical findings with memantine. 4. Clinical studies with memantine 4.1. Clinical trials of memantine in dementia patients The efficacy of oral memantine has been evaluated in three recently concluded short-term random clinical trials (RCT) [116] and one post-marketing surveillance (PMS) [117] study in patients of age 60–80 years already diagnosed with moderate to severe AD (Table 5). One RCT and one PMS showed improved global symptoms and functional task performance in patients whereas the other RCT showed reduced deterioration of global functions in memantine-treated patients. Three recent trials of memantine have already been completed—one in Latvia, one US phase III trial testing memantine as a single drug therapy, and another phase III trial testing memantine in combination with donepezil (Aricept® ), a cholinesterase inhibitor marketed by Eisai, Inc. and Pfizer, Inc. Data from the combination therapy trial suggests that individuals who received both memantine and donepezil performed better in terms of their thinking skills and ability to perform daily activities than those who took donepezil and a placebo. Combination therapy of memantine with donepezil was well tolerated (no adverse drug reactions reported), safe and effective [118]

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Table 5 Clinical trials on memantine About the trial

Number and type of patients

Dose (mg per day)

Duration

Assessment

Reference

Randomized, double blind, placebo-controlled Double-blind, randomized, parallel-group study Post-marketing surveillance, combination therapy (memantine + donepezil) Double-blind, placebo-controlled Double-blind, placebo-controlled, parallel-group, randomized, unconfounded Double-blind, parallel group, randomized placebo controlled Randomised, double blind, placebo-controlled Placebo-controlled, multi-centred Post-marketing surveillance Randomized, two-centred, placebo-controlled Randomised, double blind, placebo controlled

Outpatients with moderate to severe AD patients, n = 252 Moderate to severe AD or VaD patients, n = 166 Moderate to severe AD out-patients, n = 158

20

28 weeks

ADCS-ADL, CIBIC-plus

[121]

10

12 weeks

BGP, CGI-C

[116]

20

16 weeks

SIB, ADCS-ADL, CIBIC-plus

[118]

20

28 weeks

[123]

20

28 weeks

ADAS-Cog, CGI-C ADL, CGI-C, CIBIC-plus

20

28 weeks

CGI-C, MMSE, ADCS-ADL

[58]

20

28 weeks

CGI-C, BGP

[122]

20

28 weeks

[57]

20

6 weeks

ADAS-Cog, CIBIC-plus CGI-C, ADL

[117]

10 from D1 to D3, 20 from D4

42 days

SCAG, GBS, DL

[151]

Starting dose 5 mg per day, increase to 20 mg per day

24 weeks

SIB, ADCS-ADL, CIBIC-plus, BGP

[120]

Patients with mild-to moderate VaD, n = 900 Moderate to severe AD or VaD

Patients with Wernicke–Korsakoff syndrome, n = 16 Out-patients with moderate to severe AD Patients with VaD, n = 321 Patients with advanced dementia, n = 531 Patients with mild to moderate dementia, n = 88 Patients with moderate to severe AD, n = 404

[3]

ADCS: Alzheimer’s Disease Cooperative Study; ADL: activities of daily living; CIBIC-plus: clinician’s interview based impression of change; BGP: Beurteilungsskala fur Geriatrische Patienten, rating scale for geriatric patients; CGI-C: clinical global impression of change; SIB: severe impairment battery; ADAS-Cog: Alzheimer’s Disease Assessment Scale—Cognitive subscale; MMSE: Mini-Mental Status Examination; SCAG: total sum Scores of Clinical Assessment of Geriatric scale; GBS: Gottfries–Brane–Steen scale; D1: day 1.

and there was no drug–drug interaction between these two [119]. The results from a study in patients with moderate to severe dementia already receiving stable treatment with donepezil, memantine resulted in significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome and behavior and was well tolerated [120]. Whether effects of memantine in combination with cholinesterase inhibitors are complementary or synergistic needs to be determined [121]. A placebo-controlled study of memantine in dementia of Wernicke–Korsakoff syndrome in Vienna, Austria showed significant and clinically relevant benefit for memantine-treated group as compared to placebo-treated group as demonstrated by results of MMSE, CGI and ADCS-ADL [58]. In a 28-week, randomized, double-blind, placebo-controlled, multicentred study at Auckland, New Zealand, memantine at 20 mg per day slowed deterioration in patients with moderate to severe AD [122]. Another study of similar kind reported slowing of deterioration with memantine at 20 mg per day in patients

with moderate to severe AD, the variables studied were CIBIC-plus, ADCS-ADL [121]. In a 28-week multicentred study in UK, memantine (20 mg per day) was found to improve cognition relative to placebo in vascular dementia and was well tolerated [123]. In all these trials, memantine was found safe and well tolerated. The tolerability of an NMDA antagonist depends upon its affinity towards the receptors, unbinding kinetics and voltage dependency. Multiple clinical trials using NMDA receptor antagonists (phencyclidine, MK-801) have been stopped mainly due to the severe psychomimetic adverse effects. 4.2. Adverse effects of memantine observed in clinical studies Memantine has shown acceptable safety and tolerability in 2297 patients and 27 clinical trials. In contrast to high-affinity NMDA antagonists, side effects associated

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with the use of memantine are of mild intensity and include hallucinations, confusion, dizziness, headache and tiredness. Binding of dizocilpine to phencyclidine-binding site of NMDA receptors (MK-801) is associated with severe psychomimetic effects of this compound. Memantine also binds to the same site at NMDA receptors. This is the reason why many physicians are cautious while using memantine for patients of AD. In clinical trials of memantine in moderate to severe dementia, commonly seen adverse reactions as compared to placebo-treated group were (1–10% and more frequent than placebo) hallucinations (2.0% versus 0.7%), dizziness (1.7% versus 1.0%), headache (1.7% versus 1.4%), confusion (1.3% versus 0.3%) and tiredness (1.0% versus 0.3%). Other adverse effects seen during clinical trials include (as reported in Approval Labeling Text for Namenda® ) syncope, cardiac failure, vertigo, transient ischemic attacks, ataxia, hypokinesia, anaemia, increased alkaline phosphatase activity, skin rash and frequent micturition.

5. Pharmacokinetics of memantine Memantine HCl is available as a 10 mg tablet and as a 10 mg mL−1 oral solution. The maximum daily dose is 20 mg. To reduce the risk of side effects, the maintenance dose is achieved by an upward titration of 5 mg per week over first three weeks. From fourth week onwards, the treatment can be continued with maintenance dose of 20 mg per day (Lundbeck Ltd., Ebixa, Summary of Product Characteristics, 2002). In patients with moderate renal impairment, the dose can be reduced to 10 mg per day. At current prices, treatment with memantine for a year at 20 mg per day costs £890. 5.1. Animal pharmacokinetics Regional binding characteristics of memantine and other NMDA antagonists have been studied using quantitative receptor autoradiography. Drugs that are well-tolerated showed higher affinity in cerebellar region than in forebrain whereas the drugs known to cause neurobehavioral or psychomimetic side effects showed higher affinity in forebrain. This also showed that cerebellar NMDA-receptor ion channels are different from those in forebrain [124]. In a study in rats, it was shown that same dose of memantine results into about two fold higher serum levels of memantine in female rats as compared to male rats [125]. It has been reported that memantine does not have any effect on dopamine release from prefrontal cortex and does not have any psychotomimetic effects [126]. 5.2. Human pharmacokinetics Memantine crosses blood–brain barrier rapidly and within 30 min of 20 mg intravenous infusion, the drug can be de-

tected in cerebrospinal fluid (CSF). At a dose of 20 mg per day, the CSF levels match the inhibition constant of memantine at the phencyclidine-binding site of NMDA receptors, which is 0.5 ␮m in human frontal cortex [127]. CSF level attained by memantine was lower than serum level in each patient and a mean CSF/serum ratio of 0.52 has been reported [128]. The drug shows linear pharmacokinetics in the dose range of 5–40 mg. It undergoes little hepatic metabolism, so clearance of memantine may not be affected in patients with hepatic impairment. Memantine does not inhibit CYP450 isoenzymes in vitro. In humans, major metabolites are N-3,5-dimethyl gludantan which is an isomeric mixture of 4- and 6-hydroxy memantine and 1-nitroso-3,5-dimethyl adamantine, none of which is NMDA antagonist [124]. Memantine is 100% bioavailable after an oral dose and shows a tmax of 3–8 h. There are no reports showing effect of food, sex and age on absorption of the drug. It shows minimal metabolism and a terminal elimination half-life of 60–80 h. In patients with normal kidney function, total clearance (Cltot ) is around 170 mL/min/1.73 m2 . A daily dose of 20 mg takes plasma steady-state concentration to 70–150 ng mL−1 [104]. No difference was observed in steady-state plasma concentrations of memantine between healthy subjects and patients with dementia. About 45% of the drug in plasma is bound to plasma proteins [129] and volume of distribution is 10 L kg−1 . About 75% or more of the drug is excreted unchanged via urine. Acidification of urine increases the renal clearance of memantine but urine flow does not affect its renal clearance significantly [130]. In case of overdosage, excretion of memantine can be hastened by acidification of urine. 5.3. Therapeutic index Memantine has a high therapeutic index as it inhibits NMDA-receptor-mediated currents with an IC50 of 3 ␮M whereas the expression of LTP is inhibited at a much higher concentration with an IC50 of 11.6 ␮M. This is in contrast with MK-801 that inhibits both, NMDA-receptor currents as well as LTP with an IC50 of 0.14 ␮M [131,132]. 5.4. Interactions with other drugs Memantine has the potential to interact with a number of drugs. It releases dopamine in a dose-dependent manner [133,134] and hence enhances the actions of l-DOPA, dopaminergic agonists and anticholinergics. A study has shown that memantine enhances anti-Parkinsonism activity of l-DOPA when the two drugs are co-administered in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)treated mice [135]. NMDA-receptor-mediated events are involved in MPTP-induced neurotoxicity. This is another mechanism by which memantine may be helpful in Parkinsonism [98]. At the same time, memantine suppresses dopamine decarboxylase and this may render l-DOPA less

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effective for Parkinsonism treatment [136]. It reduces the activity of neuroleptics and barbiturates [137]. Memantine along with other low-affinity NMDA antagonists enhance anti-nociceptive activity of morphine recorded from the tail in rats [138]. It may restore the analgesic activity of morphine in acutely tolerant rats [139]. A role for excitatory amino acids has been implicated in epilepsy. Memantine and similar NMDA antagonists potentiate the activity of conventional antiepileptics and this combination has a potential clinical importance [98]. Memantine blocks 5-HT3 receptor currents and this activity may be responsible for clinical depression seen with memantine [85]. Concomitant administration of memantine and amantadine or ketamine should be avoided as all are chemically related NMDA antagonists, affect dopaminergic system [140] and may compete for the probenecid-sensitive organic cation transporters in renal tubules. Drugs like cimetidine, ranitidine, procainamide, quinidine, and nicotine use same cationic renal transport system [141] as amantadine and may interact with memantine increasing its plasma concentration. Drugs that increase urinary pH may result in accumulation of memantine. No clinical data regarding safety in pregnancy are available for memantine but the drug has shown a potential for reducing intrauterine growth in animals (Lundbeck Ltd., Ebixa, Summary of Product Characteristics, 2002). Hence, it is better to avoid use of the drug during pregnancy unless very necessary. It is not known whether memantine is excreted in breast milk but being a lipophillic compound, it may be excreted. Hence, women taking memantine should not breast feed. 5.5. Conclusion Discovery of memantine has shown for the first time that NMDA antagonists can also be used therapeutically in AD and other neurodegenerative diseases without causing the adverse effects of NMDA antagonists discovered earlier, in the therapeutic dose range. Memantine is a well-tolerated, moderate affinity, non-competitive NMDA-receptor antagonist. It blocks the neurotoxicity of glutamate, but not its physiological functions. The drug exerts its therapeutic effect in various conditions mainly by blocking glutamate excitotoxicity, although it has antioxidant property and also increases production of BDNF. As far as AD is concerned, once diagnosed, further neurodegeneration can be prevented by memantine treatment. At the same time, it needs to be emphasized that memantine is just a disease modifying agent and cannot revert the process of neurodegeneration. In short, though this drug is way ahead of other approved drugs for treatment of AD, in no way it is a solution to our search for cure to AD. Memantine will enjoy exclusivity for an initial period of 1–2 years. Later on, it may face competition from the emerging agents that have potential to modify underlying pathology of AD and are already under clinical trials.

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