Sage Journals: Discover world-class research

Abstract

The treatment of moderate to severe Alzheimer's disease is reviewed with regard to mechanisms of action, pharmacokinetics, metabolism, safety/tolerability, and efficacy in reducing cognitive, behavioral/psychiatric, functional and global symptoms. The cholinesterase inhibitors donepezil, rivastigmine and galantamine and the N-methyl-d-aspartate receptor channel blocker memantine are moderately beneficial. Small improvements over a few months are followed by slowed mental decline. Concerning cognitive, functional and global functions, these drugs are similarly effective. Cholinesterase inhibitors also reduce apathy, memantine counteracts agitation and aggression. Serious adverse effects are rare with all four drugs. Cholinesterase inhibitors bear a risk for patients with cardiac diseases. Adverse emetic events are typical for oral formulations of these drugs, but less for rivastigmine transdermal patches. Other routes of administration and use of a galantamine prodrug are currently investigated. The superiority of combination therapies over monotherapies requires further support. Promising investigational drugs include the copper/zinc ionophore PBT2 and multifunctional hybrid molecules.

Keywords

Alzheimer's disease Cu/Zn ionophores donepezil galantamine memantine rivastigmine

Introduction

Alzheimer's disease (AD) is characterized by amyloid-β peptide (Aβ) toxicity, formation of amyloid plaques, hyperphosphorylation of tau and cytoskeletal tangles. The progressive, devastating neurodegeneration resulting from these changes cannot be halted by current treatments. The prevalence of AD is steadily increasing and expected to rise from about 25 to over 80 million patients worldwide by 2040.^1,2 Although various risk factors and several aspects of neurotoxicity have been identified that lead to losses of neurons and reduced connectivity, the etiology of this disease is not understood in terms of initiating alterations. The frequently read statement that the origins of AD are presumably multifactorial may be correct.^3–6 This would be in accordance with the multiplicity of risk factors. However, this assumption may somehow reflect our helplessness concerning the disease onset. Consequently, the approved treatments are, in their essence, symptomatic.

Even though current AD pharmacotherapies do not stop the progressing neurodegeneration, symptomatic treatments can moderately improve cognitive functions, memory and daily life, and attenuate disease-related behavior. A transient support of the patient's quality of life and the reduction of caregivers’ burden must not be underrated.

Four approved drugs are actually in use, the cholinesterase inhibitors (ChEIs) donepezil (Aricept^®), rivastigmine (Exelon^®) and galantamine (Reminyl^®, Razadyne^®), and the N-methyl-d-aspartate (NMDA) receptor antagonist memantine (Ebixa^®). Many other compounds are in preclinical or early clinical stages of investigation. The three ChEIs have been licensed for the treatment of mild to moderate AD (in the US, donepezil also for severe AD), whereas memantine has been approved for moderate to severe AD, with several deviations and limits by national regulations.

The use of ChEIs is based on the so-called cholinergic hypothesis.^6–9 This concept had been developed in accordance with early clinical and anatomical observations as well as pharmacological studies in humans and non-human primates. Impairments of memory and cognitive functions in AD were shown to be associated with a rather specific neuronal death in the main cholinergic output system, the basal forebrain, in particular, the nucleus basalis of Meynert and medial septal nuclei, and with corresponding degeneration in the diagonal band of Broca. These changes impair the cholinergic transmission to cortex and hippocampus. Moreover, central cholinergic blockade by scopolamine led to AD-like memory deficits, which were reversed by the ChEI physostigmine. The rationale of ChEI treatment is, therefore, to normalize cholinergic transmission by reducing acetylcholine (ACh) cleavage and thereby enhancing its concentrations in the synaptic cleft.

Neurodegeneration in AD is, however, not restricted to the cholinergic system and not to the areas mentioned. With regard to the complexity of central neurotransmission and multiple interactions arising thereof, functional deficits or excitotoxic alterations were observed with various neurotransmitters, such as serotonin, norepinephrine, dopamine, some neuropeptides and glutamate.¹⁰ In AD, the glutamatergic NMDA receptor (NMDAR) is excessively stimulated, an effect that leads to Ca²⁺ overload and excitotoxicity.^11–14 As deduced from animal models and studies in transfected cells, these changes may result mainly from three causes, (i) a reduction in nicotinic ACh receptor-mediated inhibition of NMDAR activation,¹⁵ (ii) direct activation of the NMDAR by Aβ peptide,¹⁶ and (iii) indirect activation of the NMDAR by glutamate release from microglia exposed to Aβ.¹⁷ Treatment with the moderately inhibitory, uncompetitive NMDAR antagonist memantine intends to prevent fatal overstimulations of this receptor and, thus, excitotoxic cell death.

In addition to the approved drugs, numerous investigational compounds have been developed for purposes of cognitive improvements in AD. Relatively few of them have reached the stage of clinical investigation. The strategies vary from targeting other neurotransmitter systems, attempts of reducing Aβ formation and toxicity to the use of multifunctional drugs. These multi-factorial hybrid molecules combine residues that interact with different binding sites of receptors or channels or contain an additional antioxidant moiety.

In contrast to the high number of these rarely investigated compounds, the approved cognitive enhancers have been studied in numerous clinical trials. Even the number of reviews would by far exceed the frame of an article of reasonable length. Several of the reviews and meta-analyses published during the last years provide comprehensive information on design and outcome of the studies on donepezil,^18–37 rivastigmine,^{18,20,23–25,29,32,33,37–45} galantamine,^{18,20,23–25,29,32,33,37,46–51} and memantine.^{14,21,30,39,52–65} As a bottomline, the approved drugs are capable of affording moderate improvements of cognitive and behavioral functions, but only for a limited period of time. This view has not changed during the last years. Therefore, this review will, instead of repeating what has been reported and summarized many times, primarily focus on recent publications, on new insights and developments.

Mechanisms of Action, Metabolism and Pharmacokinetic Profiles

Cholinesterase inhibitors

ChEIs aim to antagonize memory, cognitive and behavioral impairments by enhancing ACh concentrations in the synaptic cleft and, thereby, improving cholinergic neurotransmission. The apparently logical rationale of normalizing synaptic ACh signaling has, however, some physiological limits, which are rarely considered by clinicians. ACh levels vary within the circadian cycle^66,67 and, during night, also between sleep stages.^66–68 These functional changes have different consequences for memory and cognition. High levels of ACh, as supported by ChEIs, favor wakefulness, facilitate memory encoding and presumably also cognition. Low ACh concentrations, as occurring during slow-wave sleep, are required for consolidation of the declarative memory. Non-declarative memory consolidation is, however, favored during REM (rapid eye movement) sleep, during which ACh is elevated.⁶⁷ Donepezil was shown to increase REM sleep in AD patients.^69,70 Therefore, the pharmacokinetics of ChEIs leads to different consequences concerning declarative memory consolidation. Donepezil, which is more slowly absorbed (t_max = 3–5 h), but even more slowly eliminated (T_½ = 50–80 h; 100% bioavailability),⁶⁷ should rather disfavor this type of consolidation. Under this aspect, the more rapidly acting rivastigmine (t_max = 0.5–2 h; T_½ = 0.6–2 h; bioavailability 35%–40%)⁶⁷ may appear to be of advantage, but only if it is orally administered and not via transdermal patches. The pharmacokinetics of galantamine is of an intermediate type (immediate release: t_max = 0.9–2 h; T_½ = 7–8 h; prolonged release: t_max = 4.4 h; T_½ = 8–10 h; 100% bioavailability for both formulations). For this reason, appropriately timed galantamine may be easily adapted to the circadian cycle of cholinergic activity (what has rarely been done),⁶⁷ whereas this is not possible with donepezil or rivastigmine capsules. Rivastigmine transdermal patches, from which the drug is much more slowly absorbed (t_max = 8.1 h), generate an almost constant plasma level over 24 h.^39,44,71 However, the circadian timing may become less relevant as soon as circadian clocks, timing of sleep and sleep architecture are severely impaired in the course of disease progression.^67,72

The considerable T_½ differences between ChEIs are explained by protein binding and elimination pathways. In the circulation, donepezil is to more than 95% protein bound¹⁹ and, therefore, slowly eliminated by hepatic CYP 2D6 and CYP 3A4 monooxygenases. Less than 40% of rivastigmine are bound to plasma proteins, which contributes to the short action of the oral formulation.⁷³ The compound is, in part, hydrolyzed by acetylcholinesterase, but excreted largely unmetabolized⁷⁴ or as a sulfate conjugate.⁷³ Because of an absent liver metabolism, drug interactions at the CYP level do not occur. Only a small fraction of galantamine is bound to plasma proteins (18%).⁷⁴ Renal and hepatic (by CYP 2D6 and CYP 3A4) pathways contribute to the elimination of this drug.⁷⁴

The inhibitory actions of ChEIs are not identical. Donepezil is a selective, reversible inhibitor of acetylcholinesterase (AChE), which blocks the enzyme's active center. Although the drug easily crosses the blood brain barrier, IC₅₀ levels are not attained in the cerebral cortex with doses of 5 or 10 mg/day, but remain in the range of 20%–34% inhibition,^75–77 findings which gave rise to the development of high-dose tablet (23 mg/day).⁷⁸ Rivastigmine is a so-called pseudo-irreversible inhibitor of both AChE and butyrylcholinesterase (BuChE), an enzyme of lower substrate specificity.^39,74 The clinical importance of BuChE inhibition is marginal. Rivastigmine is cleaved, at a low rate, by AChE, which slowly reverses the inhibition. The property of dual inhibition of AChE and BuChE is shared by two ChEIs used in earlier studies, physostigmine⁷⁹ and tacrine.⁷³ Tacrine was withdrawn mainly because of CYP-dependent hepatotoxicity^80–82 and poor efficacy.⁸³ Velnacrine, a tacrine derivative, exhibited a similar toxicity profile and was poorly effective.⁸⁴ Galantamine is a competitive, reversible inhibitor of AChE, which binds to the anionic site of the active center.⁸⁵ Its affinity to BuChE is two orders of magnitude lower⁸⁵ and, thus, clinically irrelevant.

The differences between ChEIs concerning AChE and BuChE extend to the expression levels of these enzymes after treatment. In the CSF of AD patients, donepezil and galantamine increased AChE protein levels by 215 and 51%, respectively, and BuChE rather moderately, whereas rivastigmine decreased AChE and BuChE proteins by about 9 and 22%, respectively.^86,87 Whether such differences are relevant to a higher efficacy of rivastigmine in patients carrying the AChE A/A genotype⁸⁸ remains to be clarified.

ChEIs may possess additional properties that support cholinergic signaling. In preclinical studies, donepezil, rivastigmine and galantamine were shown to enhance the expression of the particularly relevant nicotinic receptor α7nAChR, and also non-α7nAChR receptors, in a region-specific manner.^{89

91} However, α7nAChR is also upregulated in AD^92,93 and directly stimulated by Aβ_1–42 peptide.⁹⁴

Various interactions of ChEIs with other neurotransmitter systems have been described or assumed, including serotonin and dopamine, but the clinical relevance has remained questionable.⁹⁵ The situation may be different in the case of α7nAChR and glutamate signaling, since nicotine⁹⁶ as well as donepezil and galantamine^91,97 were shown to protect against glutamate excitotoxicity via α7nAChR-dependent signaling, effects which are of interest with regard to the use of memantine, alone or in combination with ChEIs.

Several earlier reports that indicated inhibition of amyloid formation by nicotine have been mostly attributed to its direct binding to Aβ_1–42 peptide, but an involvement of α7nAChR signaling has been also discussed.⁹⁸ However, convincing data for clinical efficacy of ChEIs in substantially reducing amyloid deposits are not available.

It should be briefly mentioned that several other ChEIs have been recently developed. Some of them are derived from a natural plant constituent, cardenol.⁹⁹ Various others represent derivatives of tacrine,^100–103 despite the known hepatotoxicity of the parent compound. In two series, toxicity was reduced by using 7-methoxytacrine as a core compound.^100,101 The suitability of these drugs will largely depend on the outcome of safety studies.

N-methyl-d-aspartate receptor antagonists

Several NMDAR antagonists of weak to moderate affinity have been tested to counteract the increased glutamate release and NMDAR-dependent excitotoxicity observed in AD. One of them, dimebon (= latrepirdine), proved to be too weak, in therapeutic doses, and some clinical effects were later ascribed to inhibitions of histamine H₁ and serotonin 5-HT₆ receptors.¹⁰⁴

The adamantane analog, memantine, is actually the only approved drug of this category. The compound is an uncompetitive open-channel blocker of moderate affinity to the NMDAR (IC₅₀ about 1 μM at −70 mV).^14,56 The additional property as a 5-HT₃ antagonist is presumably not of therapeutic relevance.¹⁰⁵ Memantine does not compete with agonists, but rather enters the interior of the channel, where it prevents Na⁺ and Ca²⁺ influx, similar to Mg²⁺ bound in the polarized state. The tolerability of memantine seems to be partially due to its moderate affinity which allows rapid blocking/unblocking kinetics and pronounced voltage-dependence.⁵⁶ Long-lasting inhibitions would be unfavorable under conditions of rapidly changing excitation. Other open-channel blockers such as (+)MK-801 and phencyclidine leave the channel too slowly after depolarization for being clinically suitable.⁵⁶ However, under excitotoxic conditions, in which depolarization is steadily sustained via AMPA (α-amino-3-hydroxy-5-methyl-isoxazole-propionate) receptors, the partial NMDAR blockade by memantine is functionally effective to prevent an excessive Ca²⁺ influx.¹⁴ Therefore, the fatal consequences of Ca²⁺ overload are avoided such as activation of Ca²⁺-dependent enzymes, eg, neuronal NO synthase, and the reductions of mitochondrial electron flux and membrane potential.

Memantine is slowly but almost completely absorbed (t_max = 5–6 h) and has no substantial hepatic metabolism. It is slowly excreted. In patients without renal impairment, T_½ is in the range of 60–80 h.^14,106 At a therapeutic dose of 20 mg/d, the steady-state plasma concentration of about 90 μg/L is almost attained after 10 d, with a minor increase thereafter. Similar values are obtained with 10 mg twice/d.¹⁰⁶

AMPAR potentiators

Although glutamatergic overstimulation is a feature of AD, the observations that AMPA receptor (AMPAR) expression can decline during aging and is decreased in transgenic AD mice has prompted investigators to develop AMPAR potentiators for purposes of cognitive enhancement. CX717 (Ampakine^®) has been tested preclinically and, clinically, in some non-AD trials, as summarized elsewhere.¹⁰⁷ The allosteric AMPAR activator S 18986 does exhibit properties of a cognitive enhancer in various animal models.¹⁰⁷ With regard to the undesired permanent glutamatergic stimulation in AD, one may be sceptic concerning its applicability in this disease.

Metal chelators and ionophores

An entirely different approach aims to intervene at the level of Aβ-related metal toxicity. Since attempts of reducing Aβ_1–42 formation by modulators of γ-secretase activity, such as tarenflurbil, were clinically unsuccessful in terms of cognition and daily life,¹⁰⁸ the focus of interest moved from Aβ peptide levels to the mechanisms of toxicity. Aβ is known to bind transition metal ions at histidines-6, −13, and −14 and alanine-2.^109,110 Two ions are of particular relevance in AD, namely, Cu²⁺ and Zn²⁺. Zn²⁺, which is loaded to synaptic vesicles by the zinc transporter ZnT₃, enters the synaptic cleft presynaptically by neuronal exocytosis,¹¹¹ whereas Cu²⁺ is released from the postsynapse by Menkes ATPase.¹¹² These normal processes are usually compensated by reuptake. In AD, however, binding of these metals to Aβ has several toxicological consequences. Aβ-metal complexes favor the formation of toxic soluble oligomers, which, among other effects, hyperactivate the NMDAR.¹¹³ Moreover, the Aβ-copper complex can undergo redox cycling, which results in hydroxyl radical formation by a Fenton-like reaction.¹¹⁴ Copper-dependent oxidation seems to also favor Aβ oligomerization by dityrosine crosslinks.¹¹⁵ Binding of Cu²⁺ to alanine-2 carbonyl promotes amide hydrolysis at this peptide bond and leads to the truncated Aβ_3–42,¹¹⁰ which is found in oligomers and amyloid plaques and which has been related to the severity of the AD phenotype.¹¹⁶ While considerable quantities of Cu²⁺ and Zn²⁺ are by time sequestered in amyloid plaques, intracellular stores of especially Cu²⁺ become gradually depleted. Intracellular Cu²⁺ deficiency has been discussed as a cause of further Aβ formation, which would lead to a vicious cycle.^117–119

With regard to these mechanisms, a removal of Cu²⁺ and Zn²⁺ from the synaptic cleft by chelators that form stable complexes would be counterproductive, since this would aggravate intracellular copper deficiency. However, chelators that are capable of binding the metal ions and mediate, as ionophores, their re-entry into the cytosol and allow dissociation from the chelator, may be beneficial. Several compounds have been developed that fulfil these requirements.^113,119,120 One possibility is that of using a chelator whose complex stability depends on the redox state of copper, such as glyoxal-bis (N⁴-methyl-3-thiosemicarbazonate).¹¹³ In the extracellular space, it forms a stable Cu²⁺-complex, but, in the cytosol, it becomes destabilized by reduction and releases Cu⁺. Other examples are found among derivatives of 8-hydroxyquinoline.^113,119,120 The first-tested drug, clioquinol, is not recommendable because its Zn²⁺ complex is a potent mitochondrial toxin.¹²¹ Actually, the best choice seems to be PBT2, a compound that is sufficiently amphiphilic to cross membranes as an ionophore and has only moderate affinities to Cu²⁺ and Zn²⁺ allowing a release of the ions to the cytosol.^113,119,120 Mode of action and efficacy have been confirmed in preclinical studies. In transgenic mice, several beneficial effects of this drug have been described: reduction of interstitial soluble Aβ; improvement of cognitive performance;¹¹⁹ promotion of amyloid degradation;¹²² stimulation of neurite outgrow; increases in dendritic spine density; higher levels of several regulatory proteins, such as CaM kinase II, BDNF (brain derived neurotrophic factor) and NMDAR subtypes;¹²³ and, finally, inhibition of glycogen synthase kinase 3 (GSK3) by phosphorylation,¹²² ie, of an enzyme implicated in Aβ formation.

Multifunctional drugs

Several multifunctional drugs have been synthesized, which combine, in one molecule, properties of ligands to different binding sites. Some of the compounds were designed to bind to BuChE and/or to allosteric and catalytic sites of AChE.^124–126 Several series of molecules were composed of tacrine or 6-chlorotacrine residues with donepezil, fragments of pyrano[3,2-c]quinoline moieties or multiply substituted phenyl groups.^124,125 All of them were reported to reduce Aβ aggregation in vitro.^124–127 Some hydroxylated derivatives also displayed scavenging of peroxyl radicals.¹²⁷

Other hybrid molecules aimed to combine ChEI with antioxidant properties, by attaching residues of ferulic acid¹²⁸ or melatonin^129–131 to a tacrine moiety. Neither the toxicologic profile of tacrine was sufficiently considered in the design of these compounds, nor a possible interference with the numerous other functions of melatonin. Moreover, the antioxidant actions of reasonably-dosed melatonin are not primarily based on direct radical scavenging.¹³² Nevertheless, a tacrine-melatonin hybrid was reported to reduce Aβ-dependent cell death and memory deficits in a mouse model.¹³¹

Several hybrids synthesized by combining donepezil and tacrine fragments were reported to be potent ChEIs with additional antiamyloidogenic activity in vitro.¹³³ Similar properties were ascribed to another hybrid in which donepezil was linked to a phenyl-N-methylbenzamino residue.¹³⁴ Tacrinedihydropyridine hybrids were designed to combine ACh elevations with inhibition of voltage-dependent L-type calcium channels.^135,136 Using β-carbolines as a hybrid component, another approach was chosen to combine AChE/BChE inhibition with suppression of excitotoxicity via blockade of the NMDAR.¹³⁷

Hybrids of rivastigmine and fluoxetine were synthesized to simultaneously inhibit AChE and serotonin reuptake.¹³⁸ Other hybrids combined rivastigmine with the monoamine oxidase (MAO) B inhibitor, rasagiline, or, to reduce iron-dependent oxidotoxicity, with an iron chelator.^139,140 Metal chelators were also attached to rasagiline, donepezil,¹⁴⁰ and bis-(7)-tacrine residues.¹⁴¹ However, the tacrine dimer has, like the monomer, poor oral bioavailability.¹⁴² A peculiarity of these donepezil, rasagiline and some rivastigmine hybrids is the liberation of the chelators upon cleavage by AChE.¹⁴⁰ The possible problems arising from the use of metal chelators has been discussed above. The tacrine moiety has also been combined with 8-hydroxyquinoline analogs, including PBT2.¹⁴³ Actions as ionophores remain to be directly shown. Additionally, they were reported to display antioxidant properties superior to Trolox.¹⁴³

Another category of multifunctional drugs has been developed on the basis of a quinone/polyamine skeleton.^144–149 In the lead compound, memoquin, two polyamines attached to benzoquinone carry terminal methoxybenzene residues. Several of these compounds were shown to inhibit AChE, BuChE and Aβ aggregation. To enhance the antioxidant properties, memoquin/α-lipoic acid hybrids were designed.¹⁴⁸ In several recently developed molecules, polyamines have been combined with other aromates or heterocycles.¹⁴⁹

The metabolism of these multifunctional drugs is almost unknown. A more complicated molecule bears more possibilities of metabolism and also of side effects. Safety studies will be required on a particularly broad scale.

Clinical Studies

The clinical outcome of ChEI^18–51 and memantine^{11,14,52–65} treatment has been reviewed and metaanalyzed repeatedly, with extensive and detailed considerations in papers until 2009. More specialized reviews have been published until recently. Studies not incorporated into these summaries mainly concern ethnic populations, identification of non-responders, dosage, daily living, alternate routes of administration and combinations of ChEIs and memantine.

Three studies on donepezil in rather low numbers of Japanese patients were designed to discriminate between responders and non-responders on the basis of cognitive parameters,^150–151 donepezil positron emission tomography (PET),¹⁵¹ or presence of the apolipoprotein E ε4 (ApoEε4) genotype.¹⁵² Conclusions from these studies were not entirely consistent. While the first trial¹⁵⁰ identified non-responders especially among young patients with early disease onset, and the PET study indicated higher efficacy in patients with high ACh levels and high baseline attention,¹⁵¹ the third one concluded that the drug is particularly effective in advanced AD.¹⁵² A small, three-year study on donepezil treatment in Japanese patients with or without ApoE ε4 shall be briefly mentioned, although it started with Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale/Cognitive Subscale Japanese version (ADAS-Jcog) scores of about 24 and about 14, respectively¹⁵³ Apart from weak statistical tendencies for more pronounced MMSE declines and ADAS-Jcog increases in ApoEε4 patients, donepezil seems to have been more efficient in non-ApoEε4 patients. An open-label study on donepezil in 106 Hispanic patients with mild-to-moderate AD is of particular interest since this population has a higher incidence and earlier onset of AD.¹⁵⁴ A 6-month donepezil trial on behavioral symptoms in Spanish patients with mild to moderately severe AD indicated improvements in MMSE and especially Neuropsychiatric Inventory (NPI) scores.¹⁵⁵ A safety study of galantamine conducted in Thai patients included a dose-escalation phase.¹⁵⁶

Effects of donepezil in mild to moderate AD (MMSE 26-10 at baseline) recently focussed on apathy in a meta-analysis of two earlier 6-month trials.¹⁵⁷ Studies on severe AD were conducted using either galantamine¹⁵⁸ or high doses (20, in a pilot study,¹⁵⁹ or 23 instead of 10 mg) of donepezil, aiming to overcome the poorer efficacy in advanced AD by higher levels of the drug.^78,160 Effects of dosage were investigated in a 24-week, randomized, double-blind multicenter, multinational study at 219 sites.⁷⁸ Other data from this study were analyzed with regard to language dysfunction¹⁶⁰ and to efficacy in more severe cases.¹⁶¹ With regard to severity, a retrospective study analysis compared non-hallucinators with hallucinators, which mostly have stronger cortical cholinergic deficits and show a greater decline on placebo. Rivastigmine was more effective in the hallucinator group.¹⁶²

Several trials have been conducted on combinations of ChEIs with other drugs. In depressed AD patients, combined treatment of ChEIs (67% of patients donepezil, 20% rivastigmine, 13% galantamine) with serotonin reuptake inhibitors (citalopram, escitalopram, sertraline, fluoxetine, paroxetine) was compared with ChEI treatment only in depressed and non-depressed persons, over 9 months with individually escalating ChEI doses.¹⁶³ Findings indicate advantages for cognitive measures by the combined treatment, although some reservations have to made with regard to the heterogeneity of medication. A combination of donepezil with a mixture of antioxidants tested in a small number of patients claimed cognitive improvements relative to donepezil alone.¹⁶⁴ However, the complex pharmacology of the mixture may justify some reservation. An exploratory double-blind, placebo-controlled study compared the efficacy of donepezil and the 5-HT₆ antagonist SB-742457.¹⁶⁵ Although some improvements were described for the serotonergic antagonist, donepezil seemed to be superior. A combined treatment might be worth an investigation.

Memantine, which has been approved for treatment of moderate to severe AD, has been investigated in two 6-month postmarketing surveillance studies.^59,65 A proportion of about 27% responders showed no deterioration at time of assessment.⁵⁹ Significant behavioral improvements were reported for the memantine group.⁶⁵ Decreased agitated and aggressive behavior was also observed in a small open-label study on long-term care residents.¹⁶⁶ A recent development, the combination of memantine and ChEIs, has been addressed in a safety study on rivastigmine capsules plus memantine,¹⁶⁷ an evaluation of safety, cognitive and global functions with rivastigmine transdermal patches and oral memantine,¹⁶⁸ a published study design for donepezil plus memantine,¹⁶⁹ and a long-term study on non-specified ChEIs plus memantine.¹⁷⁰ After a follow-up of at least one year, cognitive measures were approximately the same in patients with ChEI monotherapy and those treated with the combination.¹⁷⁰ Psychiatric symptoms were, on the average, lower in the combination cohort, but statistically not significant. Comparisons with memantine monotherapy were not provided.¹⁷⁰

In conceptual terms, the majority of new studies mentioned do not substantially deviate from earlier ones and the progress obtained thereof is limited, relative to previous knowledge. A few minor advances, in addition to earlier data, may have been made concerning the subpopulations of patients that do not or poorly respond to ChEI treatment, such as carriers of the ApoEε4 genotype. Another tendency concerns the study of combinations of ChEIs with either antidepressants or memantine. In the first case, tests of this type can be meaningful because of symptoms of depression in many AD patients. However, future trials should focus more on homogeneous cohorts, in which a single antidepressant is studied in a higher number of patients. The combination with memantine, performed in the hope of improvements in more severe cases of AD, still requires convincing support of superiority over monotherapies. For the moment, it seems justified to conduct more studies using higher ChEI doses in severe AD, as already done with donepezil,^78,160,161 even though the improvements may remain moderate. The newly developed rivastigmine transdermal patches may be regarded as an innovation, which concerns the ease of administration, the longer-lasting bioavailability because of extented absorption, and reduction of emetic events. Safety, skin tolerability and efficacy of this method have been compared, in several studies of different design, with capsules of the same drug and after a switch from donepezil.^{40,45,171–180}

Published data on the Cu/Zn ionophore PBT2 are to date only available for two analyses of a phase II trial in which doses of 50 and 250 mg had been tested.^181,182

Safety

Adverse effects/events (AEs) of ChEIs are mostly related to ACh elevations. They mainly concern the gastrointestinal tract, less frequently heart and CNS. Safety studies and reviews consistently report that donepezil, rivastigmine and galantamine are usually well tolerated and that most AEs are mild. Such statements somewhat contrast with the frequencies of gastrointestinal AEs, at standard therapeutic doses: nausea (11%, 44%, 24%), vomiting (7%, 30%, 14%), and diarrhea (12%, 13%, 8%) for donepezil, rivastigmine (capsules) and galantamine, respectively, according to a meta-analysis of 26 trials.¹⁸³ Other more frequent AEs are weight loss (7%, 11%, 10%) dizziness (8%, 22%, 10%)¹⁸³ and, with lower incidence, headache, abdominal pain, and muscle cramps.^18,20,23,32 Insomnia and vivid dreams may be sometimes associated with donepezil, and weakness or fatigue with rivastigmine and galantamine.^184,185 A higher donepezil dose of 23 mg/d, instead of 5 or 10 mg/d, developed for the treatment of moderate to severe AD, was associated with increased AE frequencies, which remained, however, in the lower percent range.⁷⁸

Replacement of galantamine immediate release (12 mg twice per day) by an extended release formulation (24 mg/day; 25% immediate release; 75% controlled release) has been reported to not substantially augment AEs.⁴⁹ In a preclinical study, AEs have been strongly reduced by using the galantamine prodrug, Memogain^® (Gln-1062),¹⁸⁶ which may be a future option. Another possibility may be intranasal administration of galantamine (as lactate instead of hydrobromide),^187,188 which avoids first-pass metabolism and high gastrointestinal concentrations. In an animal model, this led to strongly reduced AEs,¹⁸⁷ but clinical confirmation and dose adjustment would be required.

In order to circumvent the short action of oral rivastigmine and to avoid high gastrointestinal levels, rivastigmine transdermal patches have been developed. Compared to capsules, emetic AEs were strongly reduced.^{39,40,42–45,71,172,173,175,177,189} Nausea and vomiting occur only in the 4% range. Dermatological AEs, which are generally possible with patches, have been observed but are infrequent.^38,42 Case reports have described allergic contact dermatitis¹⁹⁰ and a delayed hypersensitivity reaction.¹⁹¹ A case of hepatitis with cholestasis reported in conjunction with rivastigmine patches¹⁹² should be seen as an exception. Rivastigmine's negligible liver metabolism would not explain hepatotoxicity. A case of hepatotoxicity was reported for a patient treated with the long-acting, hepatically metabolized donepezil.¹⁹³

Nevertheless, rarely occurring, but severe AEs deserve particular attention, eg, concerning exceptionally strong vagotonic effects on cardiac function. After several case reports on bradycardia, syncopes and atrioventricular block in patients treated with ChEIs, a thorough study on a very large cohort has determined AE frequency, multivariate-adjusted hazard ratio (HR) and contributing risk factors.¹⁹⁴ A moderately increased HR of bradycardia is demonstrable with all approved ChEIs, with greatest risk for higher doses of donepezil, but the overall treatment-related incidence remained below 0.02%. Increases of total or cardiovascular mortality due to donepezil were not evident.¹⁹⁵ Over 120 cases of overdoses reported for rivastigmine transdermal patches, with sometimes dramatic AEs, have been caused by inappropriate use, especially failure to remove old patches or simultaneous application of several patches.¹⁹⁶

Pleurothotonus (Pisa syndrome), another rare AE with considerable inconvenience to the patient, has been observed with all three approved ChEIs. The dystonia is resolved after discontinuation.¹⁹⁷

AEs due to drug interactions are highly divergent among the ChEIs in use, because of considerable differences in hepatic metabolism. While rivastigmine is not a CYP substrate, the pharmacokinetics of donepezil and galantamine is strongly affected by CYP3A4 and CYP2D6 inhibitors, such as ketoconazole and paroxetine.^19,48 Another type of drug interaction is related to anticholinergic effects of some antihistamines and tricyclic antidepressants, which lead, however, only to reductions in ChEI efficacy.¹⁹⁸

In patients treated with the NMDAR inhibitor, memantine, AEs are almost indistinguishable from those with placebo.^11,14,198 Constipation, headache, hypertension and somnolence were reported to occur in the low percent range.¹⁸⁵ Hallucinations and aggressive reactions were observed in an open-label study.¹⁹⁹ A warning concerning heart failure due to memantine treatment²⁰⁰ concerns rare exceptions, but should be taken as a caveat in patients with cardiovascular diseases. Memantine, which is devoid of substantial hepatic metabolism,¹⁴ does not show drug interactions based on CYP isoforms. With regard to multiple interconnections between central nervous neurotransmission systems, interactions with neuropharmacological drugs are not unlikely. Hallucinations induced by combination of memantine with riluzole have been observed.²⁰¹

The ionophore PBT2 was reported to be safe and devoid of serious AEs, in a Phase IIa trial,¹⁸¹ but final conclusions should not be drawn without confirmation in more extended studies. Since the application will require long-term administration, the tolerability of the high dose of 250 mg/day may become a crucial issue.

Efficacy

Most of the studies on ChEIs have been conducted in patients with mild to moderate AD. However, these findings cannot be neglected here, because of a considerable overlap of MMSE and ADAS scores with cohorts of moderate to severe AD. Most of the trials, meta-analyses and reviews accordantly state that the efficacy of the three approved ChEIs is only moderate and temporally limited.^{9,18–20,22–31,37,38,41,46,47,49,50,95,150–154,171,179,183,202–206} This judgment has not substantially changed over the years. Occasionally, the usefulness of ChEIs has been questioned, either under aspects of cost-effectiveness or with regard to possible sponsors’ influences on the publication of vendor-supported trials.²⁰⁷ However, the very large body of evidence for an, albeit modest, efficacy is clearly in favor of the usefulness of ChEIs. This is not contradictory to a percentage of non-responders related to disease stage or genetic disposition,^208,209 or to trials without demonstrable efficacy, because of unfavorable cohort size, heterogeneity or study design.^45,150–152

The multiply reviewed beneficial effects of ChEIs concern cognitive measures such as MMSE, ADAS-cog, and Severe Impairment Battery (SIB); global assessments such as Clinician's Interview-based Impression of Change (CIBIC; with variant CIBIC+ including caregivers’ input), Gottfries, Brane and Steel scale (GBS), and Global Deterioration Scale (GDS); measures of daily living activities such as Progressive Deterioration Scale (PDS), Disability Assessment of Dementia (DAD) and the AD Cooperative Study Activity of Daily Living scale (ADCS); for assessment of behavioral disturbances, the Neuropsychiatric Instrument (NPI), all based on several subscales. Depending on studies, improvements are not always observed in every domain or subscale. With regard to efficacy, donepezil, rivastigmine and galantamine show a considerable overlap in the various domains, so that fundamental differences cannot be deduced. Although some evaluations have indicated minor deviations in efficacy,^{18,20,183,202} eg, concerning the starting dose,¹⁸ they do not justify a preference for one of these drugs. Rivastigmine capsules and transdermal patches were found to be approximately equally effective.^{44,176,179,180} Small clinical improvements relative to baseline are mostly seen during the first 6 months,^25,74,171 but longer-lasting beneficial effects are observed relative to placebo. In moderate AD, the decline in especially cognitive measures can be significantly slowed over a year or even longer,^{74,171,205,210,211} but this should not be misinterpreted in terms of halting the disease. Differences in the various domains of assessment are frequent during prolonged treatment. In a number of patients with active treatment, cognitive measures more slowly decline than in the placebo group, whereas benefits in psychiatric, global and daily living measures may disappear, however, with considerable interindividual variation.

In many studies and meta-analyses on behavioral and psychological symptoms, no data are provided for NPI or CGIC subscales. Therefore, symptoms as different as agitation/aggression, anxiety, apathy and hallucinations are merged. Because of the particular importance for the patient's life, it should be emphasized that relatively marked improvements are frequently observed in the reduction of apathy with donepezil,¹⁵⁷ galantamine,⁵¹ and rivastigmine.^212–215 This should be expected with drugs enhancing the availability of an important activating neurotransmitter with multiple influences on other activating systems. Although apathy is usually regarded as a “noncog“ symptom, its improvement may be a cofactor in cognitive ameliorations, and facilitation of daily living, too. Merging apathy and other subscales, especially that of agitation/aggression, can obscure the final outcome. Improvements in the agitation/aggression domain by a ChEI, frequently mentioned, would be less plausible from a mechanistic point of view and have been questioned.²¹⁶

The usefulness of ChEIs in severe AD has been differently judged. Earlier studies on donepezil in moderate to severe AD revealed benefits in MMSE and SIB scores. Post hoc analyses on subcohorts with more advanced disease also indicated positive effects on cognitive measures (MMSE and ADAS-cog) for rivastigmine and galantamine.^210,217 For donepezil, findings were confirmed in a recent pooled data analysis on patients with different baseline MMSE scores, including a group starting with 1–5 points.³⁶ In the advanced AD stages, the higher donepezil dose of 23 mg/d has been tested and found to be superior to the standard dose of 10 mg/d in these patients.^78,161 In addition to measures of cognition and global functioning, greater benefits of the high dose were observed in attenuating language dysfunction.¹⁶⁰ Higher doses have also been tested with rivastigmine transdermal patches (17.4 instead of 9.5 mg/d).¹⁸⁰ Although this caused improvements of MMSE and ADCS-ADL scores in moderate and moderately severe AD, changes in severe AD revealed only non-significant trends. Effects on CGIC were statistically demonstrable in severe AD, but remained very modest in their extent.¹⁸⁰ An advantage of the higher dose was not convincingly demonstrated. In patients with MMSE scores of 5–12 points, galantamine was found to slightly improve SIB domains of memory, praxis and visuospatial ability, in contrast to worsening in the placebo group.¹⁵⁸

According to the approval, most studies on memantine have been conducted in patients with moderate to severe AD. This drug, which is not primarily acting on ACh levels, but rather antagonizes overexcitation and inflammation-related excitotoxicity, should differ from ChEIs in influencing the various measures of cognition, daily functioning and behavior. Statistically significant improvements have been reported for most relevant measures, such as SIB, MMSE, ADAS-cog, CIBIC+, ADL, FAST (Functional Assessment Staging Tool), GDS, NPI, or subscales thereof.^{11,14,52–54,57,59,63–65,166,199,217} However, a closer look reveals that these benefits are often only demonstrable for some of these parameters in the single trial. Moreover, statistically significant improvements have sometimes been considered clinically marginal, with a same rating for ChEIs.^218–220 As a general tendency, positive effects seem to be rather modest in cognitive scores. Typically, the benefits consist in a delay of worsening for about three months. Some hopes of a better outcome have been expressed for the use of a higher dose (28 mg/d) of an extended-release formulation, instead of 10 mg immediate release twice a day.⁶² With regard to the slow, but complete resorption and long-lasting persistence of memantine in the plasma, this idea may be critically seen. A possibly important observation, with considerable implications for the caregivers’ burden, concerns significant reductions in agitation and aggression.^57,64,166 This may not be surprising for a drug that reduces glutamate-dependent neuronal excitation. Thus, the question arises to what extent these behavioral/psychiatric symptoms are explained by mild sedation or by improvements in neurological functions. The latter possibility may be favored by other findings on reductions of language impairment, using the SIB-language (SIB-L) scale.⁶⁰

In the last years, combinations of ChEIs, mostly donepezil, with memantine have been or are being explored.^{37,61,169,170,211,221–227} This might be of particular interest for advanced AD stages, also with regard to the approval of donepezil and memantine in severe AD. Despite reports on further improvements in subsets of responders, the evidence for a general superiority of the combination over the respective monotherapies is still weak and requires further investigation.

Among the numerous investigational drugs mentioned, clinical data are only available for the ionophore PBT2. The phase II trial was conducted for only 12 weeks, on a relatively small number of patients with mild AD, who were also treated with ChEIs. Cognitive improvements were only demonstrated in several scores of the Neuropsychological Test Battery (NTB), but remained non-significant in MMSE and ADAS-cog scales.^181,182 This should not yet justify a conclusion on poor efficacy. This drug, which acts on Aβ levels, Aβ-related metal toxicity, release from amyloid and distribution of transition metals, may require much more time than 12 weeks for profound improvements. It seems also important to not reduce the discussion on PBT2 to antiamyloid activity and, thus, to confound this with negative findings on drugs like tramiprostrate and tarenflurbil, which do not antagonize Cu and Zn toxicity. Whether PBT2 will be suitable for treating moderate to severe AD remains to be studied.

In summary, most of the recent findings in moderate to severe AD do not deviate in their essence from that what has been known before. ChEIs and also memantine are moderately and transiently effective in responders to active treatment. In the course of disease progression, the therapeutic success decreases. Higher doses of donepezil (eg, 23 mg/d) and, perhaps, of the other ChEIs can partially overcome this difficulty. However, elevated doses of memantine extended-release appear to be unnecessary under aspects of pharmacokinetics and bioavailability. The positive effects of memantine on non-cognitive measures such as reduction of aggression and agitation, deserve particular consideration. Whether or not combinations of donepezil and memantine lead to substantial improvements in late AD remains an open question.

Patient Preference

Preferences of demented patients may be, in part, deduced from frequency and reason of discontinuations because of adverse events. In larger trials on ChEIs, dropouts are mostly in the range of 15%–18% for donepezil and galantamine standard doses, and of 19%–29% for rivastigmine capsules, compared to <10% in the placebo groups, however, with considerable inter-study variation.^{23,32,40,46,78} Among quantitatively relevant AEs, emetic effects prevail and represent a major cause of discomfort. Increased doses of the three ChEIs are associated with higher frequencies of withdrawal.^20,32,46,78 Gastrointestinal AEs are markedly reduced in rivastigmine transdermal patches.^40,43,172 Nevertheless, the frequency of treatment-associated discontinuation is still in the 15% range, due to other causes. As long as no skin irritations or problems because of continually elevated plasma levels occur, patients may prefer rivastigmine patches. The patches may also be of advantage in patients who have difficulties in swallowing.

With memantine, AEs and discontinuations are almost indistinguishable from the placebo groups.^{11,14,185,199} Therefore, patients might have a preference for this drug. However, usefulness and responsiveness have to be decided by the physician. The reductions of aggression and agitation by memantine are certainly of advantage for the caregivers, and a more balanced mood may be positively perceived by patients as well.

Place in Therapy

Donepezil, rivastigmine, galantamine and memantine are to date the only drugs approved for the treatment of moderate AD, donepezil and memantine those for severe AD. As long as no causal therapy of the disease is available, these four drugs offer the only accepted methods of treatment, despite their limited efficacy. In responders, all of them are capable of improving cognitive and other measures for several months and of slowing the decline of the respective functions over extended periods. Attempts of identifying, prior to therapy, patients that will presumably not respond seems useful, but this may not be possible with high certainty. It is even more important to identify, before ChEI treatment, patients with high risks for AEs, especially those with cardiovascular diseases. Comorbidities and concomitant medications possibly causing drug interactions deserve particular attention before prescribing ChEIs.

The drugs differ less with regard to cognitive enhancement, but in behavioral functions and AEs. ChEIs have advantages in counteracting apathy, whereas memantine seems to be favorable in reducing aggressive behavior and agitation. AEs are more pronounced with ChEIs than memantine and especially concern emetic responses. In the case of rivastigmine, the undesired gastrointestinal effects are largely reduced by transdermal patches, which is an advantage over capsules and other ChEIs. If Memogain^® will be approved in the future, this prodrug of galantamine may replace the active drug. Other methods of ChEI administration, such as the use of intranasal sprays, may also reduce AEs.

Higher doses for the treatment of severe AD seem to be favorable, in the case of donepezil, with regard to cognitive and global functions, whereas this is less evident for memantine. The use of elevated doses may be limited by increased frequencies of AEs. Especially in severe AD, the combination of donepezil and memantine has been suggested. Whether this will be a future gold standard,²²⁷ remains uncertain, as long as the combination has not convincingly shown substantial superiority over monotherapies.

Treatments with ChEIs and/or memantine should not only be regarded under the aspects of modest efficacy or cost-effectiveness. Even temporally limited improvements and slowed declines in functions of cognitive, daily living and global measures represent a gain for both patients and caregivers. Reductions in apathy can be valuable for interacting with the patient and his/her—albeit limited—participation in daily life, and those in agitation and aggression represent a considerable relief to caregivers.

Conclusions

Although donepezil, rivastigmine and galantamine differ considerably in their pharmacokinetics, bioavailability, metabolism and inhibitory mechanisms, their clinical efficacy, safety and tolerability profiles are similar. The additional property of rivastigmine of inhibiting both AChE and BuChE does not seem to be of clinical relevance. Severe AEs of ChEIs are rare, but others frequent or very frequent. Attempts have been undertaken to reduce especially emetic AEs. For regular clinical use, this is to date only possible with rivastigmine transdermal patches. The efficacy in improving cognitive, behavioral, functional and global symptoms and in delaying a further decline is moderate with all three ChEIs. It is not possible to halt the disease by these treatments.

Memantine, an uncompetitive open-channel blocker of the NMDAR, with moderate affinity and rapid blocking/unblocking kinetics, reduces neuronal overexcitation and neuroinflammatory excitotoxicity. AE frequencies are relatively low. The clinical outcome is, however, similarly moderate as with ChEIs. A difference to those drugs exists in a more effective reduction of agitation and aggression. Efficacies of monotherapies and combinations of ChEIs and memantine differ only marginally.

Many attempts have been undertaken to develop alternate strategies of treatment. Preclinical studies and a phase IIa trial on the Cu/Zn ionophore PBT2 are encouraging, but its suitability will depend on efficacy and non-toxicity during prolonged treatment. Several investigational drugs, such as the AMPAR potentiators CX717 and S 18986 as well as numerous multifunctional hybrid molecules, await thorough preclinical or clinical investigation. However, these pleiotropically acting drugs are still designed for symptomatic treatments. Whether they will be superior to currently approved drugs remains to be shown. As long as the etiology of AD is not understood in its initial causes, it is impossible to develop, on a rational basis, drugs that definitely halt the disease.

Disclosures

Author(s) have provided signed confirmations to the publisher of their compliance with all applicable legal and ethical obligations in respect to declaration of conflicts of interest, funding, authorship and contributorship, and compliance with ethical requirements in respect to treatment of human and animal test subjects. If this article contains identifiable human subject(s) author(s) were required to supply signed patient consent prior to publication. Author(s) have confirmed that the published article is unique and not under consideration nor published by any other publication and that they have consent to reproduce any copyrighted material. The peer reviewers declared no conflicts of interest.

References

Ferri

C.P.

, Prince

, Brayne

. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005; 366: 2112–7.

Geldmacher

D.S.

Cost-effectiveness of drug therapies for Alzheimer's disease: A brief review.

Neuropsychiatr Dis Treat. 2008; 4: 549–55.

McDonald

R.J.

Multiple combinations of co-factors produce variants of age-related cognitive decline: a theory.

Can J Exp Psychol. 2002; 56: 221–39.

Iqbal

, Grundke-Iqbal

Alzheimer's disease, a multifactorial disorder seeking multitherapies.

Alzheimers Dement. 2010; 6: 420–4.

Chopra

, Misra

, Kuhad

Current perspectives on pharmacotherapy of Alzheimer's disease.

Expert Opin Pharmacother. 2011; 12: 335–50.

Craig

L.A.

, Hong

N.S.

, McDonald

R.J.

Revisiting the cholinergic hypothesis in the development of Alzheimer's disease.

Neurosci Biobehav Rev. 2011; 35: 1397–409.

Bartus

R.T.

, Dean

3rd , Beer

, Lippa

A.S.

The cholinergic hypothesis of geriatric memory dysfunction.

Science. 1982; 217: 408–14.

Bartus

R.T.

On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis.

Exp Neurol. 2000; 163: 495–529.

Martorana

, Esposito

, Koch

Beyond the cholinergic hypothesis: do current drugs work in Alzheimer's disease?

CNS Neurosci Ther. 2010; 16: 235–45.

10.

Carreiras

M.C.

, Marco

J.L.

Recent approaches to novel anti-Alzheimer therapy.

Curr Pharm Des. 2004; 10: 3167–75.

11.

Reisberg

, Doody

, Stöffler

. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003; 348: 1333–41.

12.

Chohan

M.O.

, Iqbal

From tau to toxicity: emerging roles of NMDA receptor in Alzheimer's disease.

J Alzheimers Dis. 2006; 10: 81–7.

13.

Parsons

C.G.

, Stöffler

, Danysz

Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system—too little activation is bad, too much is even worse.

Neuropharmacology. 2007; 53: 699–723.

14.

van Marum

R.J.

Update on the use of memantine in Alzheimer's disease.

Neuropsychiatr Dis Treat. 2009; 5: 237–47.

15.

Chen

, Chen

, Tan

. Regulation of the NMDA receptor-mediated synaptic response by acetylcholinesterase inhibitors and its impairment in an animal model of Alzheimer's disease. Neurobiol Aging. 2008; 29: 1795–804.

16.

Texidó

, Martín-Satué

, Alberdi

, Solsona

, Matute

Amyloid β peptide oligomers directly activate NMDA receptors.

Cell Calcium. 2011; 49: 184–90.

17.

Floden

A.M.

, Li

, Combs

C.K.

β-Amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor α and NMDA receptors.

J Neurosci. 2005; 25: 2566–75.

18.

Geldmacher

D.S.

Long-term cholinesterase inhibitor therapy for Alzheimer's disease: practical considerations for the primary care physician.

Prim Care Companion J Clin Psychiatry. 2003; 5: 251–9.

19.

Geldmacher

D.S.

Donepezil (Aricept®) for treatment of Alzheimer's disease and other dementing conditions.

Expert Rev Neurother. 2004; 4: 5–16.

20.

Ritchie

C.W.

, Ames

, Clayton

, Lai

Metaanalysis of randomized trials of the efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer disease.

Am J Geriatr Psychiatry. 2004; 12: 358–69.

21.

Forchetti

C.M.

Treating patients with moderate to severe Alzheimer's disease: implications of recent pharmacologic studies.

Prim Care Companion J Clin Psychiatry. 2005; 7: 155–61.

22.

Birks

, Harvey

R.J.

Donepezil for dementia due to Alzheimer's disease.

Cochrane Database Syst Rev. 2006; 1: CD001190.

23.

Birks

Cholinesterase inhibitors for Alzheimer's disease.

Cochrane Database Syst Rev. 2006; 1: CD005593.

24.

Takeda

, Loveman

, Clegg

. A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer's disease. Int J Geriatr Psychiatry. 2006; 21: 17–28.

25.

Seltzer

Is long-term treatment of Alzheimer's disease with cholinesterase inhibitor therapy justified?

Drugs Aging. 2007; 24: 881–990.

26.

Seltzer

Donepezil: an update.

Expert Opin Pharmacother. 2007; 8: 1011–123.

27.

Benjamin

, Burns

Donepezil for Alzheimer's disease.

Expert Rev Neurother. 2007; 7: 1243–9.

28.

Miller

L.J.

The use of cognitive enhancers in behavioral disturbances of Alzheimer's disease.

Consult Pharm. 2007; 22: 754–62.

29.

Campbell

, Ayub

, Boustani

M.A.

. Impact of cholinesterase inhibitors on behavioral and psychological symptoms of Alzheimer's disease: a meta-analysis. Clin Interv Aging. 2008; 3: 719–28.

30.

Wilkinson

, Schindler

, Schwam

. Effectiveness of donepezil in reducing clinical worsening in patients with mild-to-moderate Alzheimer's disease. Dement Geriatr Cogn Disord. 2009; 28: 244–51.

31.

Jones

R.W.

, Schwam

, Wilkinson

. Rates of cognitive change in Alzheimer disease: observations across a decade of placebo-controlled clinical trials with donepezil. Alzheimer Dis Assoc Disord. 2009; 23: 357–64.

32.

Lockhart

I.A.

, Mitchell

S.A.

, Kelly

Safety and tolerability of donepezil, rivastigmine and galantamine for patients with Alzheimer's disease: systematic review of the ‘real-world’ evidence.

Dement Geriatr Cogn Disord. 2009; 28: 389–403.

33.

Rodda

, Morgan

, Walker

Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer's disease? A systematic review of randomized, placebo-controlled trials of donepezil, rivastigmine and galantamine.

Int Psychogeriatr. 2009; 21: 813–24.

34.

Gauthier

, Lopez

O.L.

, Waldemar

. Effects of donepezil on activities of daily living: integrated analysis of patient data from studies in mild, moderate and severe Alzheimer's disease. Int Psychogeriatr. 2010; 22: 973–83.

35.

Fernández

, Gobartt

A.L.

, Balañá

. Behavioural symptoms in patients with Alzheimer's disease and their association with cognitive impairment. BMC Neurol. 2010; 10: 87.

36.

Cummings

, Jones

, Wilkinson

. Effect of donepezil on cognition in severe Alzheimer's disease: a pooled data analysis. J Alzheimers Dis. 2010; 21: 843–51.

37.

Delrieu

, Piau

, Caillaud

, Voisin

, Vellas

Managing cognitive dysfunction through the continuum of Alzheimer's disease: role of pharmacotherapy.

CNS Drugs. 2011; 25: 213–26.

38.

Birks

, Grimley Evans

, Iakovidou

, Tsolaki

, Holt

F.E.

Rivastigmine for Alzheimer's disease.

Cochrane Database Syst Rev. 2009; 2: CD001191.

39.

Kurz

, Farlow

, Lefèvre

Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer's disease: a review.

Int J Clin Pract. 2009; 63: 799–805.

40.

Sadowsky

C.H.

, Farlow

M.R.

, Meng

, Olin

J.T.

Safety and tolerability of rivastigmine transdermal patch compared with rivastigmine capsules in patients switched from donepezil: data from three clinical trials.

Int J Clin Pract. 2010; 64: 188–93.

41.

Farlow

M.R.

, Cummings

J.L.

, Olin

J.T.

, Meng

Effects of oral rivastigmine on cognitive domains in mild-to-moderate Alzheimer's disease.

Am J Alzheimers Dis Other Demen. 2010; 25: 347–52.

42.

Grossberg

G.T.

, Sadowsky

, Olin

J.T.

Rivastigmine transdermal system for the treatment of mild to moderate Alzheimer's disease.

Int J Clin Pract. 2010; 64: 651–60.

43.

Darreh-Shori

, Jelic

Safety and tolerability of transdermal and oral rivastigmine in Alzheimer's disease and Parkinson's disease dementia.

Expert Opin Drug Saf. 2010; 9: 167–76.

44.

Emre

, Bernabei

, Blesa

. Drug profile: transdermal rivastigmine patch in the treatment of Alzheimer disease. CNS Neurosci Ther. 2010; 16: 246–53.

45.

Alva

, Grossberg

G.T.

, Schmitt

F.A.

, Meng

, Olin

J.T.

Efficacy of rivastigmine transdermal patch on activities of daily living: item responder analyses.

Int J Geriatr Psychiatry. 2011; 26: 356–63.

46.

Loy

, Schneider

Galantamine for Alzheimer's disease and mild cognitive impairment.

Cochrane Database Syst Rev. 2006; 1: CD001747.

47.

Prvulovic

, Hampel

, Pantel

Galantamine for Alzheimer's disease.

Expert Opin Drug Metab Toxicol. 2010; 6: 345–54.

48.

Huang

, Fu

A review of clinical pharmacokinetics and pharmacodynamics of galantamine, a reversible acetylcholinesterase inhibitor for the treatment of Alzheimer's disease, in healthy subjects and patients.

Curr Clin Pharmacol. 2010; 5: 115–24.

49.

Seltzer

Galantamine-ER for the treatment of mild-to-moderate Alzheimer's disease.

Clin Interv Aging. 2010; 5: 1–6.

50.

Kavanagh

, Howe

, Brashear

H.R.

. Long-term response to galantamine in relation to short-term efficacy data: pooled analysis in patients with mild to moderate Alzheimer's disease. Curr Alzheimer Res. 2011; 8: 175–86.

51.

Kavanagh

, Gaudig

, Van Baelen

. Galantamine and behavior in Alzheimer disease: analysis of four trials. Acta Neurol Scand. 2011 [Epub ahead of print, May 26; doi: 10.1111/j.1600-0404.2011.01525.x.]

52.

Smith

, Wells

, Borrie

Treatment effect size of memantine therapy in Alzheimer disease and vascular dementia.

Alzheimer Dis Assoc Disord. 2006; 20: 133–7.

53.

McShane

, Areosa Sastre

, Minakaran

Memantine for dementia.

Cochrane Database Syst Rev. 2006; 2: CD003154.

54.

Maggiore

, Locatelli

, Grandi

F.C.

, Pizzolato

; Cochrane Neurological Network. Memantine in the treatment of dementia. Neuroepidemiology. 2007; 28: 118–9.

55.

Maidment

I.D.

, Fox

C.G.

, Boustani

, Rodriguez

, Brown

R.C.

, Katona

C.L.

Efficacy of memantine on behavioral and psychological symptoms related to dementia: a systematic meta-analysis.

Ann Pharmacother. 2008; 42: 32–8.

56.

Rammes

, Danysz

, Parsons

C.G.

Pharmacodynamics of memantine: an update.

Curr Neuropharmacol. 2008; 6: 55–78.

57.

Grossberg

G.T.

, Pejović

, Miller

M.L.

, Graham

S.M.

Memantine therapy of behavioral symptoms in community-dwelling patients with moderate to severe Alzheimer's disease.

Dement Geriatr Cogn Disord. 2009; 27: 164–72.

58.

Thomas

S.J.

, Grossberg

G.T.

Memantine: a review of studies into its safety and efficacy in treating Alzheimer's disease and other dementias.

Clin Interv Aging. 2009; 4: 367–77.

59.

Clerici

, Vanacore

, Elia

. Memantine in moderately-severe-to-severe Alzheimer's disease: a postmarketing surveillance study. Drugs Aging. 2009; 26: 321–32.

60.

Ferris

, Ihl

, Robert

. Treatment effects of memantine on language in moderate to severe Alzheimer's disease patients. Alzheimers Dement. 2009; 5: 369–74.

61.

McKeage

Memantine: a review of its use in moderate to severe Alzheimer's disease.

CNS Drugs. 2009; 23: 881–97.

62.

Bassil

, Thaipisuttikul

, Grossberg

G.T.

, Memantine

E.R.

A once-daily formulation for the treatment of Alzheimer's disease.

Expert Opin Pharmacother. 2010; 11: 1765–71.

63.

Winblad

, Gauthier

, Aström

, Stender

Memantine benefits functional abilities in moderate to severe Alzheimer's disease.

J Nutr Health Aging. 2010; 14: 770–4.

64.

Herrmann

, Li

, Lanctôt

Memantine in dementia: a review of the current evidence.

Expert Opin Pharmacother. 2011; 12: 787–800.

65.

Clerici

, Vanacore

, Elia

. Memantine effects on behaviour in moderately severe to severe Alzheimer's disease: a post-marketing surveillance study. Neurol Sci. 2011 [Epub ahead of print, May 17; doi: 10.1007/s10072-011-0618-0.]

66.

Davis

, Sadik

Circadian cholinergic rhythms: implications for cholinesterase inhibitor therapy.

Dement Geriatr Cogn Disord. 2006; 21: 120–9.

67.

Nieoullon

, Bentué-Ferrer

, Bordet

, Tsolaki

, Förstl

Importance of circadian rhythmicity in the cholinergic treatment of Alzheimer's disease: focus on galantamine.

Curr Med Res Opin. 2008; 24: 3357–67.

68.

Rasch

B.H.

, Born

, Gais

Combined blockade of cholinergic receptors shifts the brain from stimulus encoding to memory consolidation.

J Cogn Neurosci. 2006; 18: 793–802.

69.

Mizuno

, Kameda

, Inagaki

, Horiguchi

Effects of donepezil on Alzheimer's disease: the relationship between cognitive function and rapid eye movement sleep.

Psychiatry Clin Neurosci. 2004; 58: 660–5.

70.

Moraes

, dos

, Poyares

D.R.

, Guilleminault

, Ramos

L.R.

, Bertolucci

P.H.

, Tufik

The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: a double-blind placebo-controlled study.

Sleep. 2006; 29: 199–205.

71.

Cummings

, Winblad

A rivastigmine patch for the treatment of Alzheimer's disease and Parkinson's disease dementia.

Expert Rev Neurother. 2007; 7: 1457–63.

72.

Srinivasan

, Pandi-Perumal

S.R.

, Maestroni

G.J.M.

, Esquifino

A.I.

, Hardeland

, Cardinali

D.P.

Role of melatonin in neurodegenerative diseases.

Neurotox Res. 2005; 7: 293–318.

73.

Jann

M.W.

, Shirley

K.L.

, Small

G.W.

Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors.

Clin Pharmacokinet. 2002; 41: 719–39.

74.

Geldmacher

D.S.

Alzheimer's disease: current pharmacotherapy in the context of patient and family needs.

J Am Geriatr Soc. 2003; 51(5 Suppl Dementia): S289–95.

75.

Kuhl

D.E.

, Minoshima

, Frey

K.A.

, Foster

N.L.

, Kilbourn

M.R.

, Koeppe

R.A.

Limited donepezil inhibition of acetylcholinesterase measured with positron emission tomography in living Alzheimer cerebral cortex.

Ann Neurol. 2000; 48: 391–5.

76.

Bohnen

N.I.

, Kaufer

D.I.

, Hendrickson

. Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2005; 76: 315–9.

77.

Ota

, Shinotoh

, Fukushi

. Estimation of plasma IC50 of donepezil for cerebral acetylcholinesterase inhibition in patients with Alzheimer disease using positron emission tomography. Clin Neuropharmacol. 2010; 33: 74–8.

78.

Farlow

M.R.

, Salloway

, Tariot

P.N.

. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study. Clin Ther. 2010; 32: 1234–51.

79.

Asthana

, Greig

N.H.

, Hegedus

. Clinical pharmacokinetics of physostigmine in patients with Alzheimer's disease. Clin Pharmacol Ther. 1995; 58: 299–309.

80.

Summers

W.K.

, Koehler

A.L.

, Marsh

G.M.

, Tachiki

, Kling

Long-term hepatotoxicity of tacrine.

Lancet. 1989; 1(8640): 729.

81.

Becquemont

, Ragueneau

, Le Bot

M.A.

, Riche

, Funck-Brentano

, Jaillon

Influence of the CYP1A2 inhibitor fluvoxamine on tacrine pharmacokinetics in humans.

Clin Pharmacol Ther. 1997; 61: 619–27.

82.

Patocka

, Jun

, Kuca

Possible role of hydroxylated metabolites of tacrine in drug toxicity and therapy of Alzheimer's disease.

Curr Drug Metab. 2008; 9: 332–5.

83.

Qizilbash

, Birks

, Lopez Arrieta

, Lewington

, Szeto

WITHDRAWN: Tacrine for Alzheimer's disease.

Cochrane Database Syst Rev. 2007; 3: CD000202.

84.

Birks

, Wilcock

G.G.

Velnacrine for Alzheimer's disease.

Cochrane Database Syst Rev. 2004; 2: CD004748.

85.

Schuh

F.T.

On the molecular mechanism of action of galanthamine, an antagonist of nondepolarizing muscle relaxants. (Article in German)

Anaesthesist. 1976; 25: 444–8.

86.

Nordberg

, Darreh-Shori

, Peskind

. Different cholinesterase inhibitor effects on CSF cholinesterases in Alzheimer patients. Curr Alzheimer Res. 2009; 6: 4–14.

87.

Darreh-Shori

, Soininen

Effects of cholinesterase inhibitors on the activities and protein levels of cholinesterases in the cerebrospinal fluid of patients with Alzheimer's disease: a review of recent clinical studies.

Curr Alzheimer Res. 2010; 7: 67–73.

88.

Scacchi

, Gambina

, Moretto

, Corbo

R.M.

Variability of AChE, BChE, and ChAT genes in the late-onset form of Alzheimer's disease and relationships with response to treatment with Donepezil and Rivastigmine.

Am J Med Genet B Neuropsychiatr Genet. 2009; 150B: 502–7.

89.

Reid

R.T.

, Sabbagh

M.N.

Effects of cholinesterase inhibitors on rat nicotinic receptor levels in vivo and in vitro.

J Neural Transm. 2008; 115: 1437–44.

90.

Takada-Takatori

, Kume

, Ohgi

. Mechanisms of α7-nicotinic receptor up-regulation and sensitization to donepezil induced by chronic donepezil treatment. Eur J Pharmacol. 2008; 590: 150–6.

91.

Takada-Takatori

, Kume

, Izumi

. Roles of nicotinic receptors in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation. Biol Pharm Bull. 2009; 32: 318–24.

92.

Counts

S.E.

, He

, Che

. α7 nicotinic receptor up-regulation in cholinergic basal forebrain neurons in Alzheimer disease. Arch Neurol. 2007; 64: 1771–6.

93.

Ikonomovic

M.D.

, Wecker

, Abrahamson

E.E.

. Cortical α7 nicotinic acetylcholine receptor and β-amyloid levels in early Alzheimer disease. Arch Neurol. 2009; 66: 646–51.

94.

Dineley

K.T.

, Westerman

, Bui

, Bell

, Ashe

K.H.

, Sweatt

J.D.

β-Amyloid activates the mitogen-activated protein kinase cascade via hippocampal α7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease.

J Neurosci. 2001; 21: 4125–33.

95.

Pepeu

, Giovannini

M.G.

Cholinesterase inhibitors and beyond.

Curr Alzheimer Res. 2009; 6: 86–96.

96.

Shimohama

, Kihara

Nicotinic receptor-mediated protection against β-amyloid neurotoxicity.

Biol Psychiatry. 2001; 49: 233–9.

97.

Takada-Takatori

, Kume

, Sugimoto

, Katsuki

, Sugimoto

, Akaike

Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade.

Neuropharmacology. 2006; 51: 474–86.

98.

Hellström-Lindahl

, Court

, Keverne

. Nicotine reduces Aβ in the brain and cerebral vessels of APPsw mice. Eur J Neurosci. 2004; 19: 2703–10.

99.

de Paula

A.A.

, Martins

J.B.

, dos Santos

M.L.

. New potential AChE inhibitor candidates. Eur J Med Chem. 2009; 44: 3754–9.

100.

Korabecny

, Musilek

, Holas

. Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease. Bioorg Med Chem Lett. 2010; 20: 6093–5.

101.

Korabecny

, Musilek

, Holas

. Synthesis and in vitro evaluation of N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine as a cholinesterase inhibitor with regard to Alzheimer's disease treatment. Molecules. 2010; 15: 8804–12.

102.

Badran

M.M.

, Abdel Hakeem

, Abuel-Maaty

S.M.

, El-Malah

, Abdel Salam

R.M.

Design, synthesis, and molecular-modeling study of aminothienopyridine analogues of tacrine for Alzheimer's disease.

Arch Pharm (Weinheim). 2010; 343: 590–601.

103.

Samadi

, Valderas

, de los Ríos

. Cholinergic and neuroprotective drugs for the treatment of Alzheimer and neuronal vascular diseases. II. Synthesis, biological assessment, and molecular modelling of new tacrine analogues from highly substituted 2-aminopyridine-3-carbonitriles. Bioorg Med Chem. 2011; 19: 122–33.

104.

Bezprozvanny

The rise and fall of Dimebon.

Drug News Perspect. 2010; 23: 518–23.

105.

Chow

T.W.

, Graff-Guerrero

, Verhoeff

N.P.

. Open-label study of the short-term effects of memantine on FDG-PET in frontotemporal dementia. Neuropsychiatr Dis Treat. 2011; 7: 415–24.

106.

Gomolin

I.H.

, Smith

, Jeitner

T.M.

Once-daily memantine: pharmacokinetic and clinical considerations.

J Am Geriatr Soc. 2010; 58: 1812–3.

107.

Bernard

, Danober

, Thomas

J.Y.

. DRUG FOCUS: S 18986: A positive allosteric modulator of AMPA-type glutamate receptors pharmacological profile of a novel cognitive enhancer. CNS Neurosci Ther. 2010; 16: e193–212.

108.

Green

R.C.

, Schneider

L.S.

, Amato

D.A.

. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009; 302: 2557–64.

109.

Drew

S.C.

, Noble

C.J.

, Masters

C.L.

, Hanson

G.R.

, Barnham

K.J.

Pleomorphic copper coordination by Alzheimer's disease amyloid-β peptide.

J Am Chem Soc. 2009; 131: 1195–207.

110.

Drew

S.C.

, Masters

C.L.

, Barnham

K.J.

Alanine-2 carbonyl is an oxygen ligand in Cu²⁺ coordination of Alzheimer's disease amyloid-β peptide—relevance to N-terminally truncated forms.

J Am Chem Soc. 2009; 131: 8760–71.

111.

Frederickson

C.J.

, Giblin

3rd , Balaji

R.V.

. Synaptic release of zinc from brain slices: factors governing release, imaging, and accurate calculation of concentration. J Neurosci Methods. 2006; 154: 19–29.

112.

Schlief

M.L.

, Craig

A.M.

, Gitlin

J.D.

NMDA receptor activation mediates copper homeostasis in hippocampal neurons.

J Neurosci. 2005; 25: 239–46.

113.

Kenche

V.B.

, Barnham

K.J.

Alzheimer's disease and metals: therapeutic opportunities.

Br J Pharmacol. 2011; 163: 211–9.

114.

Srinivasan

, Pandi-Perumal

S.R.

, Cardinali

D.P.

, Poeggeler

, Hardeland

Melatonin in Alzheimer's disease and other neurodegenerative disorders.

Behav Brain Funct. 2006; 2: 15.

115.

Barnham

K.J.

, Haeffner

, Ciccotosto

G.D.

. Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer's disease β-amyloid. FASEB J. 2004; 18: 1427–9.

116.

Youssef

, Florent-Béchard

, Malaplate-Armand

. N-truncated amyloid-β oligomers induce learning impairment and neuronal apoptosis. Neurobiol Aging. 2008; 29: 1319–33.

117.

Bayer

T.A.

, Schäfer

, Simons

. Dietary Cu stabilizes brain super-oxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice. Proc Natl Acad Sci USA. 2003; 100: 14187–92.

118.

Phinney

A.L.

, Drisaldi

, Schmidt

S.D.

. In vivo reduction of amyloid-β by a mutant copper transporter. Proc Natl Acad Sci USA. 2003; 100: 14193–8.

119.

Adlard

P.A.

, Cherny

R.A.

, Finkelstein

D.I.

. Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ. Neuron. 2008; 59: 43–55.

120.

Barnham

K.J.

, Gautier

E.C.L.

, Kok

G.B.

, Krippner

8-Hydroxy quinoline derivatives. US Patent. (2009) US 7,619,091 B2.

121.

Arbiser

J.L.

, Kraeft

S.K.

, van Leeuwen

. Clioquinol-zinc chelate: a candidate causative agent of subacute myelo-optic neuropathy. Mol Med. 1998; 4: 665–70.

122.

Crouch

P.J.

, Savva

M.S.

, Hung

L.W.

. The Alzheimer's therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity. J Neurochem. 2011 [Epub ahead of print, Jul 28; doi: 10.1111/j.1471–4159.2011.07402.x.]

123.

Adlard

P.A.

, Bica

, White

A.R.

. Metal ionophore treatment restores dendritic spine density and synaptic protein levels in a mouse model of Alzheimer's disease. PLoS One. 2011; 6: e17669.

124.

Camps

, Formosa

, Galdeano

. Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and β-amyloid-directed anti-Alzheimer compounds. J Med Chem. 2009; 52: 5365–79.

125.

Camps

, Formosa

, Galdeano

. Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates. Chem Biol Interact. 2010; 187: 411–5.

126.

Luo

, Li

Y.P.

, Tan

J.H.

, Gu

L.Q.

, Huang

Z.S.

Synthesis and biological evaluation of novel N,N‘-bis-methylenedioxybenzyl-alkylenediamines as bivalent anti-Alzheimer disease ligands.

J Enzyme Inhib Med Chem. 2011 [Epub ahead of print, Jan 21; doi: 10.3109/14756366.2010.548329.]

127.

Luo

, Li

Y.P.

, He

. Synthesis and evaluation of heterobivalent tacrine derivatives as potential multi-functional anti-Alzheimer agents. Eur J Med Chem. 2011; 46: 2609–16.

128.

Lupp

, Appenroth

, Fang

, Decker

, Lehmann

, Fleck

Tacrine-NO donor and tacrine-ferulic acid hybrid molecules as new anti-Alzheimer agents: hepatotoxicity and influence on the cytochrome P450 system in comparison to tacrine.

Arzneimittelforschung. 2010; 60: 229–37.

129.

Rodríguez-Franco

M.I.

, Fernández-Bachiller

M.I.

, Pérez

, Hernández-Ledesma

, Bartolomé

Novel tacrine-melatonin hybrids as dual-acting drugs for Alzheimer disease, with improved acetylcholinesterase inhibitory and antioxidant properties.

J Med Chem. 2006; 49: 459–62.

130.

Fernández-Bachiller

M.I.

, Pérez

, Campillo

N.E.

. Tacrine-melatonin hybrids as multifunctional agents for Alzheimer's disease, with cholinergic, antioxidant, and neuroprotective properties. Chem Med Chem. 2009; 4: 828–41.

131.

Spuch

, Antequera

, Fernandez-Bachiller

M.I.

, Rodríguez-Franco

M.I.

, Carro

A new tacrine-melatonin hybrid reduces amyloid burden and behavioral deficits in a mouse model of Alzheimer's disease.

Neurotox Res. 2010; 17: 421–31.

132.

Hardeland

, Cardinali

D.P.

, Srinivasan

, Spence

D.W.

, Brown

G.M.

, Pandi-Perumal

S.R.

Melatonin—a pleiotropic, orchestrating regulator molecule.

Prog Neurobiol. 2011; 93: 350–84.

133.

Camps

, Formosa

, Galdeano

. Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation. J Med Chem. 2008; 51: 3588–98.

134.

Rizzo

, Bartolini

, Ceccarini

. Targeting Alzheimer's disease: Novel indanone hybrids bearing a pharmacophoric fragment of AP2238. Bioorg Med Chem. 2010; 18: 1749–60.

135.

Marco-Contelles

, León

, de los Ríos

. Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease. J Med Chem. 2009; 52: 2724–32.

136.

León

, Marco-Contelles

A step further towards multitarget drugs for Alzheimer and neuronal vascular diseases: targeting the cholinergic system, amyloid-β aggregation and Ca²⁺ dyshomeostasis.

Curr Med Chem. 2011; 18: 552–76.

137.

Rook

, Schmidtke

K.U.

, Gaube

. Bivalent β-carbolines as potential multitarget anti-Alzheimer agents. J Med Chem. 2010; 53: 3611–7.

138.

Toda

, Kaneko

, Kogen

Development of an efficient therapeutic agent for Alzheimer's disease: design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter.

Chem Pharm Bull (Tokyo). 2010; 58: 273–87.

139.

Weinreb

, Mandel

, Bar-Am

. Multifunctional neuroprotective derivatives of rasagiline as anti-Alzheimer's disease drugs. Neurotherapeutics. 2009; 6: 163–74.

140.

Zheng

, Fridkin

, Youdim

M.B.

Site-activated chelators derived from anti-Parkinson drug rasagiline as a potential safer and more effective approach to the treatment of Alzheimer's disease.

Neurochem Res. 2010; 35: 2117–23.

141.

Bolognesi

M.L.

, Cavalli

, Valgimigli

. Multi-target-directed drug design strategy: from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer's disease. J Med Chem. 2007; 50: 6446–9.

142.

Zhang

, Yu

, Li

W.M.

. Preclinical characterization of intestinal absorption and metabolism of promising anti-Alzheimer's dimer bis(7)-tacrine. Int J Pharm. 2008; 357: 85–94.

143.

Fernández-Bachiller

M.I.

, Pérez

, González-Muñoz

G.C.

. Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer's disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties. J Med Chem. 2010; 53: 4927–37.

144.

Bolognesi

M.L.

, Banzi

, Bartolini

. Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer's disease. J Med Chem. 2007; 50: 4882–97.

145.

Bolognesi

M.L.

, Cavalli

, Melchiorre

Memoquin: a multi-target-directed ligand as an innovative therapeutic opportunity for Alzheimer's disease.

Neurotherapeutics. 2009; 6: 152–62.

146.

Bolognesi

M.L.

, Bartolini

, Rosini

, Andrisano

, Melchiorre

Structure-activity relationships of memoquin: Influence of the chain chirality in the multi-target mechanism of action.

Bioorg Med Chem Lett. 2009; 19: 4312–5.

147.

Bolognesi

M.L.

, Rosini

, Andrisano

. MTDL design strategy in the context of Alzheimer's disease: from lipocrine to memoquin and beyond. Curr Pharm Des. 2009; 15: 601–13.

148.

Bolognesi

M.L.

, Cavalli

, Bergamini

. Toward a rational design of multitarget-directed antioxidants: merging memoquin and lipoic acid molecular frameworks. J Med Chem. 2009; 52: 7883–6.

149.

Bolognesi

M.L.

, Bartolini

, Tarozzi

. Multitargeted drugs discovery: balancing anti-amyloid and anticholinesterase capacity in a single chemical entity. Bioorg Med Chem Lett. 2011; 21: 2655–8.

150.

Inoue

, Hoshino

, Nojima

, Ishida

, Okamoto

Investigation of responders and non-responders to long-term donepezil treatment.

Psychogeriatrics. 2010; 10: 53–61.

151.

Kasuya

, Meguro

, Okamura

. Greater responsiveness to donepezil in Alzheimer patients with higher levels of acetylcholinesterase based on attention task scores and a donepezil PET study. Alzheimer Dis Assoc Disord. 2011. [Epub ahead of print, Jun 9; PMID: 21666432.]

152.

Nozawa

, Ichimiya

, Nozawa

. Clinical effects of high oral dose of donepezil for patients with Alzheimer's disease in Japan. Psychogeriatrics. 2009; 9: 50–5.

153.

Kanaya

, Abe

, Sakai

, Fujii

, Iwamoto

Changes in cognitive functions of patients with dementia of the Alzheimer type following long-term administration of donepezil hydrochloride: relating to changes attributable to differences in apolipoprotein E phenotype.

Geriatr Gerontol Int. 2010; 10: 25–31.

154.

Lopez

O.L.

, Mackell

J.A.

, Sun

. Effectiveness and safety of donepezil in Hispanic patients with Alzheimer's disease: a 12-week open-label study. J Natl Med Assoc. 2008; 100: 1350–8.

155.

Carrasco

M.M.

, Agüera

, Gil

, Moríñigo

, Leon

Safety and Effectiveness of Donepezil on Behavioral Symptoms in Patients With Alzheimer Disease.

Alzheimer Dis Assoc Disord. 2011 [Epub ahead of print, Mar 10; PMID: 21399485.]

156.

Senanarong

, Poungvarin

, Phanthumchinda

. Safety and tolerability of galantamine in possible Alzheimer's disease with or without cerebrovascular disease and vascular dementia in Thai patients. J Med Assoc Thai. 2009; 92 Suppl 2: S12–8.

157.

Waldemar

, Gauthier

, Jones

. Effect of donepezil on emergence of apathy in mild to moderate Alzheimer's disease. Int J Geriatr Psychiatry. 2011; 26: 150–7.

158.

Burns

, Bernabei

, Bullock

. Safety and efficacy of galantamine (Reminyl) in severe Alzheimer's disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol. 2009; 8: 39–47.

159.

Doody

R.S.

, Corey-Bloom

, Zhang

, Li

, Ieni

, Schindler

Safety and tolerability of donepezil at doses up to 20 mg/day: results from a pilot study in patients with Alzheimer's disease.

Drugs Aging. 2008; 25: 163–74.

160.

Ferris

S.H.

, Schmitt

F.A.

, Saxton

. Analyzing the impact of donepezil 23 mg/d on language dysfunction in moderate to severe Alzheimer's disease. Alzheimers Res Ther. 2011; 3: 22.

161.

Sabbagh

, Cummings

Progressive cholinergic decline in Alzheimer's Disease: consideration for treatment with donepezil 23 mg in patients with moderate to severe symptomatology.

BMC Neurol. 2011; 11: 21.

162.

Cummings

, Emre

, Aarsland

, Tekin

, Dronamraju

, Lane

Effects of rivastigmine in Alzheimer's disease patients with and without hallucinations.

J Alzheimers Dis. 2010; 20: 301–11.

163.

Rozzini

, Chilovi

B.V.

, Conti

. Efficacy of SSRIs on cognition of Alzheimer's disease patients treated with cholinesterase inhibitors. Int Psychogeriatr. 2010; 22: 114–9.

164.

Cornelli

Treatment of Alzheimer's disease with a cholinesterase inhibitor combined with antioxidants.

Neurodegener Dis. 2010; 7: 193–202.

165.

Maher-Edwards

, Dixon

, Hunter

. SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. Int J Geriatr Psychiatry. 2011; 26: 536–44.

166.

Herrmann

, Cappell

, Eryavec

G.M.

, Lanctôt

K.L.

Changes in nursing burden following memantine for agitation and aggression in long-term care residents with moderate to severe Alzheimer's disease: an open-label pilot study.

CNS Drugs. 2011; 25: 425–33.

167.

Olin

J.T.

, Bhatnagar

, Reyes

, Koumaras

, Meng

, Brannan

Safety and tolerability of rivastigmine capsule with memantine in patients with probable Alzheimer's disease: a 26-week, open-label, prospective trial (Study ENA713B US32).

Int J Geriatr Psychiatry. 2010; 25: 419–26.

168.

Farlow

M.R.

, Alva

, Meng

, Olin

J.T.

A 25-week, open-label trial investigating rivastigmine transdermal patches with concomitant memantine in mild-to-moderate Alzheimer's disease: a post hoc analysis.

Curr Med Res Opin. 2010; 26: 263–9.

169.

Jones

, Sheehan

, Phillips

. DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease—a multicentre RCT. Trials. 2009; 10: 57.

170.

Lopez

O.L.

, Becker

J.T.

, Wahed

A.S.

. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009; 80: 600–7.

171.

Minthon

, Wallin

A.K.

, Eriksson

, Wattmo

, Andreasen

Long-term rivastigmine treatment in a routine clinical setting.

Acta Neurol Scand. 2009; 119: 180–5.

172.

Grossberg

, Sadowsky

, Fröstl

. Safety and tolerability of the rivastigmine patch: results of a 28-week open-label extension. Alzheimer Dis Assoc Disord. 2009; 23: 158–64.

173.

Lee

J.H.

, Sevigny

Effects of body weight on tolerability of rivastigmine transdermal patch: a post-hoc analysis of a double-blind trial in patients with Alzheimer disease.

Alzheimer Dis Assoc Disord. 2011; 25: 58–62.

174.

Cummings

J.L.

, Farlow

M.R.

, Meng

, Tekin

, Olin

J.T.

Rivastigmine transdermal patch skin tolerability: results of a 1-year clinical trial in patients with mild-to-moderate Alzheimer's disease.

Clin Drug Investig. 2010; 30: 41–9.

175.

Sadowsky

C.H.

, Dengiz

, Meng

. Switching from oral donepezil to rivastigmine transdermal patch in Alzheimer's disease: 20-week extension phase results. Prim Care Companion J Clin Psychiatry. 2010; 12: PCC.09m00852.

176.

Cummings

J.L.

, Ferris

S.H.

, Farlow

M.R.

, Olin

J.T.

, Meng

Effects of rivastigmine transdermal patch and capsule on aspects of clinical global impression of change in Alzheimer's disease: a retrospective analysis.

Dement Geriatr Cogn Disord. 2010; 29: 406–12.

177.

Farlow

M.R.

, Grossberg

, Gauthier

, Meng

, Olin

J.T.

The ACTION study: methodology of a trial to evaluate safety and efficacy of a higher dose rivastigmine transdermal patch in severe Alzheimer's disease.

Curr Med Res Opin. 2010; 26: 2441–7.

178.

Grossberg

G.T.

, Olin

J.T.

, Somogyi

, Meng

Dose effects associated with rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease.

Int J Clin Pract. 2011; 65: 465–71.

179.

Grossberg

, Meng

, Olin

J.T.

Impact of rivastigmine patch and capsules on activities of daily living in Alzheimer's disease.

Am J Alzheimers Dis Other Demen. 2011; 26: 65–71.

180.

Farlow

M.R.

, Grossberg

G.T.

, Meng

, Olin

, Somogyi

Rivastigmine transdermal patch and capsule in Alzheimer's disease: influence of disease stage on response to therapy.

Int J Geriatr Psychiatry. 2010 Dec [Epub ahead of print, Dec 23; doi: 10.1002/gps.2669.]

181.

Lannfelt

, Blennow

, Zetterberg

. Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008; 7: 779–86.

182.

Faux

N.G.

, Ritchie

C.W.

, Gunn

. PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses. J Alzheimers Dis. 2010; 20: 509–16.

183.

Hansen

R.A.

, Gartlehner

, Webb

A.P.

, Morgan

L.C.

, Moore

C.G.

, Jonas

D.E.

Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis.

Clin Interv Aging. 2008; 3: 211–25.

184.

Mayeux

Clinical practice. Early Alzheimer's disease.

N Engl J Med. 2010; 362: 2194–201.

185.

Jones

R.W.

A review comparing the safety and tolerability of memantine with the acetylcholinesterase inhibitors.

Int J Geriatr Psychiatry. 2010; 25: 547–53.

186.

Maelicke

, Hoeffle-Maas

, Ludwig

. Memogain is a galantamine pro-drug having dramatically reduced adverse effects and enhanced efficacy. J Mol Neurosci. 2010; 40: 135–7.

187.

Leonard

A.K.

, Sileno

A.P.

, Brandt

G.C.

, Foerder

C.A.

, Quay

S.C.

, Costantino

H.R.

In vitro formulation optimization of intranasal galantamine leading to enhanced bioavailability and reduced emetic response in vivo.

Int J Pharm. 2007; 335: 138–46.

188.

Costantino

H.R.

, Leonard

A.K.

, Brandt

, Johnson

P.H.

, Quay

S.C.

Intranasal administration of acetylcholinesterase inhibitors.

BMC Neurosci. 2008; (9 Suppl 3): S6.

189.

Winblad

, Grossberg

, Frölich

. IDEAL: a 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease. Neurology. 2007; (69 Suppl 4): S14–22.

190.

Allain-Veyrac

, Lebreton

, Collonnier

, Jolliet

First case of symmetric drug-related intertriginous and flexural exanthema (sdrife) due to rivastigmine?

Am J Clin Dermatol. 2011; 12: 210–3.

191.

Makris

, Koulouris

, Koti

, Aggelides

, Kalogeromitros

Maculopapular eruption to rivastigmine's transdermal patch application and successful oral desensitization.

Allergy. 2010; 65: 925–6.

192.

Mumoli

, Carmignani

, Luschi

, Cei

, Chiavistelli

Hepatitis with cholestasis caused by rivastigmine transdermal patch.

Am J Gastroenterol. 2009; 104: 2859–60.

193.

Dierckx

R.I.

, Vandewoude

M.F.

Donepezil-related toxic hepatitis.

Acta Clin Belg. 2008; 63: 339–42.

194.

Hernandez

R.K.

, Farwell

, Cantor

M.D.

, Lawler

E.V.

Cholinesterase inhibitors and incidence of bradycardia in patients with dementia in the veterans affairs new England healthcare system.

J Am Geriatr Soc. 2009; 57: 1997–2003.

195.

Sato

, Urbano

, Yu

. The effect of donepezil treatment on cardiovascular mortality. Clin Pharmacol Ther. 2010; 88: 335–8.

196.

Anonymous.

Rivastigmine patches: fatal overdoses.

Prescrire Int. 2011; 116: 127.

197.

Chen

C.F.

, Hsu

H.C.

, Ouyang

W.C.

, Lin

Y.C.

Galantamine-induced pisa syndrome: memantine as an alternative.

Int J Geriatr Psychiatry. 2008; 23: 660–1.

198.

Defilippi

J.L.

, Crismon

M.L.

Drug interactions with cholinesterase inhibitors.

Drugs Aging. 2003; 20: 437–4.

199.

Reisberg

, Doody

, Stöffler

, Schmitt

, Ferris

, Möbius

H.J.

A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease.

Arch Neurol. 2006; 63: 49–54.

200.

Anonymous.

Memantine: heart failure: harmful drug.

Prescrire Int. 2009; 18: 167.

201.

Pittenger

, Naungayan

, Kendell

S.F.

. Visual hallucinations from the addition of riluzole to memantine and bupropion. J Clin Psychopharmacol. 2006; 26: 218–20.

202.

Hansen

R.A.

, Gartlehner

, Lohr

K.N.

, Kaufer

D.I.

Functional outcomes of drug treatment in Alzheimer's disease: A systematic review and meta-analysis.

Drugs Aging. 2007; 24: 155–67.

203.

Assal

, van der Meulen

Pharmacological interventions in primary care: hopes and illusions.

Front Neurol Neurosci. 2009; 24: 54–65.

204.

Gauthier

, Scheltens

Can we do better in developing new drugs for Alzheimer's disease?

Alzheimers Dement. 2009; 5: 489–91.

205.

Nelson

P.T.

, Kryscio

R.J.

, Abner

E.L.

. Acetylcholinesterase inhibitor treatment is associated with relatively slow cognitive decline in patients with Alzheimer's disease and AD + DLB. J Alzheimers Dis. 2009; 16: 29–34.

206.

Rockwood

, Fay

, Gorman

The ADAS-cog and clinically meaningful change in the VISTA clinical trial of galantamine for Alzheimer's disease.

Int J Geriatr Psychiatry. 2010; 25: 191–201.

207.

Gilstad

J.R.

, Finucane

T.E.

Results, rhetoric, and randomized trials: the case of donepezil.

J Am Geriatr Soc. 2008; 56: 1556–62.

208.

Pilotto

, Franceschi

, D'Onofrio

. Effect of a CYP2D6 polymorphism on the efficacy of donepezil in patients with Alzheimer disease. Neurology. 2009; 73: 761–7.

209.

Chianella

, Gragnaniello

, Maisano Delser

. BCHE and CYP2D6 genetic variation in Alzheimer's disease patients treated with cholinesterase inhibitors. Eur J Clin Pharmacol. 2011 [Epub ahead of print, Jun 1; doi: 10.1007/s00228-011-1064-x.]

210.

Johannsen

Long-term cholinesterase inhibitor treatment of Alzheimer's disease.

CNS Drugs. 2004; 18: 757–68.

211.

Froelich

, Andreasen

, Tsolaki

. Long-term treatment of patients with Alzheimer's disease in primary and secondary care: results from an international survey. Curr Med Res Opin. 2009; 25: 3059–68.

212.

Cummings

J.L.

, Koumaras

, Chen

. Effects of rivastigmine treatment on the neuropsychiatric and behavioral disturbances of nursing home residents with moderate to severe probable Alzheimer's disease: a 26-week, multicenter, open-label study. Am J Geriatr Pharmacother. 2005; 3: 137–48.

213.

Gauthier

, Juby

, Rehel

, Schecter

EXACT: rivastigmine improves the high prevalence of attention deficits and mood and behaviour symptoms in Alzheimer's disease.

Int J Clin Pract. 2007; 61: 886–95.

214.

Gauthier

, Juby

, Dalziel

. Effects of rivastigmine on common symptomatology of Alzheimer's disease (EXPLORE). Curr Med Res Opin. 2010; 26: 1149–60.

215.

Granero

A.L.

, Lucchetti

Treatment of apathy in Alzheimer's disease with transdermal rivastigmine: report of three cases.

Rev Bras Psiquiatr. 2010; 32: 94–5.

216.

Pelosi

Donepezil is no more effective than placebo for agitation in people with Alzheimer's disease.

Evid Based Ment Health. 2008; 11: 84.

217.

Schmitt

F.A.

, Wichems

C.H.

A systematic review of assessment and treatment of moderate to severe Alzheimer's disease.

Prim Care Companion J Clin Psychiatry. 2006; 8: 158–69.

218.

Raina

, Santaguida

, Ismaila

. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008; 148: 379–97.

219.

Williams

Progress in Alzheimer's disease drug discovery: an update.

Curr Opin Investig Drugs. 2009; 10: 23–34.

220.

Modrego

P.J.

, Fayed

, Errea

J.M.

, Rios

, Pina

M.A.

, Sarasa

Memantine versus donepezil in mild to moderate Alzheimer's disease: a randomized trial with magnetic resonance spectroscopy.

Eur J Neurol. 2010; 17: 405–12.

221.

van Dyck

C.H.

, Schmitt

F.A.

, Olin

J.T.

. A responder analysis of memantine treatment in patients with Alzheimer disease maintained on donepezil. Am J Geriatr Psychiatry. 2006; 14: 428–37.

222.

Geerts

, Grossberg

G.T.

Pharmacology of acetylcholinesterase inhibitors and N-methyl-D-aspartate receptors for combination therapy in the treatment of Alzheimer's disease.

J Clin Pharmacol. 2006; 46(Suppl 1): 8S–16.

223.

Schmitt

F.A.

, van Dyck

C.H.

, Wichems

C.H.

. Cognitive response to memantine in moderate to severe Alzheimer disease patients already receiving donepezil: an exploratory reanalysis. Alzheimer Dis Assoc Disord. 2006; 20: 255–62.

224.

Feldman

H.H.

, Schmitt

F.A.

, Olin

J.T.

. Activities of daily living in moderate-to-severe Alzheimer disease: an analysis of the treatment effects of memantine in patients receiving stable donepezil treatment. Alzheimer Dis Assoc Disord. 2006; 20: 263–8.

225.

Schneider

L.S.

, Insel

P.S.

, Weiner

M.W.

. Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer's Disease Neuroimaging Initiative. Arch Neurol. 2011; 68: 58–66.

226.

Riordan

K.C.

, Hoffman Snyder

C.R.

, Wellik

K.E.

, Caselli

R.J.

, Wingerchuk

D.M.

, Demaerschalk

B.M.

Effectiveness of adding memantine to an Alzheimer dementia treatment regimen which already includes stable donepezil therapy: a critically appraised topic.

Neurologist. 2011; 17: 121–3.

227.

Patel

, Grossberg

G.T.

Combination therapy for Alzheimer's disease.

Drugs Aging. 2011; 28: 539–46.

Cognitive Enhancers in Moderate to Severe Alzheimer's Disease

Abstract

Keywords

Introduction

Mechanisms of Action, Metabolism and Pharmacokinetic Profiles

Cholinesterase inhibitors

N-methyl-d-aspartate receptor antagonists

AMPAR potentiators

Metal chelators and ionophores

Multifunctional drugs

Clinical Studies

Safety

Efficacy

Patient Preference

Place in Therapy

Conclusions

Disclosures

References