Memantine A7 Nachr Donepezil

symptomatic treatment of DAT. Donepezil was the second cholinesterase inhibitor which became available for the symptomatic treatment of DAT. It is a noncompetitive, reversible AChE inhibitor (► Acetylcholinesterase inhibitors as cognitive enhancers) with a high central versus peripheral cholinomimetic specificity and a long duration of inhibitory action. In large-scale clinical studies it was shown to be a well-tolerated drug that causes improvement of cognitive and global function in mild to moderate DAT. Rivastigmine is a noncompetitive, pseudoirreversible AChE and butyrylcholinesterase inhibitor indicated for treatment of mild to moderately severe DAT. It has a long-lasting inhibitory effect, and besides being brain-selective, rivastigmine acts brain region-specific being most effective in hippocampus and cortex, which are in the main associated with cholinergic dysfunction in DAT. Rivastigmine significantly ameliorates cognitive function, activities of daily living and disease severity. Galantamine enhances central cholinergic activity through a dual mode of action. Besides its action as a brain-selective, competitive, reversible AChE inhibitor, galantamine is an ► allosteric potentiating ligand of the nicotinic acetylcholine receptor (nAChR). Clinical efficacy if this compound is based on improvement of cognitive function, as well as functional and behavioral symptoms of mild to moderate DAT.

Although the second-generation AChE inhibitors have a better safety and tolerability profile compared with the first-generation compounds, e.g., tacrine, on an average, approximately 75% of participants randomized to active AChE inhibitor treatment reported at least one adverse effect. The most frequently reported adverse events are of gastrointestinal origin, including nausea, diarrhea, vomiting, weight loss, as well as dizziness. For memantine, the most frequently reported adverse events in placebo-controlled trials included agitation, falls, dizziness, accidental injury, influenza-like symptoms, headache and diarrhea.

Although a substantial relation has not been established between sex and responsiveness to the second-generation cholinesterase inhibitors, some indications toward sexual dimorphism in response to these agents warrant further investigation, especially in regard to its role in the development of novel DAT therapies.

In focusing on DAT, it is useful to note that conclusions drawn from DAT studies, will frequently apply to other dementia entities. Cerebrovascular dementia consists mainly of patients with DAT and notable concomitant cerebrovascular disease (mixed dementia or DAT with cerebrovascular disease). Cerebrovascular disease is now believed to represent a continuum of relevance for DAT as well as cerebrovascular dementia. Lewy body dementia is frequently noted to be accompanied by DAT neuropathol-ogy and is sometimes seen to be a Lewy body variant of DAT. These latter clinical entities have also been shown to benefit - at least to a certain degree - from treatment with AChE inhibitors as has also been demonstrated for Parkinson's disease dementia. Nevertheless, additional clinical evidence is required since studies have reported contradictory efficacy levels. Cholinesterase inhibitors and memantine produce (although sometimes limited) benefits in cognition, including executive functioning, but often not in activities of daily living, as is the case in DAT.

Besides neurotransmitter replacement therapy, several routinely available treatment strategies for DAT are based on knowledge of underlying pathophysiological mechanisms. Their potential disease modifying efficacy is, however, in many cases still a matter of debate.

The therapeutic use of enzyme inhibitors in treatment of neurodegenerative diseases has its origin in the antiParkinson action of the selective, irreversible monoamine oxidase (MAO) B inhibitor, ► selegiline, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. Clinical evidence for therapeutic efficacy in DAT is controversial with few studies showing improvement of cognitive function, mood, and behavior. Recently, selegiline was demonstrated to have a synergistic cognition-improving effect with done-pezil, whereby selegiline potentiates the effect of donepezil on the cognitive impairment presumably through both the cholinergic and dopaminergic systems.

Dysfunction of the excitatory glutamatergic neuro-transmitter system has been implicated in neurodegener-ative disorders, including DAT. Under physiological conditions, N-methyl-d-aspartic acid ► (NMDA) receptors are blocked by Mg2+ in the absence of their ligand, glutamate. Excitatory toxicity is based on the permanent activation of NMDA receptors by continuous presynaptic release of low glutamate levels, and subsequent toxic Ca2+ influx. ► Memantine is a noncompetitive, voltage-dependent NMDA receptor antagonist that blocks the ion channel in the presence of sustained release of low glutamate quanta, thereby inhibiting a toxic Ca2+ influx. Symptomatic efficacy of memantine treatment is presumably based on the brief removal of memantine from the channel in case of transient high glutamate release into the synap-tic cleft during learning and memory processes. Meman-tine is indicated for treatment of moderate-to-severe DAT, where it improves cognitive, functional and behavioral parameters. Given the fact that based on its mode-of-action, memantine may prevent glutamatergic excitotoxi-city, it has been proposed as a neuroprotective agent with disease-modifying potential.

Although originally developed as symptomatic treatment agents, neuroprotective effects have been allotted to the cholinesterase inhibitors as well. For donepezil this is presumably based on the inhibition of AChE-induced ► amyloid-b (Ab) aggregation and fibrillogen-esis, since it is the only AChE inhibitor currently marketed that targets both the catalytic site of the enzyme and the peripheral anionic site, with latter triggering amy-loid-b fibril formation. Galantamine's dual mode of action is supposed to underlie its neuroprotective capacities. Galantamine distinctively operates upon the a4b2 nAChR subtype, which upon stimulation inflicts neuroprotective effects. In addition, neuroprotective efficacy of both donepezil and galantamine seems to be linked to the a7 nAChR. Rivastigmine favorably modulates the human cellular response to injury through potentiating of heat-shock tran-scriptor factor-1, which elevates heat-shock protein 70 levels leading to cell protection. Advanced studies are required to further scrutinize action mechanisms underlying presumed neuroprotective mechanisms of cholinester-ase inhibitors.

Based on the cholinergic hypothesis of DAT, the use of nicotinic agonists has incited a large research endeavor. There are significant numbers of nicotinic receptors within the brain, both pre- and postsynaptically, that are known to be important in learning and memory. DAT patients exhibit a loss of some subtypes of nicotinic receptors and the degree of loss correlates with the severity of the symptoms. There is a large body of evidence to indicate that nicotinic drugs indeed affect learning and memory. ► Nicotine and other ► nicotinic agonists can improve cognitive and psychomotor function, whereas nicotinic antagonists lead to cognitive impairment. Nicotine is reported to improve attention and information processing in DAT patients and small short-term studies have been carried out looking at the use of nicotine skin patches. Nicotine or nicotinic agonists are likely to have marked vascular effects and this may limit their use. In addition, direct stimulation by nicotinic agonists may induce desensitization of nicotinic receptors reducing the efficacy of such compounds in the longer term. Receptor modulation, as is the case for the allosteric potentiating ligand galantamine, may therefore be a better approach to overcome this hurdle.

The main drug target of commercially available neu-roprotectants is oxidative stress by oxygenized free radicals. Ginko biloba extract has been used for treatment of memory problems for many years despite the lack of proven clinical efficacy. Its presumed mode of action is based on the presence of flavonoids, terpenoids and organic acids in the extract acting as free radical scavengers.

A recent randomized controlled clinical trial found that it was not effective in reducing either the overall incidence rate of dementia or DAT incidence in elderly individuals with normal cognition or those with MCI. Vitamin E or a-tocopherol is another free radical scavenger used for treatment of DAT, despite of insufficiently proven clinical efficacy.

Given the central role of amyloid-b pathology in the DAT disease process, future treatment strategies should mainly focus on the prevention or reversal of amyloid-b peptide deposition. Several experimental strategies focusing on amyloid-b are presently under intense preclinical and clinical investigation, including interventions modulating proteolytic amyloid precursor protein processing with e.g., secretase inhibitors, passive or active immunization against amyloid-b, and treatments blocking amy-loid-b aggregation. Data from animal models suggests that antibodies raised against the amyloid-b can decrease Ab deposition through several mechanisms, as well as decrease amyloid-b associated damage such as dystrophic neurite formation, and improve behavioral performance. Data from human studies suggests that active immunization can result in plaque clearance and that passive im-munotherapy might result in slowing of cognitive decline. Despite this, a recent analysis from a phase I trial evaluating active immunization with Ab1-42, while not powered to determine efficacy, suggested no large effect of active immunization despite the fact that plaque clearance was very prominent in some subjects. An important issue to consider is when active or passive immunization targeting amyloid-b has the chance to be most effective. Pathological and biomarker studies have shown that amyloid-b deposition probably begins about 10-15 years prior to DAT symptom onset. By the time the earliest clinical signs of DAT emerge, amyloid-b deposition may be close to reaching its peak and tangle formation and neuronal cell loss is substantial, though still not at its maximal extent. Since immunization targeting amyloid-b does not appear to have major effects on tangle pathology, for immunization to have the most chance for success, performing clinical trials in individuals who are cogni-tively only very mildly impaired or even in those with preclinical DAT would likely offer a much better chance for success. Current work with DAT biomarkers suggests that such individuals can now be identified and it seems likely that targeting this population with antiAb immunization strategies is likely to be successful.

Epidemiological data collected between the mid 1980s-late 1990s suggested that prolonged exposure to ► nonsteroidal antiinflammatory drugs (NSAIDs) in conditions like arthritis entailed a reduced risk and delayed onset of

DAT. NSAIDs exert antiinflammatory, analgesic and antipyretic activities and are involved in the suppression of prostaglandin synthesis by inhibiting cyclo-oxygenase, a key mediator of the inflammatory cascade. Initially, the diminishing effect of prolonged usage of NSAIDs on the risk of DAT was attributed to a reduction of inflammation. Several subsequent clinical trials testing NSAIDs in DAT patients based on this rationale, however, yielded negative results. In recent years, several studies have proven that a subset of NSAIDs (e.g., ibuprofen, indometha-cin, flurbiprofen) reduce Ab1-42 production in cultured cells and mouse brain, whereas other NSAIDs do not affect Ab metabolism (e.g., aspirin, sulindac, ketoprofen), and others (e.g., celecoxib) even increase Ab1-42 production. The use of NSAIDs may prove efficacious in other protein-misfolding disorders besides DAT, given the fact that some of these compounds may exhibit antifibrillo-genic and fibril-destabilizing activities for other proteins that can aggregate and form amyloid-like fibrils besides amyloid-b, including alpha-synuclein in Lewy body dementia. Nevertheless, a large body of preclinical and clinical research is required to underpin these presumed disease-modifying effects of certain NSAIDs.

Until a therapy is developed that can prevent or reverse the disease, the optimal goal for effective DAT management is to develop a treatment regimen that will yield maximum benefits for individual patients across multiple domains, including cognition, daily functioning, and behavior, and to provide realistic expectations for patients and caregivers throughout the course of the disease.

Besides focusing on cognitive symptomatology, treatment of DAT should also include managing BPSD and related behavioral alterations, especially given their major impact on patients, caretakers, and society at large. Behavioral symptoms, particularly aggression, agitation and circa-dian rhythm disturbances, or sundowning behavior, have been described as the primary predictor of caregiver burden and often motivate institutionalization in specialized care facilities. In addition, the presence of BPSD in DAT is associated with more rapid cognitive deterioration.

A variety of pharmacological agents has been evaluated for the treatment of BPSD, including cholinomimetics, antidepressants, anticonvulsants, anxiolytics, hormonal preparations and antipsychotic (neuroleptic) drugs. Unfortunately, clinical evidence is rather anecdotal or based on open-label clinical trials for most of these substances. In addition, although the categories of BPSD are superficially similar to symptoms in, for example, the psychosis of schizophrenia or depression in major affective disorders, the specific nature of these symptoms in DAT and related disorders may be different based on DAT-specific neurochemical alterations and the interaction with psychological, cognitive and functional factors.

Neuroleptics are implemented most frequently, although the use of classic neuroleptics in an elderly population implicates the risk of irreversible movement disorders, extrapyramidal side effects, anticholinergic effects and adverse drug interactions. Novel (atypical) antipsychotic agents should be screened in placebo-controlled randomized double-blind clinical trials assessing efficacy and safety profile. Two atypical antipsychotic agents, ► risperidone and ► olanzapine, are presently the most optimal treatment options for BPSD and have been evaluated in a series of placebo-controlled randomized clinical trials, albeit with rather variable results. Nevertheless, the increased risk of cerebrovascular accident in patients taking risperi-done or olanzapine may limit their use in demented subjects. Risperidone is a strong dopamine antagonist with high affinity for D2 dopaminergic receptors, as well as serotonin (5-HT2) receptors. It is well absorbed after oral administration and peak plasma levels are reached in 1 h. Olanzapine has a higher affinity for 5-HT2 serotonin receptors than D2 dopamine receptors. Peak plasma levels are reached within 5-8 h following oral administration. Taking into account the rather limited efficacy and the importance of side effects observed with psychotropic agents overall in this indication, the majority of existing guidelines underline the importance of nonpharmacolo-gical strategies.

The proportion of dementia patients experiencing major or minor depression is estimated to be around 25%, and 20-50% in patients diagnosed with DAT. The etiology of depression in DAT is heterogeneous as indicated by the four subtypes identified: adjustment disorder, recurrence of earlier depressive episode, vascular depression and depression associated with neurodegeneration. Given the symptom overlap between nondepressed DAT patients and depression associated with dementia, including psy-chomotor retardation and difficulty thinking and concentrating, as well as depression-like symptoms in case of DAT-associated apathy, diagnosing depression in DAT may be complex. Beyond the inherent burden on patients and caretakers, comorbid depression may cause a decline in quality of life, impairment in functionalities of daily living and has been linked to greater and faster cognitive decline. In addition, controlled pharmacological treatment trials of depression in DAT yielded conflicting results. DAT-associated depression has been treated with ► tricyclic antidepressants (TCAs) (e.g., imipramine, clomipramine) or ► selective serotonin reuptake inhibitors (e.g., setraline, citalopram). SSRIs increase the extracellular level of serotonin by inhibiting its reuptake into the presynaptic cell, increasing the level of serotonin available to bind to the postsynaptic receptor. SSRIs are currently the first choice for treatment of comorbid depression in dementia because of a superior safety and tolerability profile compared to TCAs, as well as the fact that worsening of cognitive impairment with TCAs has been observed. Interestingly, some DAT patients experienced significant improvement of cognitive and emotional functioning with ► citalopram compared to placebo (<individual items on the Gottfries-Brane-Steen Dementia rating scale).

Treatment goals clearly change with the severity of DAT. In patients with mild to moderate disease, goals are to improve or maintain baseline performance through the administration of disease-modifying drugs targeting crucial etiological processes that thereby are neuroprotective. As the disease progresses, the goal of treatment is to slow the rate of decline in performance, mainly through highly efficacious symptomatic therapeutics improving cognitive and behavioral deficits that impair the well being of patients and caregivers. Symptomatic therapies, however, do not address the cause of the disease. If predisposition for the development of DAT should become predictable in the future, for example based on biomarker profiling in patients with mild cognitive impairment, the development of truly preventive therapies will become mandatory.

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