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PubMed2006

The effect of drugs for Alzheimer disease assessed by means of neuroradiological techniques.

UNLABELLED: Cholinesterase inhibitors constitute the standard of care for Alzheimer's disease in western countries. Donepezil, rivastigmine and galantamine had showed similar efficacy according to meta-analysis from randomised clinical trials. A mean modest 2 point-improvement has been observed in the Alzheimer's disease Assessment Scale (ADAS). Memantine has emerged as an alternative for advanced stages of the disease. Apart from clinical scales, neuroradiologic techniques have proven useful to assess the effect of these drugs on the brain of AD patients. METHODS: An extensive search for papers dealing with neuroradiological techniques in the assessment of AD drugs has been conducted, especially based on MEDLINE and EMBASE systems. RESULTS: Several techniques have demonstrated to be useful to assess the effects of drugs and disease progression. Magnetic Resonance Imaging (MRI)-based volumetry of the hippocampus showed more consistency to monitor progression than clinical variables, and thus, the sample size for clinical trials may be reduced. Donepezil is able to slow progression of atrophy in two controlled studies suggesting a neuroprotective effect. Proton Magnetic Resonance Spectroscopy (MRS) measures metabolite concentration of living tissues. In AD the most characteristic findings are decreased N-acetyl aspartate (neuronal marker) and choline-compounds elevation (marker of cell membrane turnover and degradation). A placebo controlled trial showed that treatment with donepezil increased transiently the NAA/Cr ratio in both hippocampi in AD. Changes in aspartate levels correlated to clinical response to rivastigmine in a non-randomised trial. Some studies evaluated cholinesterase inhibition in vivo with PET (Positron Emission Tomography) with higher reductions for rivastigmine than for donepezil in several cortical areas. Metabolism of glucose was also studied in patients taking galantamine or rivastigmine. Rivastigmine may stabilise glucose metabolism in a small series of AD patients. Correlation between glucose metabolism and changes in clinical scales has been observed in patients treated with galantamine. Most studies point to the frontal cortex as the best area to detect changes after treatment with cholinesterase inhibitors. CONCLUSIONS: Neuroradiologic techniques are of help to evaluate the effect of drugs in AD, and to monitor disease progression.

Alzheimer Disease↗
PubMed2006

Brain inflammation, cholesterol, and glutamate as interconnected participants in the pathology of Alzheimer's disease.

Alzheimer's disease (AD) represents one of the most common ailments afflicting the rapidly growing elderly segment of today's population. Despite the vast amount of effort expended in developing a cure, currently approved drugs address only cognitive symptoms that, although important for improving a patient's daily living standard, do not provide a significant delay or halt to disease progression. Early reports that individuals taking anti-inflammatory medications reduce their risk of developing AD has led to the "inflammation hypothesis" of AD and the subsequent testing of these drugs in the clinic. Tests of a select few of these medications in AD clinical trials have, however, yielded disappointing results. Reports of statin-based medications reducing the risk of AD have also led to the testing of this class of drugs in the clinic. Recently, the approval of the NMDA receptor antagonist memantine (Namenda) has provided clinical support for glutamatergic processes in the disease and generated a renewed interest in the role of excitatory amino acids in the etiology of AD. In this review, we take a closer look at these three compelling areas for addressing AD therapeutics: inflammation, cholesterol, and glutamate. We present arguments that these components are interconnected and mutually regulate processes involved in AD progression. Special focus is given to inflammation as a central feature of AD that may be acting in synergy with cholesterol and glutamate to mediate the observed pathophysiology.

Alzheimer Disease↗
PubMed2006

Pharmacological intervention at ionotropic glutamate receptor complexes.

L-glutamate is considered the main excitatory neurotransmitter in the mammalian brain. Paradoxically, L-glutamate is also the most important excitotoxin pivotally involved in the aetiology of several neurodegenerative diseases such as stroke, Alzheimer, Parkinson, amyotropic lateral sclerosis, Huntington and neuropathic pain. L-glutamate signalling is transduced both presynaptically and postsynaptically by metabotropic and ionotropic receptors. Three types of glutamate-gated channels integrate the synaptic signal, namely AMPA, kainate and NMDA receptors. Sustained activation of these receptors, and especially of the NMDA receptor, is a casuistic phenomenon that leads to the neuronal death underlying neurodegeneration. Thus, pharmacological intervention at these neuronal receptors and their synaptic protein complexes is a valuable therapeutic strategy. The approval of memantine, a safe, well-tolerated uncompetitive NMDA antagonist for the treatment of moderate to severe Alzheimer dementia validates ionotropic glutamate receptors as key therapeutic targets of neurodegenerative diseases in humans. As a consequence, an enormous effort is being carried out to identify and develop safe and potent antagonists for the clinics. In this review, we will describe progress in this important arena of human health.

Excitatory Amino Acid Antagonists↗
PubMed2006

Discovery of neurogenic, Alzheimer's disease therapeutics.

Many researchers have questioned whether new potential therapies aimed at reversing Alzheimer's disease (AD) are indeed scientifically feasible. A number of approved therapies already exist for Alzheimer's disease, yet these drugs only slow the disease progression for a period of time and treat the symptoms of this devastating disease. New therapies intended to reverse the disease would necessarily need to replace dead, dying and dysfunctional neurons in affected regions of the brain. This complex drug discovery problem is further complicated by the knowledge that AD is mainly an aging disorder and that aging, though not considered a disease, causes biological changes that may also need to be overcome [1]. The requirement for new, functional neurons under neurodegenerative diseases, as seen in AD and stroke suggests that an inhibitor of neuronal death, like Memantine, is insufficient to reverse the cognitive and physical loss. New neurons, or neurogenesis, may be required for real improvement or reversal of the cognitive deficit. Adult neurogenesis, first described by Altman in the early 1960s [2, 3], has more recently been observed as a response to injury or disease. Of interest was the finding that new neurons appear to migrate to disease/injury-affected areas in the brain not normally neurogenic in the adult. This pathological-stimulation of neurogenesis does not appear sufficient to stave off the disease and subsequent behavioral decline. Therefore, the desire to amplify and improve upon the neurogenesis-response to neurodegenerative disease appears warranted, if not yet feasible. The key to doing so lies in identifying what signals are required to promote neurogenesis and neuron survival, either in injury and disease or under environmental stimuli. This could provide clues for how to pharmacologically induce neurogenesis under neurodegenerative conditions. Currently, progress in identifying therapeutics that appear to promote ameliorative neurogenesis for AD is lagging behind the pharmacological induction of neurogenesis as a therapy for depression.

Alzheimer Disease↗
PubMed2006

NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling.

Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memory-related signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.

Alternative Splicing↗
PubMed2006

Can selective ligands for glutamate binding proteins be rationally designed?

A major neurotransmitter, L-Glutamate must be stored, transported and received, and these processes are mediated by proteins that bind this simple yet essential amino acid. Detailed evidence continues to emerge on the structure of Glu binding proteins, which includes both receptors and transporters. It appears that receptors and transporters bind to Glu in different conformations, which may present a pharmacological opportunity. This review will compare and contrast information available on Glu Receptors (AMPA, NMDA, KA and mGlu), excitatory amino acid transporters (EAATs), the system Xc- transporter (XCT) and the vesicular Glutamate transporter (GVT). The cross-reactivity of ligands which have been previously used to characterize the glutamate binding proteins with system Xc- raises some fundamental interpretational issues regarding the mechanisms through which these analogues produce CNS damage. Although at one time it was thought that unraveling selectivity among glutamate binding proteins was an intractable problem, recently the NMDA antagonist (memantine) has been approved for general medical practice for treatment of Alzheimer's disease. Two other agents are in advanced clinical trials: an Ampakine for potential improvement of cognitive disorders, and a selective mGlu agonist for treatment of anxiety. The prospects for unraveling cross-reactivity will be weighed in light of a critical comparison of the glutamate binding protein targets.

Amino Acid Transport System y+↗
PubMedDate not supplied

[Pharmacology of Alzheimer's disease: where do we go from here?].

Ten years after the introduction of the first drug for the treatment of Alzheimer's disease, tacrine, it seems appropriate to reappraise the pharmacological processes of innovation in the field of research in dementia. The aim of this review is to pinpoint concrete improvements achieved in this field, in terms of experimental methods and clinical evaluation of the compounds, as well as the neurochemistry of the disease and cellular targets deserving of initial consideration. * The article first considers the use of animal models of Alzheimer's disease, which are classified according to two categories: animals with lesions of some neuronal pathways specifically implicated in clinical symptoms (i.e. lesions of the nucleus basalis of Meynert, the origin of cholinergic projections to the cortex underlying memory processes); and transgenic models, which are intended to reproduce some of the neuropathological hallmarks of Alzheimer's disease. Drugs can be tested in animals with such alterations for their effect on neuropathology, neurochemistry and behavioural disturbances. More recently, in silico models have been developed, which offer the possibility of simulating the pharmacodynamic effects of drugs in specific areas of the brain. These experiments are helpful in distinguishing purely symptomatic effects from disease-modifying effects, the latter being the ultimate goal of the modern pharmacology of dementia. * The second breakthrough considered in this article is the codification and standardisation of clinical methods for obtaining a more accurate and earlier diagnosis (the recent introduction of the concept of "Mild Cognitive Impairment", which includes patients who will later develop a true clinical dementia syndrome). In that respect, the determination of the biological markers of Alzheimer's disease (apolipoprotein E, amyloid substance, protein-tau, isoprostane) as well as progress in neuroimaging (functional positron emission tomography [fPET]-scan, single photon emission-computed tomography [SPECT], functional nuclear magnetic resonance [fNMR]) are discussed in terms of their potential as new tools in the early stages of drug development (surrogate markers). The methods used during the comparative clinical trials (phase III) have been elaborated and internationally standardised during the assessment of the different acetylcholinesterase inhibitors (AChE-I), with the knowledge that, since 1994, four of these have been officially approved: tacrine, donepezil, rivastigmine and galantamine; the same methods have been used for developing memantine, a recently-launched modulator of glutamatergic neurotransmission. The validated scales now take into consideration not only the cognitive dimensions of Alzheimer's disease but also the behavioural symptoms, with the introduction of the concept of BPSD (behavioural psychological symptoms of dementia). Some proposals to improve this clinical assessment of anti-dementia drugs are presented here. * The section of this article dealing with prospective issues considers the main pathways of interest in drug innovation and the elucidation of new targets for the future compounds. As well as their symptomatic effects on the different components of cognition, drugs should be neuroprotective and limit the lesions documented in Alzheimer's disease, with the aim of progressing far beyond the amyloid hypothesis (immunisation, beta-sheet breakers, secretase inhibitors). The field of excitotoxicity (which is mainly glutamate dependent) appears fruitful, because of the possibility of pharmacological intervention at the different steps in the excitotoxic process. All the new directions presented in this article support the concept of true disease-modifying agents. In conclusion, this prospective review should be considered as a guide in fostering drug innovation in Alzheimer's disease and related disorders and should help to decrease the gap existing between neuroscience and therapeutics.

Aged↗
PubMed1991

Physostigmine (alone and together with adjunct) pretreatment against soman, sarin, tabun and VX intoxication.

A pretreatment for organophosphorus (OP) anticholinesterase (e.g., soman) intoxication should prevent lethality and convulsions (CNV) at 2 LD50s and be behavioral-decrement-free when given alone. Behavioral-deficit-free pretreatment regimens (PRGs) for guinea pigs consisted of Physostigmine (0.15 mg/kg, im) and adjunct. Adjuncts [mg/kg, im] tested were akineton [0.25], aprophen [8], trihexyphenidyl [2], atropine [16], azaprophen [5], benactyzine [1.25], cogentin [4], dextromethorphan [7.5], ethopropazine [12], kemadrin [1], memantine [5], promethazine [5], scopolamine [0.08] and vontrol [2]. PRGs were given 30 min before soman (60 micrograms/kg, sc; 2 LD50s) or other OP agents. Animals were then observed and graded for signs of intoxication, including CNV at 7 time points and at 24 hr. Physostigmine alone reduced the incidence of CNV and lethality induced by 2 LD50s of soman by 42 and 60%, respectively. All of the PRGs tested abolished lethality and 12 shortened recovery time to 2 hr or less. Also, PRGs including azaprophen or atropine prevented CNV. When selected PRGs were tested against intoxication by sarin, tabun or VX, the efficacy was generally superior to that for soman. The data show that several PRGs are effective against soman intoxication in guinea pigs.

Animals↗
PubMed2004

Caregiver burden in Alzheimer's disease.

OBJECTIVE: To review the literature pertaining to caregiver burden in Alzheimer's disease (AD) and the role of medications and the pharmacist in reducing caregiver burden. DATA SOURCES: A MEDLINE search was conducted to identify relevant studies, review articles, case reports, and letters in the English language published from 1985 to September 2003. Additional references were obtained from bibliographies of these articles. STUDY SELECTION: All studies evaluating caregiver burden and AD, as well as the role of medications in reducing caregiver burden that were accessible to the authors. DATA SYNTHESIS: Caring for the caregiver is a significant part of managing a patient with AD. Many predictors of caregiver burden in AD have been identified. A number of measurement tools have been developed to assess caregiver burden in the research setting. A wide variety of interventions to reduce caregiver burden have been studied. These interventions range from education and support services to drug therapies. Most often these strategies have been studied individually; however, combining drug treatments with nonpharmacologic interventions may be the best approach to improve the quality of life for the caregiver of a patient with dementia and the care recipient. Most of the studies to date of drug therapy and caregiver burden have evaluated cholinesterase inhibitors. Other drug therapies that have been studied include memantine, antipsychotics, antidepressants, and selegiline. PRIMARY CONCLUSIONS AND CLINICAL APPLICATIONS: The pharmacist can play an important part in reducing the caregiver burden associated with AD. It is important to identify caregivers at risk for experiencing significant caregiver burden since the consequences of excess burden to the caregiver-and the care recipient-can be devastating. Among the many tasks of providing such care, caregivers are responsible for administering and managing medications. The difficulties associated with the care recipient's medications can be reduced through effective communication, education, and services available from a pharmacist. Pharmacists are probably the most accessible health care professional for the caregiver. Being able to provide accurate information about AD and its management is an important way to ease the burden of care. Finally, pharmacists can play a significant part in supporting the community in caring for the families of patients with Alzheimer's disease by volunteering with the local chapter of the Alzheimer's Association.

Journal Article↗
PubMed2003

Therapeutic strategies for Alzheimer's disease based on new molecular mechanisms.

BACKGROUND AND OBJECTIVE: Alzheimer's disease (AD)--the main cause of dementia--is characterized by the presence of neuritic plaques containing the amyloid-beta peptide (A beta) and an intraneuronal accumulation of tubule-associated protein called tau. The current and future therapeutic strategies for AD will be discussed. Currently available treatment used in AD is based on acetylcholinesterase inhibitors, since in the course of AD there is a substantial loss in cholinergic neurons. Another registered drug used in more severe AD is NMDA antagonist--memantine. Available strategies for AD include vitamin supplementation for reducing homocysteine levels, statins and non-steroidal anti-inflammatory drugs. The big hope of the last few years--vitamin E and estrogen supplementation have not been proved efficient, but more studies are needed. There are several strategies aimed at acting directly on A beta or amyloid precursor protein (APP) processing: vaccination with A beta peptide, A beta passive immunization, beta and gamma secretases inhibitors. Nerve growth factors and neurotrophines could also be targeted by new therapies. CONCLUSIONS: A better understanding of the role of APP processing and folate and homocysteine in neuronal homeostasis throughout life consist revealing novel and relatively inexpensive approaches for preventing and treating AD.

Alzheimer Disease↗
PubMed2000

Induction of cAMP response element modulator (CREM) and inducible cAMP early repressor (ICER) expression in rat brain by uncompetitive N-methyl-D-aspartate receptor antagonists.

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor mediates fast excitatory neurotransmission, and agents that attenuate this function are neuroprotective, anesthetic, and psychotropic. To determine whether cAMP regulatable transcription factors play a role in the neurochemical actions of agents acting through NMDA receptors, the effects of the acute administration of uncompetitive and competitive antagonists on the expression of cAMP response element modulator (CREM) and inducible cAMP early repressor (ICER) transcription factors were examined. In situ hybridization to rat brain sections revealed that ICER mRNA expression was significantly increased by uncompetitive NMDA receptor antagonists (MK-801, phencyclidine, ketamine, memantine) but not by the competitive antagonist CPP [(+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid] or other psychotropic agents (clozapine, haloperidol, desipramine). Major brain regions where ICER transcripts were increased were the hippocampus, parietal cortex layers IV and VI, temporal cortex, cingulate cortex, thalamus, and granule cell layer of the olfactory bulb. Northern and Western blot analyses indicated that CREM mRNA and protein, respectively, were also increased after MK-801 treatment, but ICER isoforms predominate during both basal and induced conditions. MK-801 also transiently increased the binding of proteins to cAMP response element, which was supershifted by anti-CREM antibody, indicating that increased mRNA and protein levels have functional consequences on gene transcription. These results provide evidence for the involvement of CREM and ICER family transcription factors in the pharmacologic effects of uncompetitive NMDA receptor antagonists.

Animals↗
PubMed2000

Transient NMDA receptor inactivation provides long-term protection to cultured cortical neurons from a variety of death signals.

NMDA receptor antagonists, such as (+)-5-methyl-10, 11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801), potently block glutamate-induced neuronal death in myriad in vitro cell models and effectively attenuate ischemic damage in vivo. In this report, a novel role for MK-801 and other NMDA receptor antagonists in preconditioning neurons to withstand a wide range of subsequent lethal insults is described. A brief 30 min exposure to 0.1 microM MK-801, applied up to 96 hr before a "lethal" insult, protected primary cortical neurons from a diverse group of neurotoxic agents, including NMDA, beta-amyloid, staurosporine, etoposide, and oxygen-glucose deprivation. This neuroprotective preconditioning by MK-801 arose from transient NMDA receptor inactivation, because the noncompetitive NMDA receptor antagonists memantine and nylindin and the competitive antagonist AP-5 gave similar effects. MK-801 protection was dependent on new protein synthesis during the first 2 hr, but not from 2 to 5 hr, after MK-801 exposure. The MK-801 transient did not alter the ability of NMDA to trigger normally lethal [Ca(2+)](i) influx 48 hr later, but it did block early downstream signaling events coupled to NMDA neurotoxicity, including PKC inactivation and the activation of calpain. Moreover, MK-801 protected neurons from staurosporine-induced apoptosis, although caspase activation in these cells was unimpeded. It is likely that the stress associated with transient inactivation of NMDA receptors triggered a rapid compensatory survival response that provided long-term protection from a spectrum of insults, inducing apoptotic and nonapoptotic death. The possibility that MK-801 preconditioning blocks an event common to seemingly diverse death mechanisms suggests it will be an important tool for obtaining a clearer understanding of the salient molecular events at work in neuronal death and survival pathways.

Adrenergic beta-Agonists↗
PubMedDate not supplied

[Perspectives of therapy of Alzheimer's disease].

Alzheimer's disease is the most common cause of memory disruption in elderly people. The main pathogenic factor of the disease is beta-amyloid protein, which may cause toxic damage of neurones. Other suggested pathogenic factors include an inflammatory process around the senile plaques, apoptosis and necrotic death of neurones, and, in consequence, changes in functioning of neurotransmitter systems. In this article the authors present the main directions in pharmacotherapy of Alzheimer's disease: causal therapy, which prevents the neurodegenerative changes and slows down the pathogenetic process, and symptomatic therapy. The aim of symptomatic therapy is to reduce memory disruption and psychiatric symptoms associated with the disease. Positive influence on cognitive processes is exerted by cholinergic drugs, e.g. the actually used inhibitors of acetylcholinesterase (rivastigmine, donepezil), the nootropic agents (piracetam, nefiracetam) and extracts of Gingko biloba. For treatment of the disease accompanying psychiatric symptoms (anxiety, depression, hallucinations, sleepness) the drugs with minimal influence on cognitive processes are recommended. Attempts at causal therapy are focussed on searching for the substances that can prevent the formation and toxicity of beta-amyloid (droloksifen, estrogens, agonists of muscarinic receptors M1), the cytotoxic influence of excitatory aminoacids (memantine, lamotrigine), calcium (nimodipine) and free radicals (selegiline, alpha-tocoferol), and the development of inflammatory process (non-steroidal antiinflammatory drugs). The new target of research is correction of deficits of nerve growth factor and neurotransmitters by intracerebral implantation of modified fibroblasts. Another way is prevention of the formation of amyloid plaques using appropriate antisense oligonucleotides.

Alzheimer Disease↗
PubMed2000

[Ototoxic mechanism of aminoglycoside antibiotics--role of glutaminergic NMDA receptors].

Recent studies have indicated that glutamatergic NMDA receptors in the cochlea may be involved in ototoxic effects of aminoglycosides in animal subjects. Aminoglycoside antibiotics enhance the function of NMDA receptors by interaction with a polyamine modulatory site. Accordingly, high doses of aminoglycosides may increase calcium entry through the NMDA receptor-associated channel and promote degeneration of hair cells and cochlear nerve fibers. In line with the above, a polyamine site antagonist, ifenprodil as well as a high-affinity channel blocker, dizocilpine (MK-801) attenuates ototoxic effects of aminoglycosides in rats. Notably, ifenprodil as well as low-affinity channel blockers (e.g. memantine and amantadine) may be safely used in humans. Taken together, the above findings seem to open new avenues of research on selective pharmacotherapy of aminoglycosides-induced ototoxicity in humans.

Aminoglycosides↗
PubMed2001

[Ability of novel non-competitive glutamate receptor blocking agents to weaken motor disorders in animals].

Action of mono- and dication derivatives of phenylcyclohexyl was compared with effects of known NMDA-antagonists memantine and dizocilpine. Seizures induced with the NMDA were effectively prevented both by mono- and dications, whereas against the kainate seizures dication alone was effective. Anticataleptic activity was much stronger in monocations, and the side effect of the substances under study on motor co-ordination was obviously weaker than in dizocilpine. Thereupon, the phenylcyclohexyl derivatives might be regarded as potential means for treatment of parkinsonism and other motor disorders.

Animals↗
PubMedDate not supplied

Drug addiction. Part III. Pharmacotherapy of addiction.

The last decade brought a considerable progress in pharmacotherapy of addiction. Basing on recently gained knowledge of mechanisms of development of addiction and the physiology of the brain reward system, several therapeutic strategies have evolved. The strategies aimed at targeting the basic mechanisms of addiction rely on the premises that addiction is caused by adaptive changes in the central nervous system and that craving, which is the main cause of relapse, depends on dopaminergic mechanisms and requires high general excitability. The pharmacological approach involves drugs that reduce neuronal adaptability by inhibiting the calcium entry to neurons both through voltage-gated channels (e.g. nimodipine) and NMDA receptors (e.g. memantine), and drugs that stimulate the inhibitory GABAergic system (gamma-vinyl-GABA, baclofen), Particular attention is paid to the compounds that may attenuate dopaminergic hyperactivity, without considerable suppression of tonic activity of dopaminergic neurons (e.g. BP 897, a partial dopamine D3 receptor antagonist). Specific strategies are aimed at interference with the action of particular drugs of addiction. An important group includes the agonistic therapies (known also as substitution or maintenance therapies) in which a long-acting agonist is used in order to reduce the action of the drugs of high addictive potential (e.g. methadone against heroin addiction or vanoxerine (GBR 12909) against psychostimulants). Other specific strategies aimed at reduction of the transport of molecules of addictive substances into the brain: the approaches involve preparation of antibodies that form complexes unable to cross blood-brain barrier or enzymes accelerating the metabolism of the compounds in the blood (e.g. variants of butyrylcholinesterase). A considerable progress has been made in combating the abuse of legal addictive substances, alcohol (naltrexone, acamprosate) and tobacco (bupropion). The prospects for developing effective pharmacotherapies against addiction are bright. Unfortunately, ideological and social implications, as well as the conflict of interest with illegal narcotic manufacturers and distributors, may considerably hamper the progress in combating addiction (e.g. difficulties in introduction of methadone).

4-Aminobutyrate Transaminase↗
PubMed2002

[Starting Alzheimer therapy in early stages whenever possible. Activities of daily living remain intact longer].

In recent years, the efficacy of symptomatic antidementive drugs in the treatment of Alzheimer's disease (AD) has been well documented. A prerequisite for maximally effect antidementive treatment is early diagnosis and a subsequent specific diagnostic clarification. A further essential is early initiation of treatment to delay progression of the disease and thus early loss of daily skills and independence ending in the need for intensive nursing care. Currently, cholinesterase inhibitors, the efficacy of which has been confirmed in placebo-controlled multicenter studies, are recommended for the treatment of mild to moderate AD. Further substances with proven efficacy are memantine, ginkgo biloba extract EGb761 and certain classical nootropics. To treat behavioral and other psychological disturbances, symptom-related substances such as selective serotonin reuptake inhibitors and atypical neuroleptics should be employed. In addition to their positive effect on cognitive disturbances, cholinesterase inhibitors also have an appreciable impact on concomitant psychopathological symptoms.

Activities of Daily Living↗
PubMedDate not supplied

[Treatment of mild cognitive impairment: value of citicoline].

AIMS: The course of mild cognitive impairment (MCI) involves a slight loss of memory without any significant effects on other cognitive functions. Around 12% of these patients advance annually toward Alzheimer s disease, and for this reason it is important to search for medications that can prevent or slow down the evolution to dementia. Memory training programs, with relaxation techniques, the repetition of facts, information or pictures, categorizing information and the use of mnemonic rules can be effective. Drugs that can improve the cognitive faculties include piracetam, selegiline, vitamin E, Ginkgo biloba extract, estrogens, nonsteroidal antiinflammatory drugs (NSAIDs), acetylcholinesterase inhibitors and memantine. The aim of this study is to evaluate whether citilcoline can be effective in this clinical situation. METHOD: It has been shown in several animal models that citicoline improves scoring in learning and memory tests. Likewise, citicoline has been shown to improve memory and other cognitive functions in patients with chronic cerebrovascular disease or dementia and in old people suffering from memory deficit without dementia. Furthermore, a meta analysis of 12 clinical trials conducted by the Cochrane Collaboration, researchers reached the conclusion that citicoline improves memory, behaviour and the overall clinical impression in old people suffering from chronic brain diseases. CONCLUSION: Citicoline could be effective in the treatment of MCI, although more studies are needed in order to check whether the effect continues in the long term and whether it manages to slow down the progression to dementia.

Animals↗