Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondria are involved directly in cell survival and death. The assumption has been made that drugs that protect mitochondrial viability and prevent apoptotic cascade-induced mitochondrial permeability transition pore (MPTp) opening will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor anti-Parkinson drug. Unlike selegiline, it is not derived from amphetamine, and is not metabolized to neurotoxic L-methamphetamine derivative. In addition, it does not have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to levodopa for patients with early and late Parkinson's disease (PD) and adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Phase III controlled studies indicate that it might have a disease-modifying effect in PD that may be related to its neuroprotective activity. Its S isomer, TVP1022, is more than 1,000 times less potent as an MAO inhibitor. Both drugs, however, have neuroprotective activity in neuronal cell cultures in response to various neurotoxins, and in vivo in response to global ischemia, neurotrauma, head injury, anoxia, etc., indicating that MAO inhibition is not a prerequisite for neuroprotection. Their neuroprotective effect has been demonstrated to be associated directly with the propargylamine moiety, which protects mitochondrial viability and MTPp by activating Bcl-2 and protein kinase C (PKC) and by downregulating the proapoptotic FAS and Bax protein families. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective, neurotrophic, soluble APP alpha (sAPPalpha) by PKC- and MAP kinase-dependent activation of alpha-secretase. The identification of the propargylamine moiety as the neuroprotective component of rasagiline has led us to development of novel bifunctional anti-Alzheimer drugs (ladostigil) possessing cholinesterase and brain-selective MAO inhibitory activity and a similar neuroprotective mechanism of action.
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PMID:Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. 1557 6

Degeneration of nigrostriatal dopamine neurons and cholinergic cortical neurones are the main pathological features of Parkinson's disease (PD) and for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB), respectively. Many PD and DLB subjects have dementia and depression resulting from possible degeneration of cholinergic and noradrenergic and serotonergic neurons. On the other hand, AD patients may also develop extrapyramidal features as well as depression. In both PD and AD there is, respectively, accumulation of iron within the melanin containing dopamine neurons of pars compacta and with in the plaques and tangle. It has been suggested that iron accumulation may contribute to the oxidative stress induced apoptosis reported in both diseases. This may result from increased glia hydrogen peroxide producing monoamine oxidase (MAO) activity that can generate of reactive hydroxyl radical formed from interaction of iron and hydrogen peroxide. We have therefore prepared a series of novel bifunctional drugs from the neuroprotective-antiapoptotic antiparkinson monoamine oxidase B inhibitor, rasagiline, by introducing a carbamate cholinesterase (ChE) inhibitory moiety into it. Ladostigil (TV-3326, N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), has both ChE and MAO-AB inhibitory activity, as potential treatment of AD and DLB or PD subjects with dementia Being a brain selective MAO-AB inhibitor it has limited potentiation of the pressor response to oral tyramine and exhibits antidepressant activity similar to classical non-selective MAO inhibitor antidepressants by increasing brain serotonin and noradrenaline. Ladostigil inhibits brain acetyl and butyrylcholinesterase in rats and antagonizes scopolamine-induced inhibition of spatial learning. Ladostigil like MAO-B inhibitor it prevents MPTP Parkinsonism in mice model and retains the in vitro and in vivo neuroprotective activity of rasagiline. Ladostigil, rasagiline and other propargylamines have been demonstrated to have neuroprotective activity in several in vitro and in vivo models, which have been shown be associated with propargylamines moiety, since propargylamines itself possess these properties. The mechanism of neuroprotective activity has been attributed to the ability of propargylamines-inducing the antiapoptotic family proteins Bcl-2 and Bcl-xl, while decreasing Bad and Bax and preventing opening of mitochondrial permeability transition pore. Iron accumulates in brain regions associated with neurodegenerative diseases of PD, AD, amyotrophic lateral sclerosis and Huntington disease. It is thought to be involved in Fenton chemistry oxidative stress observed in these diseases. The neuroprotective activity of propargylamines led us to develop several novel bifunctional iron chelator from our prototype brain permeable iron chelators, VK-28, possessing propargylamine moiety (HLA-20, M30 and M30A) to iron out iron from the brain. These compounds have been shown to have iron chelating and monoamine oxidase A and B selective brain inhibitory and neuroprotective-antiapoptotic actions.
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PMID:Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. 1562 Dec 13

Individuals with neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease are benefiting from drugs developed to act on a single molecular target. However, current pharmacological approaches are limited in their ability to modify significantly the course of the disease, and offer incomplete and transient benefit to patients. New therapeutic strategies comprise drug candidates designed specifically to act on multiple neural and biochemical targets for the treatment of cognition impairment, motor dysfunction, depression and neurodegeneration. Examples include the development of single molecular entities that combine two or more of the following properties: (i) cholinesterase inhibition; (ii) activation or inhibition of specific subtypes of acetylcholine receptors or alpha-adrenoceptors; (iii) anti-inflammatory activity; (iv) monoamine oxidase inhibition; (v) catechol-O-methyl transferase inhibition; (vi) nitric oxide production; (vii) neuroprotection; (viii) anti-apoptotic activity; and (ix) activation of mitochondrial-dependent cell-survival genes and proteins. These bi- or multi-functional compounds might provide greater symptomatic efficacy, and better utility as potential neuroprotective disease-modifying drugs.
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PMID:Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. 1562 2

Approximately 25% of patients with idiopathic Parkinson's disease (IPD) later develop dementia, with the typical characteristics as detailed in ICD-10 and DSM-IV. Differential diagnosis has to exclude dementia due to Lewy bodies, subcortical vascular encephalopathy and subcortical dementia due to progressive supranuclear paralysis or corticobasal degeneration. Several studies showed promising results for cholinesterase inhibitors such as donepezile, rivastigmine and galantamine. The demented Parkinsonian patients then present with improvement in cognitive function while motor skills do not deteriorate.
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PMID:Dementia in idiopathic Parkinson's syndrome. 1567 22

Behavioural symptoms such as anxiety, depression and psychosis are common in Parkinson's disease (PD), and dementia occurs in about 90% of the patients. These symptoms can be more disabling than the motor dysfunction and they negatively impact quality of life, increase caregiver distress and are more frequently associated with nursing home placement. Depression can be treated with counselling and pharmacotherapy. Tricyclic antidepressants or selective serotonin reuptake inhibitors are widely used, but there is still need for controlled clinical trials. Management of psychosis in PD is complex and includes elimination of identifiable risk factors, reduction of polypharmacy and administration of atypical neuroleptics, which can alleviate psychotic symptoms without worsening motor functions. Clozapine is the best documented atypical neuroleptic shown to be effective against psychosis in PD patients. Cholinesterase inhibitors may prove additional benefit in psychotic PD patients. Recent evidence from small double-blind and open-label trials suggests that cholinesterase inhibitors may be effective in the treatment of dementia associated with PD.
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PMID:Treatment of behavioural symptoms and dementia in Parkinson's disease. 1581 Aug 93

Fluctuations in consciousness and visual hallucinations are common neuropsychiatric features of dementia with Lewy bodies and Parkinson's disease dementia. To investigate potential neural correlates, we compared how changes in brain perfusion over a 1-year period were related to changes in the severity of these key clinical features. We recruited 29 subjects with either Parkinson's disease with dementia (15 subjects) or dementia with Lewy bodies (14 subjects). Cerebral perfusion was measured using HMPAO SPECT at baseline, and repeated 1 year later. The presence of hallucinations (Neuropsychiatric Inventory), severity of fluctuations in consciousness (fluctuation assessment scale) and cognitive ability (CAMCOG) were assessed at both time points. After controlling for changes in cognitive ability and effect of cholinesterase medication, we found a significant correlation between an increase in perfusion in midline posterior cingulate and decrease in hallucination severity. There was also a significant correlation between increased fluctuations of consciousness and increased thalamic and decreased inferior occipital perfusion. We have identified important neural correlates of key clinical features in Lewy body dementia and postulate that the associations can be understood through the influence of the cholinergic system on attention.
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PMID:Change in perfusion, hallucinations and fluctuations in consciousness in dementia with Lewy bodies. 1596 48

Cognitive decline and dementia affect approximately 30% to 40% of patients with idiopathic Parkinson's disease during the course of their illness. PD-dementia (PDD) and dementia with Lewy bodies (DLB) are second to Alzheimer's disease in causing degenerative dementia in the elderly. The nosological distinction of the conditions has remained controversial because of broad clinical and pathological overlap. Treatment issues in both clinical settings are virtually identical. Treatment of Parkinsonism is often complicated by drug-induced psychosis and reduced levodopa responsiveness. Cognition, alertness, attention, as well as apathy or aggressive behavior have been shown to respond to treatment with cholinesterase inhibitors in randomized controlled trials both in DLB and PDD. Such treatment may also improve hallucinosis, but many patients will require add-on treatment with atypical neuroleptics to control drug-induced psychotic reactions. Clozapine and quetiapine are the drugs most commonly used and, contrary to classic neuroleptics, risperidone or olanzapine do not seem to cause severe side effects according to published data.
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PMID:Treatment of dementia with Lewy bodies and Parkinson's disease dementia. 1609 95

Alzheimer's disease is the most common form of neurodegenerative dementia and poses considerable health challenges to both patients and their families. Rivastigmine is a powerful slow-reversible, noncompetitive carbamate cholinesterase inhibitor that is approved for the treatment of mild-to-moderate Alzheimer's disease. Randomized, double-blind, placebo-controlled trials of up to 6 months duration have shown beneficial effects of rivastigmine compared with placebo in measures of cognition and global functioning. Less rigorous but growing data suggest that the beneficial effects may endure for up to 5 years, extend to more advanced stages of Alzheimer's disease and may occur in noncognitive domains, such as activities of daily living and the behavioral symptoms of Alzheimer's disease. Evidence from controlled studies also supports the use of rivastigmine for cognitive and behavioral symptoms in Alzheimer's disease associated with vascular risk factors, dementia with Lewy bodies and Parkinson's disease dementia. Early and continued treatment of Alzheimer's disease with rivastigmine maximizes the observed beneficial effects. The most prominent adverse effect of rivastigmine is centrally mediated cholinergic gastrointestinal events, which can be minimized by slower dose-escalation intervals and administration with a full meal. Therapeutic dosing is 6-12 mg/day given twice daily, with higher doses having the potential for greater benefits.
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PMID:Rivastigmine for Alzheimer's disease. 1616 80

Neurodegenerative disorders result from premature progressive degeneration of specific neurons, and manifest as diseases or syndromes with varied combinations of cognitive, motor, sensory and autonomic dysfunctions. The management involves pharmacotherapy as well as non-pharmacological measures and also to lessen the burden of the care-givers. The medications available for medical treatment are: Levodopa, dopamine agonists, amantadine, anticholinergics, enzyme inhibitors, etc. Advanced Parkinson's disease is concerned with management of motor complications and non-motor complications. Recently surgical treatment is a great option for managing motor complication. Orthostatic hypotension, gait distiurbances, emotional and psychiatric problems, sleep disturbances can be managed and had been discussed in brief. Currently there is no medication available for the cure of Alzheimer's disease. The specific medications claimed to improve patient's well being and cognition include cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonist, anti-oxidants, and anti-amyloid therapy. While medical and surgical treatments for Parkinson's disease have revolutionised the management, still drug therapy for Alzheimer's disease is dismal.
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PMID:Management of neurodegenerative disorders: Parkinson's disease and Alzheimer's disease. 1617 94

The neuropsychiatry of Parkinson's disease (PD) and its correlates are reviewed. Dementia occurs in up to 30% and can be treated with cholinesterase inhibitors. Cognitive impairments involve executive, visuospatial, attentional, and memory dysfunctions. Apathy may respond to dopamine agonists or cholines-terase inhibitors. Cognitive impairment, psychosis, and depression predict quality of life. Visual hallucinations and paranoia are common, and respond to low dose clozapine. Depression is common and predicts caregiver burden and depression. The best data suggest the efficacy of nortriptyline and the safety of SSRIs. Anxiety disorders occur in 40% of patients, especially off-period panic attacks and specific phobias. Bromazepam has proven useful for anxiety in PD, but buspirone has only diminished drug-induced dyskinesias to date. Sleep disorders occur in up to 94% of patients. Insomnia is common and is treated by dopaminergic agent dose reduction, nocturnal dosing, treatment of depression, or use of short half-lived hypnotics, depending on etiology. Parasomnias include REM behavior disorder and vivid dreams and nightmares. Excessive daytime somnolence occurs in at least 15% of patients. Sleep attacks are common and patients should be warned about driving when taking dopamine agonists. Sexual disorders occur in most patients. Paraphilias are associated with dopamine agonists, and clozapine may be useful in their treatment. Surgical therapies are associated with a wide variety of neuropsychiatric features, and vigilance for suicide attempts with subthalamic nucleus stimulation seems warranted. Neuropsychiatric disorders are important determinants of quality of life and caregiver burden in PD. More clinical research is needed to establish effective treatments.
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PMID:The neuropsychiatry of Parkinson's disease. 1617 59


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