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

Alzheimer's disease is the most common cause of dementia, but Parkinson's disease also shows dementia in the later stages. Donepezil is a cholinesterase inhibitor used for the treatment of Alzheimer's disease. Variable responses to this drug suggest that Alzheimer's disease is clinically heterogeneous. In the clinical trial of tacrine, a first developed cholinesterase inhibitor, three cases markedly improved and, several years later, they were pathologically confirmed as dementia with Lewy bodies (DLB). In recent years, another cholinesterase inhibitor, rivastigmine, has also been reported to be effective for patients with DLB by a placebo-controlled, double-blind, multicenter study. Parkinson's disease with dementia, which is known to fulfill the pathological criteria of DLB, also shows a favorable response to donepezil. In some cases, not only does cognitive function improve, but also parkinsonism. Both DLB and Parkinson's disease with dementia show characteristic CBF patterns: While the parietal and temporal lobes are involved in Alzheimer's disease, the occipital lobe is additionally affected in these diseases. Alzheimer's disease and Parkinson's disease have been considered discrete disease entities. However, viewed from the aspects of response to donepezil treatment and CBF patterns, both diseases overlapped. A brain SPECT may be a useful tool to detect such treatable conditions.
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PMID:Responses to donepezil in Alzheimer's disease and Parkinson's disease. 1248 Jul 91

Traditionally, the neuropsychiatric symptoms of Alzheimer's disease (AD) have been managed with neuroleptics or benzodiazepines, which have serious side effects. Preliminary observations suggest the possible value of cholinesterase inhibitors in the amelioration of psychotic symptoms in patients with dementia of the Alzheimer's type, dementia with Lewy bodies, and in patients with Parkinson's disease. Twelve inpatients with AD with psychotic symptoms and lack of improvement of their delusions/hallucinations during perphenazine treatment (8 mg/day) for 3 weeks received random open-label donepezil 5 mg daily in addition to an ongoing treatment of 8 mg/day perphenazine or 16 mg/day perphenazine. Assessments conducted at baseline and after weeks 2 and 4 included the Mini-Mental State Examination, the Global Deterioration Scale, the Positive and Negative Symptoms Scale, and the Clinical Global Impressions scale. Frequency of extrapyramidal symptoms was measured according to the Abnormal Involuntary Movement Scale. The donepezil-perphenazine group exhibited substantially greater and clinical improvements in mental state. At the end of the trial (4 weeks), Positive and Negative Symptoms Scale scores revealed significant differences between both groups (p = 0.006). The Clinical Global Impressions scale and the Mini-Mental State Examination scores also showed significant differences between the donepezil-perphenazine group and the perphenazine group (p = 0.028 and p = 0.027 respectively). No significant differences were found in the Global Deterioration Scale scores. Abnormal Involuntary Movement Scale scores showed a significant deterioration in extrapyramidal symptoms in the perphenazine group compared with the donepezil-perphenazine group (p = 0.016). Donepezil augmentation of neuroleptics may be appropriate for those patients for whom neuroleptic monotherapy either does not lead to symptom remission or is associated with intolerable adverse effects. This was an open-label study and there is need for larger studies with double-blind control and a long-term study design to define the efficacy of donepezil for patients with AD and psychotic symptoms.
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PMID:Donepezil as add-on treatment of psychotic symptoms in patients with dementia of the Alzheimer's type. 1267 28

Visual hallucinations (VHs) are common psychiatric symptoms in patients with long-standing Parkinson's disease (PD). Treatment with neuroleptics or withdrawal of anti-PD drugs may improve VHs but will worsen motor dysfunctions. The authors report on 3 patients with long-standing PD who were treated with the cholinesterase inhibitor donepezil for the treatment of VHs. Each received a daily dose of 5 mg of donepezil, after reducing or discontinuing anti-PD medications had failed to relieve the VHs. In 2 patients (patient 1, 2), donepezil decreased VHs without worsening motor dysfunctions. In addition, the cognitive status of patient 2 improved. In patient 3, donepezil also resolved VHs, but delusions developed during treatment. After discontinuing donepezil, delusions disappeared and VHs reappeared. Donepezil may ameliorate visual hallucinations in PD patients, but controlled, double-blind trials are necessary to further clarify the effect of this drug on VHs in PD.
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PMID:The beneficial effect of donepezil on visual hallucinations in three patients with Parkinson's disease. 1296 63

Enhancement of the activity of cholinergic neurons has been regarded as one of the most promising methods for treating Alzheimer's disease (AD). Donepezil is a representative acetylcholinesterase inhibitor (AChEI) and is a great success among the AChEI drugs. AChEIs are being studied for other mechanisms of action, neuroprotective action, and nicotinic receptor enhancement. AD is a type of neurodegenerative disease and AChEIs have been found to be an effective anti-AD medication. AChEI can alleviate the symptoms and delay the progression of AD, but it cannot cure the disease. However, AChEIs are now the subject of a wide range of clinical studies for other diseases, for example, other types of dementia (such as Lewy body disease, cerebral vascular dementia, and Parkinson's disease dementia), and migraine. These drugs are also being studied as a combination therapy, for example, with an antioxidant, SERM, and NMDA antagonist.
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PMID:[Scope and limitations of acetylcholinesterase inhibitors]. 1533 89

Anticholinesterase (AChE) drugs are being prescribed off label for nonmotor symptoms in Parkinson's disease (PD). Theoretically, these drugs can impair motor function. A small literature suggests AChE therapy has little effect on clinical motor evaluation; however, no study has made objective motor kinematic measures or evaluated brain function. We hypothesized that even if clinical examination was normal in PD patients on dopamine therapy, (1) sensitive kinematic measures would be abnormal during AChE therapy or (2) normal kinematic measures would be maintained by compensatory brain activation. We carried out a randomized, double-blind, placebo-controlled trial of 8 weeks donepezil (10 mg/day) in 17 PD subjects. Subjects carried out a computerized motor task during a positron emission tomography (PET) scan before starting the drug and again after 8 weeks of donepezil or placebo. Kinematic measures of motor function and PET scans were analyzed to compare the effects of donepezil and placebo. Neither placebo nor donepezil altered motor kinematic measures. Furthermore, movement integrity while on donepezil was maintained without compensatory brain activity. Donepezil 10 mg/day can be given for nonmotor symptoms in PD without adverse motor effects or compensatory brain activity.
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PMID:Anticholinesterase effect on motor kinematic measures and brain activation in Parkinson's disease. 1622 97

The objectives of the present study were first to determine the feasibility of conducting a randomized clinical trial of 5 mg/day donepezil in patients with mild to moderate dementia with Lewy bodies (DLB) and second, to obtain preliminary data of possible intervention effects. Twelve patients with probable DLB were evaluated at weeks 4, 8, and 12 using modified Neuropsychiatric Inventory (NPI) with an extra domain to additionally evaluate fluctuation in cognitive functions (NPI-11); the Japanese version of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-J cog); and the Unified Parkinson's Disease Rating Scale (UPDRS). The NPI-11 scores were significantly improved at weeks 8 and 12 compared with baseline. Despite a significant improvement in ADAS-J-cog at week 4, no more improvement was noted thereafter. Deterioration was not noted in UPDRS scores. Donepezil is expected to be therapeutically useful and safe in treating DLB patients, indicating marked improvements in behavioral and psychological symptoms of dementia (BPSD) rather than in cognitive deficit, without deteriorating parkinsonism.
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PMID:Efficacy and safety of donepezil in patients with dementia with Lewy bodies: preliminary findings from an open-label study. 1659 43

Treatments for the symptomatic relief of Alzheimer's disease are available but despite advances in our ability to treat persons with various forms of dementia, more effective treatments are needed. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have demonstrated efficacy in improving cognition and global status and to a lesser extent, behavioral abnormalities relative to placebo in patients with mild-to-moderate Alzheimer's disease. Rivastigmine has been shown to benefit patients with dementia with Lewy Bodies and with dementia associated with Parkinson's disease. Donepezil and galantamine have also been shown to be mildly effective in dementia due to cerebral ischemia. Memantine has a distinct mechanism of action and is effective in moderate-to-severe AD. The benefits from these drugs, however, are limited and their long-term effectiveness has not been well-demonstrated. Their clinical utility is controversial. Many novel approaches that promise to provide more effective treatments are currently being pursued.
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PMID:Current and emerging pharmacological treatment options for dementia. 1672 Sep 56

Donepezil is a selective acetylcholinesterase inhibitor that is widely prescribed for Alzheimer's disease (AD). It has been shown to be of benefit in mild, moderate and severe stages of AD, vascular dementia and dementia associated with Parkinson's disease. Donepezil is absorbed slowly, but completely, from the gut, reaching peak plasma levels in 3-4 h and, with daily dosing, steady-state concentration in 15-21 days. Within a relatively narrow range, there is a linear relationship between dose and pharmacodynamic effects, measured as red blood cell acetylcholinesterase inhibition and clinical efficacy. Donepezil is principally excreted unchanged in the urine, but there is also hepatic metabolism; some of its metabolites may be active. Despite being 96% bound to plasma proteins, it has few interactions with other drugs, and the 5-mg dose can be given safely to patients with mild-to-moderate hepatic and renal -disease. Side effects, which are mainly a consequence of its cholinomimetic mechanism of action, are usually mild and transient. Although donepezil was originally developed to inhibit the breakdown of the neurotransmitter acetylcholine as symptomatic therapy for AD, recent studies raise the possibility of other effects this drug has on the pathogenesis of AD.
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PMID:Donepezil: a review. 1686 59

Current treatment of nerve agent poisoning consists of prophylactic administration of pyridostigmine and therapy using atropine, an oxime and a benzodiazepine. Pyridostigmine does however not readily penetrate the blood-brain barrier giving ineffective protection of the brain against centrally mediated seizure activity. In this study, we have evaluated donepezil hydrochloride, a partial reversible inhibitor of acetylcholinesterase (AChE) clinically used for treating Alzheimer's disease, in combination with procyclidine, used in treatment of Parkinson's disease and schizophrenia, as prophylaxis against intoxication by the nerve agent soman. The results demonstrated significant protective efficacy of donepezil (2.5 mg/kg) combined with procyclidine (3 or 6 mg/kg) when given prophylactically against a lethal dose of soman (1.6 x LD(50)) in Wistar rats. No neuropathological changes were found in rats treated with this combination 48 h after soman intoxication. Six hours after soman exposure cerebral AChE activity and acetylcholine (ACh) concentration was 5% and 188% of control, respectively. The ACh concentration had returned to basal levels 24 h after soman intoxication, while AChE activity had recovered to 20% of control. Loss of functioning muscarinic ACh receptors (17%) but not nicotinic receptors was evident at this time point. The recovery in brain AChE activity seen in our study may be due to the reversible binding of donepezil to the enzyme. Donepezil is well tolerated in humans, and a combination of donepezil and procyclidine may prove useful as an alternative to the currently used prophylaxis against nerve agent intoxication.
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PMID:The combination of donepezil and procyclidine protects against soman-induced seizures in rats. 1728 99

Although the etiology of Parkinson's disease (PD) remains elusive, a number of toxins including elevated salsolinol, an endogenous metabolite of dopamine may contribute to its pathology. It was reported recently that nicotine may have protective effects against salsolinol-induced toxicity in human neuroblastoma derived SH-SY5Y cells and that these effects of nicotine are mediated by nicotinic receptors. Donepezil (Aricept) is a reversible non-competitive acetylcholinesterase inhibitor that is approved for use in mild to moderate Alzheimer's disease. The increase in acetylcholine concentrations is believed to be the major contributory factor in donepezil's therapeutic efficacy. However, cholinesterase inhibitors may also directly interact with nicotinic receptors and possess neuroprotective properties. In this study, we sought to determine whether donepezil may have protective effects against salsolinol-induced toxicity in SH-SY5Y cells and whether the combination of donepezil and nicotine may result in additive protection. Moreover, it was of interest to elucidate the role of nicotinic receptors as well as cell cycle and apoptosis in mechanism of action of these compounds. SH-SY5Y cells were exposed to 0.6 mM salsolinol with and without various drug pretreatments for 48 h. Nicotine (50 muM) resulted in approximately 54% protection and donepezil (5 muM) resulted in approximately 40% protection, and the combination of the two resulted in an additive (approximately 93%) protection against salsolinol-induced toxicity. Salsolinol caused an arrest of the cells in G(1)-phase of cell cycle and an increase in apoptotic indices that were blocked by the combination of donepezil and nicotine. Mecamylamine, a non-selective nicotinic receptor antagonist completely blocked the effects of nicotine and partially attenuated the effects of donepezil. A combination of atropine, a muscarinic receptor antagonist and mecamylamine completely blocked the effects of donepezil, indicating involvement of both nicotinic and muscarinic receptors in donepezil's actions. The findings suggest a therapeutic potential for the combination of donepezil and nicotine in PD.
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PMID:Additive protective effects of donepezil and nicotine against salsolinol-induced cytotoxicity in SH-SY5Y cells. 1952 84


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