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)

Parkinson's disease is essentially motor. The core symptoms comprise akinesia, rigidity and tremor. Concomitantly, signs of autonomic, cognitive and affective disturbances may be found. The disease progresses slowly and, without treatment, ultimately results in disability and loss of independence. The symptoms can be controlled for a long time by pharmacotherapy. Dopaminergic drugs such as L-DOPA, dopaminreceptor agonists, and MAO-B- and COMT-blockers can essentially improve most of the symptoms. The tremor may be alleviated by central anticholinergic drugs. With time, however, unwanted side effects such as "end of dose akinesia", "on-off phenomena", hyperkinesis and exogenous psychosis come into play. Therefore, pharmacological treatment becomes very complex in the late stages of the disease and the unwanted side effects can no longer be sufficiently controlled. It is not clear whether conservative approaches will be ever able to cope with these problems. This explains the search for novel treatment strategies, e.g. neurotransplantation, stereotaxic lesion of the subthalamic nucleus or stimulation techniques.
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PMID:[Clinical aspects and conservative therapy of Parkinson disease]. 857 92

Lewy bodies (LBs) are intracytoplasmic neuronal inclusions sometimes found in the brain stem, diencephalon, basal ganglia, and cerebral cortex. Cases designated as diffuse Lewy body disease (DLBD) demonstrate widespread cortical and subcortical Lewy body formation. The fact that DLBD is possibly the second most common cause of dementia after Alzheimer's disease is not generally recognized. We hope to emphasize the importance of this common neurodegenerative disorder by reviewing the literature and our own experience with DLBD. The English-language literature dealing with the clinical and pathological features of DLBD was reviewed. Pathological material from the Canadian Brain Tissue Bank, Toronto, Ontario, was reviewed over a 2-year period from 1991 through 1993. Prominent LB pathology may occur in isolation or mixed with pathological changes seen in Alzheimer's disease. Lewy body diseases include Parkinson's disease that presents with a classic movement disorder and sometimes dementia, and DLBD where LBs occur in a widespread distribution in the cortex in addition to the usual subcortical sites. Diffuse LB disease usually presents with a neurobehavioral syndrome that may include hallucinations, delusions, and psychosis; all patients eventually become demented. A day-to-day fluctuating mental state may be an important distinguishing clinical feature. Parkinsonism may follow the psychiatric disturbance although occasionally it is a presenting feature. Serious life- threatening side effects may occur with the use of standard neuroleptics. The variable clinical features and additional presence of Alzheimer-type pathological changes in many cases of DLBD has led to a confusing and inconsistent classification of LB disease and, together with little awareness of its existence, its misdiagnosis. Although DLBD may be the second most common cause of dementia, the terminology and classification of LB disorders and their relationship to Alzheimer's disease remain sources of intense debate. Further research is needed to resolve these issues and to provide insight into the pathogenesis of LB formation and accompanying neuronal degeneration.
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PMID:Lewy body disease and dementia. A review. 860 54

Posteroventral pallidotomy as a treatment for Parkinson's disease (PD) has been the subject of increasing interest. We treated 4 nondemented patients with advanced PD, 2 with severe bradykinesia and a declining response to medication, and 2 with marked clinical fluctuations. All patients received 180 Gy delivered in one sitting to the right posteroventral pallidum site, used by Laitinen and colleagues, adjusted as needed, to avoid the optic tract. Only 1 patient changed significantly. Dyskinesia completely resolved on the side contralateral to the lesion in this patient. This same patient also became transiently demented and psychotic. The other 3 patients suffered no clearly identifiable beneficial or harmful effects. Follow-up magnetic resonance imaging scans of the brain at 1 year revealed lesions exactly where targeted although of unequal sizes. Our negative experience forces us to conclude that either larger volumes of tissue must be ablated, that physiologic monitoring is required for placing a lesion, that our subjects were poor candidates for the procedure, or that surgical ablation and radiation cause tissue damage of different types with different results.
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PMID:Gamma knife pallidotomy in advanced Parkinson's disease. 861 32

Psychosis secondary to dopaminergic therapy can limit the ability to manage motor symptoms of advanced Parkinson's disease (PD). Scholz and Dichgans (1985) were the first to report the use of clozapine in drug-induced psychosis in PD. The rationale for use of clozapine in parkinsonian patients is supported by his original pharmacological profile with weak extra-pyramidal side effects. A Medline search was performed of literature from 1985 to 1994. The literature search was not limited to the English language. Numerous authors (23 articles) using case reports or open trials among more than 100 patients suggested that clozapine would be useful in treating drug-induced psychosis in PD. We analysed the available information addressing: 1) clinical efficacy, 2) clinical predictors of outcome, 3) delay of action, 4) influence of clozapine on extrapyramidal symptomatology, 5) adverse effects and treatment withdrawal causes, 6) long-term follow-up data. However, the partially negative result of the only double-blind placebo-controlled trials, it may be stated that in some clinical situation of psychosis in PD, the use of clozapine may represent an opportune alternative when other therapeutic strategies have failed.
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PMID:[Value of clozapine in treatment of psychotic disorder in Parkinson disease]. 868 76

Psychotic symptoms such as visual hallucinations and delusions are a relatively common clinical problem in patients with Parkinson's disease (PD). A dilemma arises in the treatment of psychosis in these patients because traditional antipsychotics are dopaminergic antagonists that worsen the motor symptoms of PD. Clozapine, an atypical antipsychotic, has been successfully used in the treatment of psychosis in PD patients. The use of clozapine in these patients differs significantly, however, from its use in young, relatively healthy, treatment-resistant schizophrenic patients in the dosage required, side effects, and other aspects of management.
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PMID:Clozapine as a treatment for psychosis in Parkinson's disease: a review. 884 91

This review summarizes the amino acid sequences of the human dopamine and serotonin receptors and their human variants. The review also examines the receptor basis of the atypical antipsychotic drugs that elicit less parkinsonism than the typical antipsychotics. Because the dissociation constant of a drug varies with the radioligand, the dissociation constants of many neuroleptics are here summarized for the dopamine D2-, D4- and serotonin S2A-receptors using different radioligands. Radioligands of low solubility in the membrane (having low tissue/buffer partition) result in lower values for the neuroleptic dissociation constants, compared to radioligands of high membrane solubility. Such studies yield the intrinsic K value for a neuroleptic in the absence of a competing ligand. Clozapine, for example, has an intrinsic K value of 1.6 nM at the D4-receptor, in agreement with the value of 1.6 nM when directly measured with [3H]clozapine at D4. However, because clozapine competes with endogenous dopamine, the in vivo clozapine concentration to occupy 75% of the dopamine D4-receptors is derived to be approximately 13 nM. This agrees with the value of 12 to 20 nM in the plasma water (or spinal fluid) observed in treated patients. Moreover, in L-DOPA psychosis (in Parkinson's disease), the clozapine concentration for 75% blockade of D4 is predicted to be approximately 3 nM. This agrees with the value of approximately 1.2 nM observed by Meltzer et al. in plasma water (Neuropsychopharmacology, 12, 39-45 (1995)). This analysis supports the concept and practical value of the intrinsic K values. Some atypical neuroleptics (remoxipride, clozapine, perlapine, seroquel and melperone) have high intrinsic K values (ranging from 30 to 88 nM) at the D2-receptor, making them displaceable by high levels of endogenous dopamine in the caudate/putamen. In contrast, however, typical neuroleptics (i.e., those that typically cause parkinsonism) have intrinsic K values of 0.3 to 6 nM, making them less displaceable by endogenous dopamine. A relationship exists between the neuroleptic doses for rat catalepsy and the D2/D4 ratio of the intrinsic K values. Thus, the atypical neuroleptics appear to fall into two groups, those that bind loosely to D2 and those that are selective at D4.
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PMID:Dopamine and serotonin receptors: amino acid sequences, and clinical role in neuroleptic parkinsonism. 885 1

The records of 49 patients with Parkinson's disease and psychosis who were treated with clozapine for up to 18 months were reviewed. Average starting dose of clozapine was 16 mg. Average maximum dose was 39 mg. The psychotic symptoms improved in 76% of the patients at 3 months, and response to clozapine within the first year ranged from 71% to 80%. This response allowed a maximization of levodopa dose. Improvements in scores on the Unified Parkinson's Disease Rating Scale and tremor subscale were seen in some patients but were not statistically significant. This study, the largest of its kind to date, suggests that clozapine is well tolerated and effective in treating psychosis in patients with Parkinson's disease.
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PMID:Clozapine for the treatment of psychosis in Parkinson's disease: chart review of 49 patients. 885 98

We studied the effect of olanzapine (1 to 15 mg/d) in 15 nondemented parkinsonian patients with drug-induced psychosis. Psychotic symptoms decreased significantly during treatment, and there was no worsening of extrapyramidal symptoms. These results suggest that olanzapine is a well-tolerated and effective treatment for drug-induced psychosis in nondemented patients with Parkinson's disease.
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PMID:Olanzapine in the treatment of dopaminomimetic psychosis in patients with Parkinson's disease. 956 37

The therapeutic concentrations of antipsychotic drugs in the patient's plasma water or spinal fluid are identical to their blocking potencies in vitro at the dopamine D2 receptor, with the exception of clozapine which acts at D4. The variation in K values between laboratories stems from the fact that the apparent K value for any antipsychotic drug depends on the affinity of the competing radioligand for the receptor or the membranes. Clozapine at the D2 receptor has a K value of 420 nM using [3H]nemonapride, 180 nM using [3H]spiperone and 82 nM using [3H]raclopride. These K values are related to the tissue/buffer partition coefficients of the ligands. Extrapolating down to either 1 or 0 partition yields the intrinsic K values for the antipsychotic in the absence of any competing ligand. The extrapolated or intrinsic K value for clozapine at D4 is 1.3 nM, in agreement with the value of 1.1 nM measured directly with [3H]clozapine at D4. Clozapine in vivo, however, must compete with endogenous dopamine in the synapse, estimated as 50 nM. Thus, the in vivo concentration of clozapine for 75% occupation of dopamine D4 receptors can be derived as approximately 14 nM, in agreement with the observed value of 12-20 nM in the plasma water or spinal fluid in treated patients. In L-DOPA psychosis in Parkinson's disease, the clozapine concentration (in the plasma water or spinal fluid) for 75% blockade of dopamine D4 receptors may be predicted as approximately 3 nM, in general agreement with the value of approximately 1.2 nM in Parkinson patients who have L-DOPA psychosis. These considerations provide strong support for the conclusion that clozapine primarily targets the D4 receptor in psychosis. Using the same considerations for haloperidol, it can be shown that the haloperidol therapeutic concentration required for 75% blockade of dopamine D2 receptors in vivo will be approximately 2-3 nM, in agreement with the observed value in the spinal fluid or plasma water of 1-3 nM.
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PMID:Therapeutic receptor-blocking concentrations of neuroleptics. 886 60

Twenty patients with Parkinson's disease (PD), who developed delusions and psychotic behavior, underwent electroencephalogram (EEG) recordings before and during treatment with low-dose clozapine. Resolution of the psychotic features was observed in all cases. The EEG was unaltered in 15, whereas five patients exhibited increased generalized or focal slowing when compared with the pretreatment tracings. These findings contrast with the high incidence of EEG abnormalities, including epileptiform activity, which are observed when larger doses of clozapine are used in schizophrenic patients, but they underscore that even in low doses, clozapine may cause EEG changes.
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PMID:Electroencephalographic findings with low-dose clozapine treatment in psychotic Parkinsonian patients. 886 21


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