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)

Recent clinical studies have reported a beneficial effect of fluoxetine, a serotonin reuptake inhibitor, in patients with severe refractory orthostatic hypotension. The present study was undertaken to investigate the effect of fluoxetine in orthostatic hypotension occurring during Parkinson's disease on both blood pressure values and number of clinical symptoms during orthostatic procedure evaluated using a validated clinical rating scale. In a pilot study performed in fourteen patients with idiopathic Parkinson's disease plus orthostatic hypotension, fluoxetine hydrochloride (20 mg orally daily during one month) significantly reduced the fall in systolic blood pressure [-33 +/- 21 (SD) mmHg before fluoxetine vs -22 +/- 19 mmHg after fluoxetine, P = 0.03] elicited by standing without modifying heart rate. The drug also significantly reduced the number of postural symptoms occurring during the orthostatic procedure [2.9 +/- 1.5 (SD) before fluoxetine vs 1.2 +/- 1.3 after fluoxetine, P = 0.006]. A similar pattern of response was obtained in an experimental model of neurogenic orthostatic hypotension obtained in chronically sino-aortic denervated dogs submitted to an 80 degrees head-up tilt test procedure under chloralose anaesthesia. Fluoxetine did not change plasma noradrenaline levels. This pilot study suggests a slight but clinically significant effect of fluoxetine on both hemodynamic parameters and clinical symptoms in parkinsonian patients suffering from orthostatic hypotension.
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PMID:Fluoxetine in orthostatic hypotension of Parkinson's disease: a clinical and experimental pilot study. 971 61

The importance of the striatal dopamine (DA) deficiency and the DA substituting property of levodopa for the pathophysiology and therapy of Parkinson's disease (PD) is reiterated. In addition, it is shown that in PD, significantly reduced DA levels are also found in the nucleus accumbens, external and internal segments of the globus pallidus, the substantia nigra reticulata, and the subthalamic nucleus. It is proposed that, in addition to the critical role played by the striatal DA loss, the DA changes in the extrastriatal nuclei of the basal ganglia are importantly involved in the pathophysiologic mechanisms resulting in the parkinsonian movement disorder, and that the therapeutic and/or side effects of DA substitution therapy may, in part, be mediated through these brain regions which, like the striatum, suffer DAergic deafferentation in PD. From observations in brain of patients with secondary parkinsonism, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine parkinsonism in the rhesus monkey, as well as the regional DA transporter distribution in the primate substantia nigra, it is concluded that PD may be caused by any exogenous and/or endogenous toxin using the transporter system for DA and to some degree the other brain monoamines (noradrenaline, serotonin), to enter, and damage, the respective monoamine neurons. Based on converging evidence, the view is advanced that endogenous, genetically based (excessive) formation, or accumulation, of toxic DA transporter substrates, such as isoquinoline or beta-carboline derivatives, may in fact represent the primary cause of substantia nigra cell degeneration in patients with PD.
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PMID:Biochemical aspects of Parkinson's disease. 971 73

We investigated the role dopamine and noradrenaline in the modulation of attention in Parkinson's disease (PD) patients. We observed that PD patients with mild and moderate motor disability did not differ in their attentional accuracy in easy tests, but the severe PD group was slightly disrupted in a more arduous test of attention. Attentional accuracy was not affected by withdrawal of dopaminergic drugs in mild or severe PD patients. The movements of severe PD patients were slower, and withdrawal of dopaminergic drugs aggravated motor slowing more in severe PD patients. Clonidine (0.5 and 2 microg/kg) retarded accuracy of performance in the most difficult attention test in mild PD patients, but had no effect in the severe PD group. Clonidine had no effect on movement times. These data suggest that a defect in noradrenaline release may contribute to the impaired accuracy of attention in severe PD patients and that dopamine may be important for maintaining rapid motor responding.
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PMID:Reduction of noradrenaline impairs attention and dopamine depletion slows responses in Parkinson's disease. 974 97

Four different forms of primary autonomic failure (multiple system atrophy, pure autonomic failure, Parkinson's disease and dopamine beta-hydroxylase deficiency) have been described. The first part of the article will focus on the interest to pharmacology of elucidating pathophysiological mechanisms underlying autonomic involvement at the central level (growth hormone response to clonidine acute challenge), presynaptic level (plasma catecholamine levels after yohimbine administration) and on post-synaptic receptors (binding studies, pressor responses to noradrenaline). The second part will discuss efficacy and side-effects of some of the many drugs which are currently proposed for the treatment of one of the most disabling symptoms related to autonomic failure, orthostatic hypotension. Special attention will be paid to drugs acting on blood composition (fludrocortisone, erythropoietin), on post-synaptic alpha-adrenoceptors (midodrine and clonidine) and on noradrenaline spill-over (yohimbine and L-Threo-DOPS).
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PMID:[Pharmacologic approach to autonomic failure]. 977 98

Catechol-O-methyltransferase inhibitors have been newly introduced as adjunct drugs to the levodopa/dopa decarboxylase inhibitor therapy in Parkinson's disease. When given alone, catechol-O-methyltransferase inhibitors seem to affect behaviour. We wanted to determine whether the concentrations of free amine would be increased by catechol-O-methyltransferase inhibition with tolcapone and underpin the positive behavioural effects. To this end, dopamine and noradrenaline levels were analyzed in the microdialysis perfusion fluid collected from several brain regions in chloral hydrate anaesthetized rats. We also analyzed the turnover rate of catecholamines in the brain after single doses of tolcapone and entacapone using the alpha-methyl-p-tyrosine method. On their own, tolcapone (at 10 or 30 mg/kg) did not elevate dopamine or noradrenaline levels in any brain region studied although the formation of catechol-O-methyltransferase-dependent metabolites was strongly reduced. Neither tolcapone nor entacapone (at 30 mg/kg) affected the turnover rate of catecholamines. It seems that catechol-O-methyltransferase inhibitors do not alter behaviour by elevating extracellular levels of free catecholamines levels but other explanations are needed.
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PMID:No change of brain extracellular catecholamine levels after acute catechol-O-methyltransferase inhibition: a microdialysis study in anaesthetized rats. 977 42

The limbic system includes the complex of brain centres, nuclei and connections that provide the anatomical substrate for emotions. Although the presence of small amounts of dopamine (DA) in several limbic structures has been recognized for a long time, for many years it was thought that limbic DA represented a precursor of noradrenaline in the biosynthetic pathway of catecholamines. More recent evidence has shown that limbic centres and nuclei are supplied with a dopaminergic innervation arising from the ventral tegmental area (field A10) and in smaller amounts from the mesencephalic A9 field. The dopaminergic limbic system is sensitive to ageing. Parameters of dopaminergic neurotransmission (DA levels, biosynthetic and catabolic markers and DA receptors) undergo age-related changes which depend on the structure and species investigated and are characterized mainly by a decline of different parameters examined. In this paper, the influence of ageing on DA biosynthesis, levels, metabolism and receptors are reviewed in laboratory rodents, monkeys and humans as well as in cases of Alzheimer's disease and Parkinson's disease. The possibility that changes of dopaminergic neurotransmission markers in the limbic system are associated with cognitive impairment and psychotic symptoms affecting the elderly is discussed. Better knowledge of dopaminergic neurotransmission mechanisms in the so-called physiological ageing and in senile dementia may provide new insights in the treatment of behavioural alterations frequently occurring in old age.
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PMID:Sensitivity to ageing of the limbic dopaminergic system: a review. 988 74

So far, no clear correlation has been found between the effects of dopamine D1 receptor agonists on motor behavior in primate models of Parkinson's disease and their ability to stimulate adenylate cyclase in rats, the benzazepine SKF 83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-]H- 3-benzazepine) being the most striking example. Since this discrepancy might be attributed to: (A) the different species used to study these effects or (B) the interaction of SKF 83959 with other catecholamine receptors, the aims of this study were: (1) to study the ability of SKF 83959 to stimulate adenylate cyclase in cultured human and monkey glial cells equipped with dopamine D1 receptors and (2) to evaluate the affinity for and the functional interaction of SKF 83959 with other catecholamine receptors. Binding studies revealed that SKF 83959 displayed the highest affinity for the dopamine D1 receptor (pKi=6.72) and the alpha2-adrenoceptor (pKi=6.41) and moderate affinity for the dopamine D2 receptor and the noradrenaline transporter. In monkey and human cells, SKF 83959 did not stimulate cyclic adenosine monophosphate (cAMP) formation to a significant extent, but antagonized very potently the dopamine-induced stimulation of cAMP formation in both cell types. The compound stimulated basal dopamine outflow and inhibited depolarization-induced acetylcholine release only at concentrations > 10 microM. Finally, SKF 83959 concentration dependently increased electrically evoked noradrenaline release, indicating that it had alpha2-adrenoceptor blocking activity and interfered with the noradrenaline transporter. In conclusion, SKF 83959 is a potent dopamine D1 receptor and alpha2-adrenoceptor antagonist. Thus, the anti-parkinsonian effects of SKF 83959 in primates are not mediated by striatal dopamine D1 receptors coupled to adenylate cyclase in a stimulatory way.
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PMID:The alleged dopamine D1 receptor agonist SKF 83959 is a dopamine D1 receptor antagonist in primate cells and interacts with other receptors. 992 Jan 82

Four major components of the mechanism of action have been identified for the antiparkinsonian drug budipine up to now. 1) The primary action of budipine is an indirect dopaminergic effect as shown by facilitation of dopamine (DA) release, inhibition of monoamine oxidase type B (MAO-B) and of DA (re) up-take and stimulation of aromatic L-amino acid decarboxylase (AADC), which in sum might be responsible for enhancing the endogenous dopaminergic activity. 2) Radioligand and functional studies at the N-methyl-D-aspartate (NMDA) type glutamate receptor characterize budipine as a low-affinity, uncompetitive antagonist with fast kinetics and moderate voltage-dependency at the phencyclidine (PCP) binding site, comparable to that observed with amantadine, thereby counteracting an increased excitatory glutamatergic activity. 3) The antimuscarinic action of budipine, verified by functional and binding studies at native muscarinic M1-M3 and human recombinant m1-m5 receptor subtypes in vitro, is up to 125-fold weaker than that of biperiden and corresponds to its approximately 100-fold lower potency to cause experimentally-induced peripheral antimuscarinic effects and explains only part of its high potency, which equals biperiden, to suppress cholinergically evoked tremor. 4) An additional inhibition of striatal gamma-aminobutyric acid (GABA) release by budipine may be beneficial to suppress an increased striatal GABAergic output activity. The contribution of other observed effects to the therapeutic action of budipine, i.e. weak stimulation of noradrenaline and serotonin release, binding to brain sigma1 receptors and blockade of histamine H1 receptors, is not yet clear. By means of these multiple mechanisms, budipine might correct the imbalance of striatal output pathways by restoring DA levels in the striatum, and positively influence the secondary changes in other transmitter systems (glutamate, acetylcholine, GABA) observed in Parkinson's disease.
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PMID:Multiple mechanisms of action: the pharmacological profile of budipine. 1037 Sep 4

The present experiments investigated the effects of a specific and potent alpha(2)-adrenoceptor antagonist, atipamezole, on cognitive performance and neurochemistry in aged rats. Aged control Fisher 344 rats, which had lower activities of choline acetyltransferase in the frontal cortex, were impaired in the acquisition of the linear arm maze task both in terms of repetition errors and their behavioural activity (the speed of arm visits), and they needed longer time to complete this task as compared to adult control rats. Atipamezole treatment (0.3 mg/kg) facilitated the acquisition of this task in the aged rats as they committed fewer errors and completed the task more quickly than saline-treated aged control rats. A separate experiment indicated that atipamezole enhanced the turnover of noradrenaline both in the adult and aged rats, but this effect was more pronounced in the aged rats. Furthermore, atipamezole enhanced significantly the turnover of serotonin and dopamine only in the aged rats when analysed in the whole brain samples. As alpha(2)-adrenoceptor antagonists are known to alleviate akinesia in the experimental models of Parkinson's disease, the present results could be especially relevant for the development of palliative treatment for demented Parkinsonian patients.
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PMID:The effects of a specific alpha(2)-adrenoceptor antagonist, atipamezole, on cognitive performance and brain neurochemistry in aged Fisher 344 rats. 1065 Jan 54

Treatment of Parkinson's disease with L-dopa is plagued in a majority of patients by dyskinesias. Noradrenaline/dopamine interactions are proposed on behavioral, biochemical, physiological and anatomical grounds. The aim of the study was to test the potential antidyskinetic effect of the alpha2-adrenoceptor antagonist, idazoxan, in a primate model of Parkinson's disease. Six female cynomolgus monkeys previously rendered parkinsonian by the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and presenting an unchanged syndrome for several months were used. All responded readily to L-dopa but had developed dyskinesias which were manifested with each dose. In the first part of the study, seven doses of idazoxan (ranging from 0.25 mg/kg to 10 mg/kg, p.o.) were administered together with the vehicle or in combination with a fixed dose of L-dopa/benserazide (100/25 mg, p.o.). In the second part of the study, a fixed dose of idazoxan (7.5 mg/kg) was administered daily for 10 days and L-dopa was added to idazoxan on days 1, 4, 7 and 10. Vehicle (empty capsule) was used as control. Idazoxan, by itself (ranging from 5 mg/kg to 10 mg/kg), increased locomotor activity and improved the disability score with virtually no dyskinesias in three animals. In combination with L-dopa, idazoxan did not impair the antiparkinsonian response but significantly reduced dyskinesias in all six animals up to 65% at doses of 7.5 mg/kg and 10 mg/kg and delayed their onset, so that the "ON" state without dyskinesias was prolonged. The antidyskinetic effect of idazoxan was maintained when repeatedly administered for 10 days. On day 10, the locomotor response to L-dopa was significantly potentiated by chronic administration of idazoxan. Our results indicate that idazoxan has some antiparkinsonian effect of its own and may constitute a useful adjunct to L-dopa as it can reduce dyskinesias without impairing the relief of symptoms, this effect being maintained over time in this model.
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PMID:Noradrenoceptor antagonism with idazoxan improves L-dopa-induced dyskinesias in MPTP monkeys. 1068 74


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