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 data on the aptitude of adamantamines to inhibit or to stimulate glutamatergic (NMDA) neuromediation, to display anti-GABAergic and antiglycinergic components (by blocking the Cl- channel), on the one hand, and on the opposition of the central glutamatergic and dopaminergic systems, on the other, could suggest that the glutamatergic (NMDA) or the anti-NMDA activity, exhibited by some adamantamines, could play an important role in the expression of their pharmacological profile. Anti-NMDA properties, for the adamantamines which exhibited them, could be, by themselves or by developing their anti-GABAergic or antiglycinergic components, the first cause of the hypermotility and dopaminomimetic activity induced by these molecules. Glutamatergic (NMDA) component, which could be displayed by some lipophilic or important steric obstruction on azote exhibiting adamantamines, could amplifie the excitating effects of their anti-GABAergic and antiglycinergic components on the limbic system's brain structures (hippocampus, amygdala) and could contribute to the exhibition of hypomotility, fright, agressivity and convulsions. According to these data, which must be amplier confirmed and deeped, it would be possible to envisage the improvement of adamantamines against the Parkinson's disease (when they exhibit anti-NMDA activity) or their use against the Alzheimer's disease and the late stages of the Parkinson's disease (when they exhibit NMDA activity).
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PMID:[Action mechanism of adamantamines: do their activity on glutamatergic receptors intervene in the expression of their pharmacological profile?]. 184 25

While the cause of Parkinson's disease (PD) remains unknown, recent evidence suggests that certain external factors, ie, environmental agents, may act as neurotoxins, initiating the chain of oxidative reactions that ultimately destroy neurons in the substantia nigra. Young-onset PD might result from greater exposure to a putative neurotoxin. This hypothesis has rekindled interest in the epidemiology of PD. We therefore conducted a detailed analysis of various environmental exposures and early life experiences in 80 patients with old-onset PD (at an age older than 60 years), 69 young-onset patients (younger than 40 years), and 149 age- and sex-matched control subjects. Contrary to previous reports, we were unable to implicate well water or exposure to herbicides, pesticides, or industrial toxins as significant PD risk factors. A residential history of rural living was reported by more patient cases than control subjects and was marginally significant. On the other hand, at least one episode of head trauma "severe enough to cause vertigo, dizziness, blurred or double vision, seizures or convulsions, transient memory loss, personality changes, or paralysis" occurred significantly more often prior to disease onset in patients with both young-onset and old-onset PD than in control subjects (odds ratio = 2.7). When adjusted for head trauma and rural living, smoking was inversely associated with PD, as has been previously reported (odds ratio = 0.5). There were no significant differences in early life experiences or environmental exposures between young-onset and old-onset patients. We suggest that the risk of developing PD is influenced by a variety of factors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The epidemiology of Parkinson's disease. A case-control study of young-onset and old-onset patients. 195 12

In order to assess quantitatively the state of the disease or the effect of drugs in parkinsonian patients, it would be helpful to have at our disposal mathematical models that reflect in their parameter values the deficiencies associated with the disease. This paper proposes a class of such models that are easily obtained in practice and lend themselves to useful interpretations. A pursuit manual tracking experiment is used to derive these models for patients with Parkinson's disease undergoing drug therapy and for normal controls. The input (one-dimensional visual target) and operator's output (manual tracking) are analyzed using a time series approach aiming at obtaining an auto-regressive moving-average (ARMA) model that minimizes the mean square error between the actual and model response. This mathematical model takes the form of a difference equation expressing, in discrete time, the present output value as a linear combination of past output values and past and present input values. Our experimental results indicate that a difference equation (ARMA model) involving the two previous output values and the present and past input values fits best both patient and control data. A comparison between the mean estimated model parameters for patients and controls shows a statistically significant difference in two of these parameters. The first parameter, which is significantly increased in patients, relates the current response of the patient to the immediately preceding response which represents an increased 'damping' of the motor dynamics, reflecting the muscular rigidity associated with the disease (motor disorder). The other parameter, which is significantly decreased in patients, represents the relative degree to which the current response of the patient is influenced by the target position information at the previous point in time which points to a deficiency in sensing/processing of this information (possible a sensory disorder). Our results also showed a marked reduction in the mean-square error of a second trial of the experiment in normal subjects but failed to do so for the patients, possibly indicating learning deficiencies associated with the disease.
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PMID:Quantifying deficiencies associated with Parkinson's disease by use of time-series analysis. 244 18

The case of a 74-year-old woman, affected since the age of 20 by generalized convulsive fits and who began to show at the age of 63 signs of Parkinson's disease is reported. The epileptic features showed no change while Parkinson's disease got worse. Further, every convulsive fit was followed by a transitory improvement of the extrapyramidal disorders. After a review of the literature on the rare association of Parkinson's disease with epilepsy, the hypothesis of a biological incompatibility between the two diseases is considered.
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PMID:[Parkinson's disease and epilepsy: hypothesis of biological incompatibility]. 643 87

The article reviews the problems involved in perioperative care of patients suffering from myasthenia gravis, multiple sclerosis, Parkinson's disease as well as diseases associated with seizures or convulsions. The pros and cons of the various methods of anaesthesia are described. The problems associated with the anaesthesiological care of psychiatric patients are explained particularly regarding interactions between neuroleptics and narcosis. General rules preference of a specific method of anaesthesia in neurological and psychiatric patients do not exist.
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PMID:[Anesthesia in patients with neurologic and psychiatric diseases]. 689 Jul 78

We studied apolipoprotein E (apoE) phenotype in 113 patients with possible and probable Alzheimer's disease (AD), 49 patients with Parkinson's disease (including 11 patients with dementia) and 23 patients with mixed and vascular dementia. Normal controls were 498 young, healthy blood donors previously recorded. All patients were assayed for blood lipid parameters. All AD patients underwent a neuropsychological evaluation (including a mini-mental status and 5 subtests of Cole and Dastoor hierarchic dementia scale) and a detailed interrogation of them and their caregivers about their familial and personal medical history. The recorded data included age at onset, clinical subtype (i.e. amnesic or aphaso-apraxic), occurrence of fits, cases of probable dementia in relatives, and ages of their parents at death. There was a significant association between the fourth isoform of apoE and AD, as in previous works. We did not found such an association for PD patients (even with dementia) nor mixed and vascular demented patients. We failed to find any association between any clinical characteristic of the patients and the biological subgroups defined by the number of epsilon 4 alleles, except with regard for the age of onset. Surprisingly, the mothers of epsilon 4 bearers had a significantly longer life than mothers of other patients. We failed to found any significant difference of apoE2 isoform frequency between AD patients and controls. AD patients had higher levels of cholesterol and apoAl than did MP and mixed and vascular demented patients. ApoAl level is known to constitute a protective factor against coronary heart disease, which is usually increased by the presence of apoE-epsilon 4.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Isoform 4 of apolipoprotein E and Alzheimer disease. Specificity and clinical study]. 748 73

An in vitro mammalian model neuronal system to evaluate the intrinsic toxicity of soman and other neurotoxicants as well as the efficacy of potential countermeasures was investigated. The link between soman toxicity, glutamate hyperactivity and neuronal death in the central nervous system was investigated in primary dissociated cell cultures from rat hippocampus and cerebral neocortex. Exposure of cortical or hippocampal neurons to glutamate for 30 min produced neuronal death in almost 80% of the cells examined at 24 h. Hippocampal neurons exposed to soman for 15-120 min at 0.1 microM concentration caused almost complete inhibition (> or = 90%) of acetylcholinesterase but failed to show any evidence of effects on cell viability, indicating a lack of direct cytotoxicity by this agent. Acetylcholine (ACh, 0.1 mM), alone or in combination with soman, did not potentiate glutamate toxicity in hippocampal neurons. Memantine, a drug used for the therapy of Parkinson's disease, spasticity and other brain disorders, significantly protected hippocampal and cortical neurons in culture against glutamate and N-methyl-D-aspartate (NMDA) excitotoxicity. In rats a single dose of memantine (18 mg/kg) administered 1 h prior to a s.c. injection of a 0.9 LD50 dose of soman reduced the severity of convulsions and increased survival. Survival, however, was accompanied by neuronal loss in the frontal cortex, piriform cortex and hippocampus.
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PMID:Assessment of primary neuronal culture as a model for soman-induced neurotoxicity and effectiveness of memantine as a neuroprotective drug. 749 76

An assortment of glutamate antagonists with differing selectivities for NMDA and AMPA-type glutamate receptors, were tested for their effects in the mouse pilocarpine model of complex partial seizures. MK 801 (0.1-0.8 mg/kg) and high doses of HA 966 (50 mg/kg) were proconvulsant, whilst CGP 40116 (1-8 mg/kg) and low doses of HA 966 (0.4-10 mg/kg) inhibited pilocarpine-induced convulsions. CPP (5-20 mg/kg) and NBQX (1-50 mg/kg) were without effect. The dopamine D1 agonist SKF 38393 (10 mg/kg) facilitated the convulsant effects of low-dose pilocarpine (100 mg/kg). MK 801 (0.1-0.2 mg/kg) and HA 966 (50 mg/kg) interacted synergistically with SKF 38393 to promote the proconvulsant effects of D1 stimulation, whilst CPP (10-20 mg/kg) and HA 966 (10 mg/kg) had the opposite effect. CGP 40116 and NBQX were without effect. These results show that the convulsant qualities of MK 801 and SKF 38393, that have been detected in animal models of Parkinson's disease, can be reproduced in the pilocarpine model of epilepsy. Whilst the glutamate antagonists all interact synergistically with SKF 38393 to improve its antiparkinson activity, only MK 801 and high doses of HA 966 similarly potentiate the convulsions associated with D1 stimulation. An appropriate mixture of a glutamate antagonist and a D1 agonist could theoretically be used beneficially in the treatment of Parkinson's disease, without causing epilepsy as a side effect.
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PMID:Glutamate-dopamine interactions in the production of pilocarpine motor seizures in the mouse. 790 44

Pergolide (LY127809, CAS 66104-23-2), a dopamine agonist for the treatment of Parkinson's disease, was evaluated for toxicity in acute, subchronic, and chronic studies. Acute toxicity tests using oral, intravenous and intraperitoneal routes were conducted in rats, mice, rabbits, and dogs. The acute oral median lethal doses (MLD) ranged from 8.4 to 33.6 mg/kg in Wistar and Fischer 344 rats, and from 54.0 to 87.2 mg/kg in ICR mice. Oral doses of 20 and 25 mg/kg produced no mortality in rabbits or dogs, respectively. The MLD by the iv route ranged from 0.59 to 0.87 mg/kg for Fischer 344 rats and from 11.6 to 37.1 mg/kg for ICR mice. The predominant signs of toxicity in the acute studies included hyperactivity, poor grooming, ptosis, aggressive behavior, increased gnawing activity, tremors, convulsions, and emesis. In the subchronic and chronic studies, Fischer 344 rats, B6C3F1 mice, and beagle dogs were administered pergolide either by gavage or in the diet for up to 1 year. Daily doses in these studies ranged up to 20 mg/kg for rats, 45 mg/kg for mice, and 5 mg/kg for dogs. The predominant treatment-related effects seen in these studies were attributable to the pharmacologic activity of pergolide. These consisted primarily of CNS-mediated clinical signs in rats and dogs, weight loss or decreased weight gain, emesis in dogs, and inhibition of lysis of corpora lutea with a corresponding increase in the weight of the uterus and ovaries. Pergolide treatment was not associated with any specific target organ toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preclinical toxicology studies with the new dopamine agonist pergolide. Acute, subchronic, and chronic evaluations. 819 91

The amino-adamantane derivatives memantine (1-amino-3,5-dimethyladamantane) and amantadine (1-amino-adamantane) are relatively low affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists which have been used clinically in the treatment of dementia and Parkinson's disease respectively for several years without serious side effects. The aim of this study was to test whether memantine, amantadine and other low affinity uncompetitive NMDA receptor antagonists also have better therapeutic indices than high affinity antagonists in preclinical models of epilepsy by assessing the potency, kinetics and voltage-dependency of open channel blockade for a series antagonists in vitro and comparing these effects to anticonvulsive and motor impairment activity in vivo. The compounds tested were memantine, amantadine, 14 other amino-adamantanes, (+)-MK-801, ketamine, dextrorphan, dextromethorphan and phencyclidine. The offset kinetics of open-channel blockade assessed with whole cell patch clamp recordings from cultured superior colliculus neurones were highly correlated to potency i.e. the less potent antagonists showed faster unblocking kinetics (Koff, r = 0.904). Although, onset kinetics as assessed by Kon were not correlated to potency (r = 0.023), tau on estimated at IC50 is perhaps a more meaningful measure of onset kinetics at equieffective concentrations and was also well correlated to potency (r = -0.863). All amino-adamantanes tested were strongly voltage-dependent. There was also a good correlation between the in vitro potencies of uncompetitive NMDA receptor antagonists assessed with patch clamp recordings and displacement of equilibrium [3H](+)-MK-801 binding and their in vivo activity against maximal electroshock (MES) and pentylenetetrazol (PTZ) induced tonic convulsions and NMDA-induced lethality in mice. Memantine and four other amino-adamantanes with somewhat lower potency and faster blocking kinetics had better therapeutic indices (ED50 rotarod and traction reflex over ED50 in MES-induced convulsions; TI = 2-4) than substances with higher affinity such as ketamine, dextrorphan and (+)-MK-801 (TI < 2). However, amantadine and several other amino-adamantanes with lower potency than memantine actually had poorer therapeutic indices (TI < or = 0.5) which may have been due to additional actions at other ion channels or receptors at the doses necessary to protect against seizures. In fact, ED50 in the MES test was negatively-correlated to therapeutic indices (traction r = -0.790, rotarod r = -0.797) i.e. the less potent uncompetitive antagonists had worse therapeutic indices. The data from the present study do not lend support to the idea that low affinity, open channel NMDA receptor blockers are also effective in models of epilepsy at doses having little effect on physiological processes. It should be stressed that these data do not contradict the known therapeutic safety of memantine and amantadine in dementia and Parkinson's disease respectively. Thus the good clinical profile of memantine in dementia has been attributed not only to its fast blocking/unblocking kinetics but also to its strong voltage-dependency. These biophysical properties may allow therapeutically-relevant concentrations to block chronic, low level pathological activation of NMDA receptors whilst leaving their synaptic activation intact. Precisely these properties may also underlie the poor therapeutic indices seen in the present study on antiepileptic activity due to the synaptic nature of both seizures and normal glutamatergic transmission.
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PMID:Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo. 857 22


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