摘要:

The central benzodiazepine binding site mediates the therapeutically relevant pharmacologic actions of benzodiazepine agonists, including reducing anxiety, sedation, muscle relaxation, and antagonism of seizure production. Benzodiazepines potentiate the ability of γ-aminobutyric acid (GABA) to promote membrane chloride ion conductance by binding reversibly to a distinct site on the GABAAreceptor complex. Although the role of this central benzodiazepine binding site in mediating the pharmacologic actions of benzodiazepine agonists has been shown conclusively, its participation in an animal's response to stress is less certain. Data are reviewed consistent with an environmental stress-induced modification of the structure and function of the central benzodiazepine binding site. Modifications show brain anatomic regional selectivity. The mechanisms of these modifications include rapid enzyme-mediated phosphorylations of the GABAAreceptor complex and the selective transcription of individual polypeptide subunits. The potential relevance of the data on environmental stress-induced functional modifications of the central benzodiazepine binding site to the development of newer medications and improved understanding of the pathophysiology of stress-related neuropsychiatric disorders is discussed.

ISSN:0362-5664    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Brainstem interneuronal excitability is enhanced in patients with cervical dystonia. Treatment with local botulinum toxin (BTX) injections temporarily alleviates the pain and weakens the muscle spasms, characteristics of this condition. In 10 patients with cervical dystonia, we studied whether the clinical improvement induced by BTX was associated with modification of the blink reflex excitability recovery curve to paired supraorbital nerve electrical shocks. We found that the mean percentage recovery of the R2 to the test stimulus was abnormally enhanced before treatment and that it did not significantly change after treatment, at the time of maximal clinical improvement, in any of the interstimulus intervals tested. We conclude that the clinical improvement induced by BTX in patients with cervical dystonia is largely symptomatic and is not related to any change of the known abnormalities in brainstem interneuronal excitability that possibly underlie the pathophysiology of cervical dystonia.

ISSN:0362-5664    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The present study was designed to investigate the efficacy of clonazepam in neuroleptic-induced akathisia. Twelve patients were treated during 2 weeks with clonazepam or placebo in a double-blind randomized design. Akathisia was scored by an independent rater before and after treatment, as well as 1 week after medication withdrawal. Clonazepam (0.5–2.5 mg/day) induced a significantly higher reduction in the akathisia scores than placebo (p < 0.05). One week after stopping the drug, there was a partial but significant relapse in the treated group as compared with controls, in whom the symptoms remained stable. In addition, the clinical improvement was significantly correlated with the daily dose of clonazepam (rs= 0.827; p < 0.002). These results support the potential usefulness of clonazepam in the treatment of neurolepticinduced akathisia and suggest an optimal daily dose in the range of 10–40 μg/kg.

ISSN:0362-5664    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Apomorphine, the first dopamine agonist to be synthesized, has received a renewed interest in the last few years. This compound acts powerfully on D1and D2dopamine receptors and has the most complete pharmacological profile of all clinically available dopamine agonists. When given sub-cutaneously, apomorphine consistently reverses levodopa-resistant “off” periods in parkinsonian subjects: thus, it is used in cases with severe motor fluctuations, either by continuous infusion with a portable pump or by multiple injections. Studies based on this approach have been highly encouraging, as they have shown a significant reduction in off time and a good drug tolerability. The main side effect has been the occurrence of nodular skin lesions, especially when continuous infusions were used. At variance with other dopamine agonists, a low incidence of psychiatric morbidity has been reported with apomorphine. The few available comparative reports have shown that this compound is more potent and better tolerated than lisuride. Parenteral apomorphine has been used in Parkinson's disease (PD) to replace levodopa after surgery or to treat the malignant syndrome brought about by sudden levodopa withdrawal. Acute challenge with apomorphine has been used to test dopaminergic responsiveness in parkinsonian syndromes and in dystonia. The clinical response to apomorphine may predict the effect of a chronic therapy with levodopa in 90% of PD cases. Further studies are still necessary to evaluate the exact relationship between the acute response to apomorphine and a chronic therapy. In addition, apomorphine has been used to conduct clinical pharmacological studies in PD, for it is particularly well suited for research on the pharmacodynamics of central dopamine receptors. In summary, apomorphine appears to be an efficacious and safe drug for the treatment of advanced PD. It must still be considered under clinical evaluation as a test drug for acute challenge in PD and dystonia. Finally, in our opinion, the available data suggest apomorphine (in conjunction with domperidone) as a first-choice treatment for the neuroleptic malignant syndrome and the temporary replacement of levodopa (e.g., after gastrointestinal surgery).

ISSN:0362-5664    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Plasma levels of homovanillic acid (pHVA) following debrisoquine (DBQ) administration may be indicative of central dopaminergic activity. The effect of DBQ (10–20 mg) administration on pHVA in young healthy volunteers was studied to establish a protocol for use in de novo patients with Parkinson's disease. Subsequently, pHVA in de novo patients with Parkinson's disease were measured and compared to young healthy volunteers. Following DBQ (10 mg) administration to healthy volunteers, pHVA fell with time to a maximum of 62% of control values at 6 h. The decrease in pHVA was not affected by loading with DBQ (10 mg) 10 h previously (pHVA: 67.6 ± 5.8% of preDBQ levels) or increasing the dose to 20 mg (56.1 ± 11.8% of preDBQ levels) compared to a single 10 mg dose of debrisoquine (66.5 ± 4.5% of preDBQ levels). pHVA was reduced in both de novo patients with Parkinson's disease and in healthy volunteers following DBQ (10 mg) administration. However, there was no difference in pHVA before or after DBQ administration when comparing the two groups. These results suggest that, following DBQ administration, pHVA does not reflect dopamine neuronal loss in de novo patients with Parkinson's disease, so it is unlikely to detect the disease before the clinical symptoms manifest themselves.

ISSN:0362-5664    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Catechol-O-methyl-transferase inhibitors are promising drugs in Parkinson's disease since these drugs enhance levodopa effects and increase their duration. However, since these compounds block a pathway for the peripheral metabolism of catecholamines, they may also produce side effects related to elevation of catecholamines in plasma. We investigated the adverse effects of Ro 40–7592 in rabbits and the relationship of Ro 40–7592 to norepinephrine plasma levels. Intravenous administration of Ro 40–7592 in rabbits induced elevation of norepinephrine plasma levels in old animals after bolus injection of a dose three times the highest dose actually recommended to be taken orally by humans. Though Ro 40–7592 appears safe for humans, special precautions may be needed in patients with a high risk of adrenergic hyperactivity.

ISSN:0362-5664    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Previous studies have reported the resting tremor (RT) of Parkinson's disease to occur at frequencies between 3–7 Hz and to be characterised by an alternating pattern of electromyographic (EMG) bursting activity between opposing muscles. A postural tremor (PT), of higher frequency (>6 Hz) and with a synchronous pattern of EMG activity, has also been previously described in Parkinson's disease. We investigated the electrophysiological and pharmacological properties of both the RT and PT of 11 patients with Parkinson's disease and 10 patients with essential tremor in a double-blind, placebo-controlled study of L-Dopa/benserazide and propranolol. Tremor amplitude and frequency were assessed via bidirectional accelerometry, and the pattern of activation of the antagonist muscles of the forearm was determined with use of surface EMG. In the Parkinson's disease group studied, the frequency, EMG pattern of bursts, and response to L-Dopa were similar for the two tremors (median improvement of RT by 70% and PT by 61%). Despite some overlap between the Parkinson's disease and essential tremor groups in the electrophysiology of the tremor, there was no such dramatic pharmacological response in the latter group. These results suggest that the RT and PT of Parkinson's disease share a common pathophysiology and are distinct from essential tremor.

ISSN:0362-5664    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Cabergoline, a new ergoline derivative with potent and long-lasting dopaminergic activity, is a promising drug for overcoming the akinetic episodes in L-Dopa-treated Parkinson's disease patients with motor fluctuations. Its long plasma half-life (65 h) allows a single daily dose administration. Seventeen patients with Parkinson's disease (mean age 66 years; mean disease duration 8.8 years; median Hoehn and Yahr stage, III) were included in an open-label study. All had persistent motor fluctuations while treated with L-Dopa plus carbidopa (mean dose, 660 mg + 66 mg). Cabergoline was added until a maximal dose was achieved (5 mg daily), while L-Dopa was slightly diminished. Eight patients completed 1 year of treatment. They showed significant improvement in their motor performance (Unified Parkinson's Disease Rating Scale) (bradykinesia score decreased from 8.2 to 4.2, p < 0.005), and in the proportion of “off” time spent during waking hours (32–23%, p < 0.05). Three patients abandoned the trial because of increasing severity of dyskinesias, hallucinations, and depression (one each), six were withdrawn because of poor compliance and refusal to continue the treatment. This study suggests that cabergoline may play an important role in the treatment of Parkinson's disease with motor fluctuations.

ISSN:0362-5664    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Severe neurologic complications following treatment with cyclosporine are uncommon. They tend to occur during the first month of treatment and disappear after withdrawal or reduction of the dose of the drug. We report the case of a man who underwent a liver transplantation and subsequently developed severe central nervous system toxicity. After two years receiving cyclosporine, he presented with a brachial monoparesis and a complex visual disturbance. Symptoms slowly worsened during four months. On admission, he had confusion and seizures. Multiple areas of T2 prolongation, located in cerebral white matter, were seen on magnetic resonance imaging (MRI). Symptoms partially improved after cyclosporine withdrawal, but brain lesions shown on MRI persisted in serial imaging studies after two years of follow-up. We discuss the mechanisms that have been proposed to explain this clinical picture. Severe cyclosporine-associated neurotoxicity can also occur after chronic administration, even with serum levels in therapeutic range.

ISSN:0362-5664    

出版商:OVID    

年代:1994

数据来源: OVID