Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A dopamine agonist (apomorphine) and a cholinomimetic drug (physostigmine) were administered to five patients with blepharospasm and oromandibular dystonia (Meige disease). The effects of haloperidol and levodopa were also assessed. Apomorphine lessened and physostigmine aggravated the facial dyskinesias in all patients, while placebo injections had no consistent effect. Levodopa did not modify the symptoms, but haloperidol attentuated the facial dystonia. Dysfunction of the basal ganglia, characterized by a state of striatal dopamine preponderance, probably underlies the dystonic spasms in Meige disease. The prominent cholinergic enhancement of facial dyskinesias may distinguish this disorder pharmacologically from tardive dyskinesia, a differentiation which has practical therapeutic implications.
 ...
PMID:Meige disease: striatal dopaminergic preponderance. 37 89

In a doubleblind, placebocontrolled design subcutaneous apomorphine was given to 7 patients with dystonic movement disorders to assess dopamine sensitivity of their symptoms. Five patients who displayed a marked clinical improvement after the apomorphine test injections subsequently responded to oral or continuous dopaminergic therapy. The effective apomorphine doses correlated with the doses of dopaminergic drugs. Two non-responders to apomorphine did not benefit from dopaminergic therapy. Apomorphine application thus seems to be a valuable test predicting dopamine sensitivity in dystonia.
 ...
PMID:Apomorphine--test in dystonia. 168 23

Neurological side effects associated with neuroleptic drugs result from a complex interaction of multiple neurotransmitters. To clarify the etiology of neuroleptic-induced acute dystonic reactions, monkeys (Cercopithecus aethiops) were treated with haloperidol at doses sufficient to evoke dystonia, and the effects of agents that influenced dopaminergic, cholinergic, or GABAergic neurotransmitters were evaluated. Apomorphine, a dopamine (DA) agonist, and biperiden, an acetylcholine (ACh) antagonist, decreased acute dystonia, whereas alpha-methyl-p-tyrosine (AMPT), an inhibitor of DA synthesis, and physostigmine, an ACh agonist, agonist, increased the symptoms. Muscimol, a GABA agonist, increased the dystonias in a dose-dependent way, and GABA inhibition with picrotoxin also aggravated dystonia, complicated by systemic intoxication and seizures. The reciprocal interaction between DA and ACh influences is consistent with clinical findings and animal models of dyskinesias. Dystonia may also be modulated by GABAergic substrates, but the results suggest complex interactions among DA, ACh, and GABA neurotransmission. Symptoms involving the orofacial, limb, and trunk regions, and purposeless overactivity are discussed in comparison with acute and tardive neuroleptic-induced movement disorders.
 ...
PMID:Dopamine, acetylcholine, and GABA effects in acute dystonia in primates. 677 41

Apomorphine is a D1 and D2 dopamine receptor agonist with anti-parkinsonian properties qualitatively similar to those seen with L-dopa. It was first used in the treatment of Parkinson's disease by Schwab in the 1950s but owing to its short duration of action, the need for parenteral administration, and adverse reactions including nausea, vomiting, postural hypotension and sedation, it was not widely prescribed. In the early 1970s, Cotzias confirmed its potent anti-parkinsonian effects and that some of its secondary effects were diametrically opposite to those seen with L-dopa. The advent of peripheral dopamine receptor antagonist drugs, which counteract the unwanted effects of apomorphine, and the development of new drug delivery systems including insulin pens and ambulatory mini pumps have led to the resurrection of apomorphine for the treatment of Parkinson's disease. Over the last five years in Europe, the drug has proved to be a major advance in the treatment of refractory "on-off" oscillations in Parkinson's disease. It has also been used as a diagnostic test for dopaminergic responsiveness in Parkinson syndromes and tremors of uncertain aetiology. The drug has also proved particularly useful in dealing with certain "off-period" disabilities, including pain, bladder dysfunction, dystonia and gastro-intestinal symptoms. Continuous steady state infusion of apomorphine by mini-pump may reduce the severity of "on" phase dyskinesias over time. The drug has also proved useful in the clinical pharmacological investigation of the pathophysiology of the motor response to dopaminergic drugs in Parkinson's disease and the occurrence of involuntary movement sequences. Neuropsychiatric side-effects are relatively infrequent when compared with ergolene dopamine agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Dopamine agonists in Parkinson's disease: a look at apomorphine. 850 Jul 83

Twenty patients with idiopathic Parkinson's disease and disabling motor fluctuations were treated with intermittent subcutaneous (11 patients) or intranasal (nine patients) apomorphine for > 2 years. Apomorphine significantly reduced the mean daily "off" hours in both groups (p < 0.01) and improved "off" dystonia and end-of-dose and diphasic diskinesias. Unlike others authors, we found no difference between intranasal and subcutaneous' groups of treatment in the mean dose of apomorphine required to turn "on." Tolerance phenomenon to apomorphine could not be demonstrated in the follow-up period. Nasal crusting and vestibulitis observed in some patients treated intranasally were the more severe side effects and determined that some of them either switched to subcutaneous therapy or abandoned the treatment.
 ...
PMID:Long-term treatment with intermitent intranasal or subcutaneous apormorphine in patients with levodopa-related motor fluctuations. 919 48

Apomorphine, the first dopamine agonist to be synthesized, has received a renewed interest in the last few years. This compound acts powerfully on D1 and D2 dopamine receptors and has the most complete pharmacological profile of all clinically available dopamine agonists. When given subcutaneously, 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 approximately 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).
 ...
PMID:Clinical usefulness of apomorphine in movement disorders. 931 70

Prevention of levodopa-induced dyskinesias is a therapeutic challenge for physicians. At present, it seems only possible to delay dyskinesias and motor fluctuations. In younger patients (aged <50 years), the strategy is to use a dopamine D2 agonist as monotherapy and then to add levodopa treatment when the parkinsonian symptoms progress. In older patients, (aged >50 years to <70 years), the therapeutic approach is to use early combination therapy of levodopa and a D2 agonist. The treatment of levodopa-induced dyskinesias must be considered in regard to the subtype and the severity of dyskinesias, and the patient. The general approach to the treatment of peak dose dyskinesias is to maintain dopamine brain stimulation at as stable a level as possible by keeping plasma and brain levodopa concentrations in the therapeutic range (above the therapeutic threshold but below the dyskinesia threshold). An appropriate strategy is to reduce the individual dose of levodopa, to spread out the daily levodopa dose and/or to try treatment with the sustained-release form of the drug. Combination treatment with the standard and sustained-release levodopa formulations is also possible. Stopping selegiline (deprenyl) therapy may reduce dyskinesias; reducing the dose of, or stopping treatment with, a dopamine agonist may also be beneficial. Anti-dyskinetic drugs such as amantadine, buspirone, fluoxetine, propanolol and principally clozapine may be used. In severe dyskinesias, apomorphine infusion may be tried. In refractory dyskinesia, surgical procedures such as pallidotomy and chronic deep brain stimulation (globus pallidus/subthalamic nucleus) may be proposed. Theoretically, treatment of diphasic dyskinesias requires the maintenance of plasma levodopa concentrations above the dyskinesia threshold. However, this approach leads to constant and severe dyskinesia after only a few weeks of treatment. Thus, the strategy used to treat diphasic dyskinesia is close to the treatment of peak-dose dyskinesias. Apomorphine (or the liquid form of levodopa) may be helpful to prevent diphasic dyskinesias. In selected patients, a midday rest in the 'off' phase may decrease the duration of dyskinesia. Treatment of early morning dystonia is based on the addition to the regimen of the sustained release formulation of levodopa before bedtime. Liquid levodopa and apomorphine injection may be used just before the appearance of the dystonic posture. Botulinum toxin may be helpful in severe dystonia.
 ...
PMID:Treating and preventing levodopa-induced dyskinesias: current and future strategies. 1040 34

Dopa-responsive dystonia (DRD) is characterized by striatal dopamine depletion with preserved nigrostriatal terminals. Patients with DRD typically obtain a marked long-term benefit from low doses of levodopa, with no motor complications. By contrast, motor fluctuations and dyskinesias often occur in idiopathic parkinsonism (Parkinson's disease; PD). This suggests that nigrostriatal denervation may be necessary for the development of these levodopa-related motor complications. Six genetically confirmed DRD cases were studied. Three of the five patients who were on chronic levodopa therapy developed choreic dyskinesias, which disappeared on reduction of medication. Apomorphine also induced dyskinesias. In addition, two patients experienced acute dystonic reactions after exposure to dopamine receptor-blocking drugs. No patient showed dose-response motor flutuations during levodopa treatment. It is proposed that striatal dopamine deficiency might play a major role in the pathogenesis of drug-induced dyskinesias. Conversely, the loss of nigrostriatal dopamine terminals seems to be a prerequisite for the development of levodopa-related motor fluctuations.
 ...
PMID:Drug-induced motor complications in dopa-responsive dystonia: implications for the pathogenesis of dyskinesias and motor fluctuations. 1044 51

INTRODUCTION. Apomorphine is a D2 dopamine agonist, possibly underused despite its efficacy in situations where other medications have failed or lack of indication for stereotactic surgery. Rapidly effective (between 7 and 10 min) and potency approaching that of levodopa allows apomorphine to reduce reliably severe fluctuations, off period dystonia, biphasic dyskinesias or such symptoms as dysphagia, anismus of micturition difficulties. Unlike other agonists, apomorphine has a modest capacity to induce neuropsychiatric complications. Brief duration of response (<60 min) and the need of subcutaneous administration represent major difficulties in practice. OBJECTIVE and DEVELOPMENT. This review undertake some of the pharmacological properties of this orphan drug , its use in practice, and new pathways of development
 ...
PMID:[Use of apomorphine in Parkinson s disease]. 1238 55

Extensive published evidence supports the use of subcutaneously-administered apomorphine as an effective therapy for Parkinson's disease (PD) but to date no consensus recommendations have been available to guide healthcare professionals in the optimal application of apomorphine therapy in clinical practice. This document outlines best-practice recommendations for selecting appropriate candidates for apomorphine intermittent injection (the pen-injection formulation) or apomorphine continuous infusion (the pump formulation), for initiating patients onto therapy and for managing their ongoing treatment. Apomorphine is a suitable therapeutic option for PD patients who experience troublesome 'off' periods despite optimized treatment with oral PD medications. Due to its speed of onset, apomorphine injection is particularly suited to those patients requiring rapid, reliable relief of both unpredictable and predictable 'off' periods, those who require reliable and fast relief when anticipating an 'off', those with levodopa absorption or gastric emptying problems resulting in delayed or failed 'on', or for rapid relief of early morning dystonia or akinesia. Apomorphine infusion(1) is suited for patients whose 'off' periods can no longer be adequately controlled by standard oral PD treatment or for those in whom rescue doses of apomorphine injection are effective but either needed too frequently (more than 4-6 times per day), or are associated with increasing dyskinesia. In addition to treating motor fluctuations, there is evidence that apomorphine infusion may be effective for the management of specific non-motor symptoms of PD associated with 'off' periods. Apomorphine infusion is less invasive than other non-oral treatment options for advancing disease, intrajejunal levodopa infusion and deep-brain stimulation.
...
PMID:Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson's disease--Clinical practice recommendations. 2618 14


1