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)

Dopamine replacement therapy in patients with Parkinson's disease is plagued by the emergence of abnormal involuntary movements known as L-dopa-induced dyskinesias. It has been demonstrated that yohimbine can reduce L-dopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Yohimbine is, among other things, an alpha-adrenergic receptor antagonist. In this study, we demonstrate that the selective and potent alpha2-adrenergic receptor antagonist idazoxan reduces L-dopa-induced dyskinesia in the MPTP-lesioned marmoset model of Parkinson's disease. The alpha2-adrenergic receptor antagonists rauwolscine and yohimbine also reduce L-dopa-induced dyskinesia. Furthermore, we demonstrate that coadministration of idazoxan with L-dopa can provide an anti-parkinsonian action more than twice the length of that seen with L-dopa alone. However, idazoxan as a monotherapy displayed no anti-parkinsonian actions. We propose that idazoxan in combination with L-dopa may provide a novel approach to the treatment of Parkinson's disease that will not only reduce the dyskinetic side effects, but extend the anti-parkinsonian actions of L-dopa. Idazoxan, as an adjunct to dopamine replacement, may prove useful in the treatment of parkinsonian patients at all stages of disease progression.
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PMID:The alpha2-adrenergic receptor antagonist idazoxan reduces dyskinesia and enhances anti-parkinsonian actions of L-dopa in the MPTP-lesioned primate model of Parkinson's disease. 1049 35

Rats with unilateral dopamine-denervating lesions sustained a 3-week treatment with a daily l-DOPA dose that is in the therapeutic range for Parkinson's disease. In most of the treated animals, chronic l-DOPA administration gradually induced abnormal involuntary movements affecting cranial, trunk, and limb muscles on the side of the body contralateral to the lesion. This effect was paralleled by an induction of FosB-like immunoreactive proteins in striatal subregions somatotopically related to the types of movements that had been elicited by l-DOPA. The induced proteins showed both regional and cellular colocalization with prodynorphin mRNA. Intrastriatal infusion of fosB antisense inhibited the development of dyskinetic movements that were related to the striatal subregion targeted and produced a local specific downregulation of prodynorphin mRNA. These data provide compelling evidence of a causal role for striatal fosB induction in the development of l-DOPA-induced dyskinesia in the rat and of a positive regulation of prodynorphin gene expression by FosB-related transcription factors.
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PMID:Striatal fosB expression is causally linked with l-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson's disease. 1060 Apr 2

We report a 73-year-old Japanese woman with familial Parkinson's disease. The patient was well until her 67 years of the age, when she noted rest tremor in her right hand. Soon after her gait became short stepped. She visited our clinic on October 6, 1992 when she was 68 years old. She was alert and well oriented without dementia. She showed masked face, small voice, small stepped gait, retropulsion, resting tremor in her right hand, rigidity in the neck, and bradykinesia. She was treated with 400 mg/day of levodopa-carbidopa, which improved her symptoms, however, she developed wearing off phenomenon 3 years after the initiation of levodopa treatment. On August 26, 1998, she developed abdominal pain, diarrhea, and vomiting. She was admitted to another hospital, where abdominal plain x-ray revealed an evidence of intestinal obstruction (ileus). She was treated with nasogastric suction and intravenous fluid. Her condition did not improve and she was transferred to our hospital on August 29, 1998. Her family history revealed no consanguineous marriage. She had two elder brothers and three elder sisters. One of her brothers had been diagnosed as Parkinson's disease. Her husband also suffered from Parkinson's disease, however, her parents apparently did not have Parkinson's disease. On admission, she appeared to be drowsy. Her blood pressure was 102/70 mmHg, body temperature 36.2 degrees C. The lungs were clear and no cardiac murmur was present. Abdomen was flat and bowel sound was audible. No abnormal mass was palpable. Neurologic examination revealed mild consciousness disturbance, masked face, and small voice. No motor paralysis was noted. Muscle tone was hypotonic. No abnormal involuntary movement was noted. Abnormal laboratory findings on admission were as follows; WBC 11,300/microliter, amylase 1,373 IU/l, CK 446 IU/l, BUN 50 mg/dl, creatinine 1.17 mg/dl, CRP 22.7 mg/ dl, Na 134 mEq/l, K 3.1 mEq/l, and Cl 81 mEq/l. A chest x-ray film revealed pneumonic shadows in both lower lung fields. She was treated by nasointestinal suction, intravenous fluids, and chemotherapy for her infection. Her BP started to drop on September 2 and she developed cardiac arrest on the same day. She was discussed in a neurological CPC. The chief discussant arrived at the conclusion that the patient had a form of autosomal dominant familial Parkinson's disease. As parents did not have Parkinson's disease, some of the participants raised the possibility of autosomal recessive inheritance. But the age of onset was too late for autosomal recessive inheritance. Majority thought that the mode of inheritance was autosomal dominant with low penetrance. alpha-Synuclein mutation causes an autosomal dominant familial Parkinson's disease, but this type is very rare in non-Greek populations and the penetrance is high. Chromosome 2-linked autosomal dominant familial Parkinson's disease shows low penetrance. There are many other autosomal dominant forms of familial Parkinson's disease linked to yet unknown chromosome loci. Majority thought that this patient also had a form of Lewy-body positive autosomal dominant familial Parkinson's disease of unknown chromosome locus. Post mortem examination revealed ischemic intestinal lesion with strangulation. This was thought to be the cause of her death. In the central nervous system, the brain appeared to be normal by inspection. In the coronal sections, the substantia nigra and the locus coeruleus showed marked depigmentation. Histologic examination revealed marked neuronal loss and Lewy body formation in the remaining neurons. Pathologic examination was consistent with Parkinson's disease. Mutational analysis for the parkin gene was negative.
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PMID:[A 73-year-old woman with familial Parkinson's disease]. 1065 9

Motor fluctuations and abnormal involuntary movements are common complications encountered in advanced Parkinson's disease (PD) patients with long-term levodopa therapy. Monitoring of plasma levodopa concentrations and clinical effects has been reported to benefit the management of these complications. However, to our knowledge, there is no data available in Taiwan concerning the correlation between the plasma levodopa levels and motor fluctuations. In this study, we developed the laboratory methodology for plasma levodopa determination by using the aluminum extraction procedure and HPLC-ED. Serial blood samples and motor scores were obtained from 7 PD patients, and the correlation between plasma levodopa levels and motor responses were studied individually. In three patients with wearing-off phenomenon, plasma levodopa concentrations are compatible with the clinical "on" and "off" states. In the other four patients with complex fluctuating responses, their levodopa dosages were adjusted by the results of monitoring. Better motor responses were achieved by optimization of the levodopa pharmacokinetics in these patients. Our preliminary data suggest that simultaneous monitoring of plasma levodopa concentrations and clinical effects might be helpful to improve the therapeutic strategy in some of the parkinsonian patients with fluctuating responses to levodopa.
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PMID:Monitoring of the levodopa concentration-response relationship in Parkinson's disease. 1084 47

Dyskinesias are abnormal involuntary movements which develop as a side-effect of long-term treatment with levodopa in patients with Parkinson's disease. The pathophysiology underlying these dyskinesias remains unclear, although, it has been suggested that heightened activity of dopamine D(1) receptor-bearing striatonigral neurons may play a key role. Chronic pulsatile levodopa administration to hemiparkinsonian rats results in sensitization of rotational responses to apomorphine. This sensitization is thought to be analogous to levodopa-induced dyskinesias in humans. In these studies, we further clarify the role of the dopamine D(1A) receptor in this rodent model of levodopa-induced dyskinesias using an in vivo oligonucleotide antisense approach. Hemiparkinsonian rats received twice daily injections of levodopa for three weeks followed by intrastriatal infusion of dopamine D(1A) receptor antisense (7nmol/day, three days), a scrambled missense control sequence, or saline. Those animals treated with antisense displayed significantly fewer apomorphine-induced rotations than saline- or missense-treated controls.By reducing dopamine D(1A) receptor expression, we were able to attenuate sensitization of the response to apomorphine resulting from chronic pulsatile levodopa treatment. Thus, the dopamine D(1A) receptor appears to play a significant role in levodopa-induced dyskinesias and warrants further examination. These findings may have important implications for the development of selective treatment strategies designed to alleviate parkinsonian symptoms, while minimizing motor complications.
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PMID:Effects of oligonucleotide antisense to dopamine D(1A) receptor messenger RNA in a rodent model of levodopa-induced dyskinesia. 1085 12

We investigated the role of dopamine neurons in the manifestation of levodopa-induced dyskinesia in a rat model of Parkinson's disease. Daily treatment with a subthreshold dose of levodopa gradually induced abnormal involuntary movements (AIM) in 6-hydroxydopamine-lesioned rats, which included stereotypy and contraversive rotation. After 4 weeks of levodopa treatment, rats with mild and severe AIM were assigned to two treatment subgroups. The graft subgroup received embryonic ventral mesencephalic tissue into the striatum, whilst the sham-graft subgroup received vehicle only. Rats continued to receive levodopa treatment for 3 months post-graft. Brain sections at the level of the basal ganglia were processed for autoradiography using a ligand for dopamine transporter, and in situ hybridization histochemistry for mRNAs encoding postsynaptic markers. Levodopa-induced AIM significantly improved in grafted rats. The severity of AIM correlated inversely with the density of dopamine nerve terminals in the striatum (P < 0. 001), with almost no AIM when the density of dopamine nerve terminals was >10-20% of normal. Embryonic dopamine neuronal grafts normalized not only mRNA expression for preproenkephalin (PPE) in the indirect pathway, but also mRNA expression for prodynorphin (PDyn) in the direct pathway, which was upregulated by levodopa treatment. AIM scores correlated linearly with expression of PPE mRNA in the indirect pathway (P < 0.001) and also with PDyn mRNA in the direct pathway (P < 0.001). We conclude that embryonic dopamine neuronal grafts may improve levodopa-induced dyskinesia by restoring altered activities of postsynaptic neurons, resulting not only from dopamine denervation, but also from levodopa therapy, provided that the density of striatal dopaminergic nerve terminals is restored above a 'threshold' level.
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PMID:Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson's disease. 1086 49

Models of basal ganglia function are described which encapsulate the principal pathophysiological mechanisms underlying parkinsonian akinesia on the one hand and abnormal involuntary movement disorders (dyskinesias) on the other. In Parkinson's disease, degeneration of the nigrostriatal dopamine system leads to overactivity of the 'indirect' striatopallidal projection to the lateral (external) segment of the globus pallidus. This causes inhibition of lateral pallidal neurons, which in turn project to the subthalamic nucleus. Disinhibition of the subthalamic nucleus leads to abnormal subthalamic overactivity and, as a consequence, overactivity of medial (internal) pallidal output neurons. Dyskinesias, such as are observed in Huntington's disease, levodopa-induced dyskinesia and ballism, share mechanistic features in common and are associated with decreased neuronal activity in both the subthalamic nucleus and the medial globus pallidus.
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PMID:Functional anatomy of movement disorders. 1092 84

GAIT ARRESTS: They affect the evolution of the disease. This freezing phenomenon which induces falls sometimes constitutes an initial sign. Like the gait initiation failure, freezing can be controlled by sensory stimulation, notably visual inputs, but also by more sustained attention. FALLS ARE MAINLY CONNECTED WITH BOTH POSTURAL INSTABILITY AND RIGIDITY: They are poorly influenced by dopaminergic therapies. The progressive decrease of step width represents a main factor in their occurrence. PRECOCITY OF GAIT DISORDERS IS UNUSUAL IN PARKINSON'S DISEASE: Other parkinsonian syndromes such as progressive supranuclear palsy, multiple system atrophy and vascular parkinsonian syndrome must then be evoked. Their association with a cognitive impairment and abnormal sphincter behaviour infers a diagnosis of normal pressure hydrocephalus. GAIT IMPROVES WITH L-DOPA THERAPY: Speed, step length and duration of the swing phase are increased without change of cadence. Progressive loss of L-dopa efficiency on gait and postural stability contrasts with the persistent effect on tremor, rigidity and bradykinesia; a functional abnormality of nondopaminergic systems can explain these symptoms. In the following stages, gait troubles increased by motor fluctuations and abnormal involuntary movements are less controlled by L-dopa therapy. PHYSICAL THERAPY PLAYS A MAJOR ROLE IN THERAPEUTIC MANAGEMENT: An individual or collective rehabilitation project must be established according to the stage of evolution; the exercises aim to protect postural control and coordination. Visual or sound rhythmic inputs can be employed in the case of gait initiation failure. THE EFFECTS OF FUNCTIONAL NEUROSURGERY ARE IN THE COURSE OF EVALUATION: Thermolesion and chronic electrical stimulation of deep brain structures have opposite effects on gait troubles. Bilateral thalamotomy or pallidotomy are sometimes a source of disequilibrium. Chronic thalamic stimulation does not induce either benefits or adverse effects. On the other hand, stimulation of the internal pallidum improves gait kinematic parameters; improved postural adjustments have also been reported. The effect of subthalamic nucleus stimulation is comparable to that of L-dopa, however the long-term effect remains to be evaluated.
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PMID:[Gait disorders in Parkinson disease. Gait freezing and falls: therapeutic management]. 1128 86

We report the safety results in nine patients with advanced idiopathic Parkinson's disease (PD) who underwent ablative surgery of unilateral subthalamic nucleus (STN). In eight patients, surgical objectives were attained without induction of abnormal involuntary movements or other adverse effects. One patient developed transient hemiballistic movements which improved within 2 weeks after surgery. Assessment at 2 weeks to 20 months postoperatively revealed no long-term adverse effects. We conclude that hemiballism following unilateral ablation of STN in patients with PD is a rare phenomenon, and unilateral ablative lesions of STN can be performed safely.
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PMID:Do unilateral ablative lesions of the subthalamic nucleu in parkinsonian patients lead to hemiballism? 1221 Aug 95

Idiopathic Parkinson's disease (PD) is a common chronic progressive neuro-degenerative disorder associated with the progressive loss of dopaminergic neurons in the substantia nigra. The natural course of the disease may lead to severe disability despite a variety of pharmacological and surgical treatment options. Levodopa is still the most effective symptomatic treatment for PD; however, long term use can cause a number of adverse effects including motor complications, nausea and vomiting, postural hypotension and changes in mental status. The onset of motor complications marks a crucial point in the management of PD. They may present as changes between akinetic and mobile phases (motor fluctuations) or as abnormal involuntary movements (dyskinesias). After levodopa treatment for 3 to 5 years, motor complications occur in approximately 50% of patients, and after 10 years in >80% of patients. Treatment options have recently expanded as new drugs have been licensed and surgical procedures refined. Patients with motor complications present a demanding task in disease management, and often multiple drugs and high dosages are necessary to achieve only suboptimal control, resulting in increased healthcare utilisation. Costs increase considerably in patients with motor fluctuations and dyskinesias compared with patients without these symptoms. In a French study, 6-month direct medical costs per patient increased from 1648 euros (EUR) to EUR3028 in patients without and with motor fluctuations, respectively. In a recent French study a significant difference in monthly direct medical costs was found in patients with and without dyskinesias (EUR560 vs 170). Unfortunately, no data are available on the effect of motor complications on indirect costs. Several studies have shown that health-related quality of life (HR-QOL) is reduced when motor fluctuations occur. This may also be true of dyskinesias, but because of the limited number of studies a definite conclusion is not yet possible. Recently, surgical treatment options have been used to deal with advanced PD and late stage complications. Although their effect on motor complications and HR-QOL is well documented, they result in increased costs (total medical cost: EUR28920) compared with drug treatment alone and are increasingly restricted by healthcare providers. The purpose of this article is to review the available data from pharmacotherapeutic. surgical and economic studies on HR-QOL and healthcare expenditure in patients with PD, with a major focus on the impact of motor fluctuations and dyskinesias.
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PMID:Health-related quality of life and healthcare utilisation in patients with Parkinson's disease: impact of motor fluctuations and dyskinesias. 1173 71


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