Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

threo-Dihydroxyphenylserine (DOPS) is a synthetic amino acid which can be decarboxylated by L-aromatic amino acid decarboxylase to yield natural form of norepinephrine (l-NE), a principal neurotransmitter in both central and peripheral (sympathetic) nervous systems. Like L-Dopa as an agent for dopamine precursor therapy, DOPS was expected to have a potential as an agent for NE precursor therapy. Previous studies carried out by several groups in early 1970s, however, reached a negative conclusion that threo-DOPS was not an effective precursor of NE in the brain because of its low NE-increasing activity and weak pharmacological action. Since the latter half of 1970s, on the contrary, three Japanese research groups have successfully shown the possibility of DOPS as a useful NE-precursor. That is, Tanaka (Kobe Univ.) showed that L-threo-DOPS is the real l-NE precursor among four DOPS-enantiomers, and that it has several pharmacological activities such as a slow-onset and long-lasting pressor effect, an inhibitory effect on harmaline-induced tremor and so on. Hayashi and Suzuki (Osaka Univ.) found through the mobility study on familial amyloid polyneuropatchy (FAP) that the progress of the disease develops NE-deficiency (NE-D), that severe orthostatic hypotention in FAP might be due to NE-D, and that L-DOPS has favorable effects on this symptom. Narabayashi (Juntendo Univ.) found that NE-D develops in patients with advanced Parkinson's disease (PD), that a freezing phenomenon in these patients might be associated with NE-D, and that L-DOPS improves the phenomenon. Based on these findings, the development of L-DOPS for registration had been undertaken by Sumitomo Pharmaceuticals Co., and an approval was given to it in 1989 as an agent for the treatment orthostatic hypotention in FAP or Shy-Drager syndrome and freezing phenomenon in PD. Preclinical and clinical studies done in the R&D confirmed that L-DOPS markedly restored NE-D and improved related-syndrome in the NE-deficient animals/patients, and that its actions were slow-onset, long-lasting and gentle. The R & D of L-DOPS described in this paper includes studies on industrial production, efficacy pharmacology (mode of action), metabolism and clinical trial of this agent.
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PMID:[Development of L-threo-DOPS, a norepinephrine precursor amino acid]. 785 46

We report a case of juvenile Parkinson's disease which initially presented as bulbar incoordination at the age 12. The condition was characterized by dystonia of the upper extremities. The patient was a 14-year-old female. The patient's main symptoms were bulbar dysfunction. Resting and action tremor, akinesia, stooped posture, distortion of the trunk, dystonia of the upper extremities, oculogyric crisis, and impairment of the postural reflex were seen. The bulbar symptoms were considered to be attributable to circumoral uncoordination. Although L-dopa decarboxylase inhibitors were markedly effective in alleviating these symptoms, an adverse reaction due to the agent was observed as the form of oral dyskinesia. Since the changes in blood concentration of L-dopa after administration of the agent was clearly reflected in the surface electromyogram, we concluded that this diagnostic procedure is useful in evaluating the therapeutic efficacy of L-dopa.
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PMID:[Juvenile Parkinson's disease initially presenting as bulbar incoordination: a case report]. 818 82

We present a 71 year old woman with predominantly right sided parkinsonism of sudden onset, but without tremor. Magnetic resonance imaging (MRI) depicted lesions affecting the substantia nigra (SN) bilaterally, but more pronounced on the left side. There were no other discernible structural lesions. Using positron emission tomography (PET), we investigated regional cerebral metabolic rate of glucose (rCMRG) using the tracer [18F]-fluorodeoxyglucose (FDG), and striatal dopa decarboxylase capacity using the tracer [18F]-L-6-fluorodopa (FDOPA). The degree and pattern of distribution of FDOPA uptake reductions (putamen > caudate nuclei) were similar to those in idiopathic Parkinson's disease (PD). FDG uptake also revealed similar changes (reductions in frontal cortex and cerebellum, but increases in thalamus), except for putamen which showed reduced rCMRG. In conclusion, the absence of tremor at rest accords with experimental SN lesions. The PET findings in this atypical condition are explained in terms of deafferentation of various brain regions involved in motor control. Furthermore, they illustrate the metabolic effects related to acute focal lesions of the SN as opposed to the progressive degeneration in idiopathic PD and may serve to help unravel the complicated pathophysiology underlying these conditions.
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PMID:Secondary parkinsonism due to focal substantia nigra lesions: a PET study with [18F]FDG and [18F]fluorodopa. 883 98

Tremor, akinesia, rigidity and postual instability are key signs of Parkinson's disease. The most important one is akinesia, which includes decreased spontaneous locomotor activity, slowness of movement, awkwardness and freezing. On the other hand, an electrical focal lesion in the brain, neurotoxin to dopaminergic neurons such as 6-hydroxydopamine (6-OHDA) or I-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), cholinomimetic tremorogenic agents such as oxotremorine or tremorine, monoamine depleting agents such as reserpine or tetrabenazine, or dopamine receptor antagonists such as haloperidol are applied to render animal parkinsonism. The estimation of locomotor activity can be done accurately in animal models. Tremor can be studied using the animals treated by cerebral focal lesion, neurotoxins or cholinomimetics. Skillfulness is hard to estimate in animals, however, it can be done in primates. Freezing appeared in patients with levodopa treatment over a long period. This is a specific motor sign in Parkinson's disease, and cannot be observed in animals. Supplementing dopamine by levodopa administration, retarding the metabolism of levodopa or dopamine by dopa decarboxylase inhibitor (DCI), monoamine oxidase inhibitor type B (MAO-B) inhibitor or catechol-O-methyltransferase (COMT) inhibitor, dopamine receptor agonists, anticholinergic agents, dopamine release enhancer/ uptake inhibitor, N-methyl-D-aspartate (NMDA) receptor antagonists, adenosine receptor antagonists, neurotrophic factors, GM1-ganglioside and nicotinic receptor agonists have been applied in the treatment of Parkinson's disease or are under investigation for patients. Agents to facilitate nerve growth or to inhibit the degeneration of nerves will be developed in the future.
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PMID:[Recent progress in development of psychotropic drugs (3)--Antiparkinsonian agents applied in the treatment of Parkinson's disease or are under investigation for patients or model animals]. 890

Postural instability and gait disorders (PIGD) are the primary causes of disability in many but not all advanced Parkinson's disease (PD) patients. We have measured the concentrations of serotonin, 5-hydroxytryptophan (5-HTP), 5-hydroxy-3-indoleacetic acid (5-HIAA), and homovanillic acid (HVA) in samples of ventricular cerebrospinal fluid from ten PD patients with severe disability from PIGD and from ten PD patients with tremor and levodopa induced dyskinesia as their predominant motor dysfunction. The two groups were prospectively matched for duration of disease and age. No significant differences between the two groups were found in the concentration (mean +/- SD in ng/ml, PIGD dominant vs. tremor-dyskinesia dominant) of 5-HIAA (106 +/- 50 vs. 99 +/- 34) or HVA (1,068 +/- 595 vs. 881 +/- 469). Serotonin concentration was significantly lower (0.7 +/- 0.5 vs. 1.5 +/- 0.9) and 5-HTP concentration was substantially higher (684 +/- 1,054 vs. 6 +/- 5) in the patient group with PIGD as their predominant symptoms. Thus, the distinguishing feature of patients with severe PIGD appears to be a derangement in indoleamine metabolism at the reaction step catalyzed by aromatic amino acid decarboxylase (AADC). These findings suggest that aggravation of PIGD in advanced Parkinson's may be related in part to impaired serotonergic transmission secondary to inhibition or down regulation of AADC.
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PMID:Concentrations of indoleamine metabolic intermediates in the ventricular cerebrospinal fluid of advanced Parkinson's patients with severe postural instability and gait disorders. 929 77

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

Antiparkinsonian agents applied or under the investigation for the treatment of patients with Parkinson's disease were reviewed. Tremor, akinesia, rigidity and postual instability are key signs of Parkinson's disease. The most important one is akinesia, which includes decreased spontaneous locomotor activity, slowness of movement, awkwardness and freezing. The main pathophysiology of Parkinson's disease is neurodegeneration of nigrostriatal dopaminergic neurons. Neurotoxins or oxidative stress to the dopaminergic neurons have been discussed as one of the etiologies of degeneration. Antioxidant or neuroprotective agents will be the future drugs for Parkinson's disease. At present, supplement of dopamine by levodopa administration, retarding the metabolism of levodopa or dopamine by a dopa decarboxylase inhibitor (DCI), MAO-B (monoamine oxidase inhibitor type B) inhibitor or catechol-O-methyltransferase (COMT) inhibitor, dopamine receptor agonists, anticholinergic agents, dopamine release enhancer/uptake inhibitor, N-methyl-D-aspartate (NMDA) receptor antagonists are applied for the treatment of Parkinson's disease. New agents such as adenosine receptor antagonists, serotonergic agents and nicotinic receptor agonists are under investigation. Agents to facilitate the growth of nerves or to inhibit degeneration of nerves are also studied and will be developed for the treatment of Parkinson's disease in the future. In the case of familial Parkinson's disease, abnormal genes were identified. Gene therapy might be another future treatment for these cases.
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PMID:[Pharmacological treatments of Parkinson's disease]. 1123 2

Parkinson's disease is a disorder of the extrapyramidal system resulting from the deficiency of dopamine in the basal ganglia. We experienced the perioperative management of a patient with Parkinson's disease with intravenous infusion of levodopa, precursor of which is dopamine. A 73-year-old woman with Parkinson's tremor in her bilateral fingers of Hoehn and Yahr stage II was scheduled for repair of bladder prolapse under general anesthesia. Antiparkinson drug levodopa/dopa decarboxylase inhibitor (carbidopa) 400 mg per day had been administered orally to control her bilateral tremor. Three hours before the operation, oral medication including levodopa/carbidopa 100 mg was withdrawn, and intravenous infusion of levodopa 100mg was started. Without any premedication, anesthesia was induced with intravenous infusion of propofol, fentanyl, and vecuronium, and tracheal intubation was facilitated. Anesthesia was maintained with inhalation of air, oxygen, and sevoflurane, and intravenous infusion of fentanyl. After emergence, we found no neurological disorders excluding her tremor. Levodopa/carbidopa 100 mg was readministered orally four hours after the operation and total of 300 mg had been administered orally on the operative day. Levodopa/carbidopa 400 mg per day had been administered orally after the first operative day. She did not show deterioration of her symptom of Parkinson's disease, and develop any complications during the perioperative period. We need to manage Parkinson's disease with intravenous infusion of levodopa during the perioperative period, taking care of the symptom of Parkinson's disease and the occurrence of complications.
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PMID:[Perioperative management of a patient with Parkinson's disease with intravenous infusion of levodopa]. 1986 Feb 35

Parkinson disease (PD) is a progressive movement disorder marked by tremor, rigidity, bradykinesia and postural instability. Levodopa (l-dopa), usually combined with a peripheral dopa decarboxylase inhibitor, has been proved to provide the best symptomatic benefit for PD. However, its long-term efficacy is limited because of motor complications and drug-induced dyskinesia. Dopamine agonists, catechol-O-methyltransferase inhibitors and monoamine oxidase-B inhibitors are anti-parkinsonian (anti-PD) drugs that have been found to further improve the potency of l-dopa and prevent the onset of motor complications. However, as PD is a progressive disorder, all the drugs used for its therapy, manifest reduced efficacy and adverse effects with time. Research on the field of pharmacogenetics has pointed out that the genetic variability of each individual determines to a large extent the inter-individual variability in response to anti-PD drugs. Clinicogenetic trials show that drug efficacy or toxicity or susceptibility to side effects are features governed by genetic principles. This article is a review of the present pharmacological treatment of PD and current pharmacogenetic data for PD.
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PMID:Pharmacological treatment and the prospect of pharmacogenetics in Parkinson's disease. 2209 36

Dopa decarboxylase (DDC) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that by catalyzing the decarboxylation of L-Dopa and L-5-hydroxytryptophan produces the neurotransmitters dopamine and serotonin. The functional properties of pig kidney and human DDC enzymes have been extensively characterized, and the crystal structure of the enzyme in the holo- and apo-forms has been elucidated. DDC is a clinically relevant enzyme since it is involved in Parkinson's disease (PD) and in aromatic amino acid decarboxylase (AADC) deficiency. PD, a chronic progressive neurological disorder characterized by tremor, bradykinesia, rigidity and postural instability, results from the degeneration of dopamine-producing cells in the substantia nigra of the brain. On the other hand, AADC deficiency is a rare debilitating recessive genetic disorder due to mutations in AADC gene leading to the inability to synthesize dopamine and serotonin. Development delay, abnormal movements, oculogyric crises and vegetative symptoms characterize this severe neurometabolic disease. This article is an up to date review of the therapies currently used in the treatment of PD and AADC deficiency as well as of the recent findings that, on one hand provide precious guidelines for the drug development process necessary to PD therapy, and, on the other, suggest an aimed therapeutic approach based on the elucidation of the molecular defects of each variant associated with AADC deficiency.
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PMID:Biochemical and computational approaches to improve the clinical treatment of dopa decarboxylase-related diseases: an overview. 2326 32


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