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)

Thirteen patients with idiopathic Parkinson's disease and "on-off" fluctuations on oral levodopa plus dopa decarboxylase inhibitor (DDI) were treated with continuous (24 hour) subcutaneous lisuride infusions together with a reduced dose of levodopa (plus DDI). An improvement in motor performance was seen in 10 patients, with a mean increase in percentage of waking time spent "on" of 32 per cent (range 13-59 percent). However, adverse effects were common, especially psychiatric effects, leading to treatment withdrawal in 11 of 13 subjects after a mean of 40 days' treatment. Continuous lisuride infusion together with a small dose of levodopa (plus DDI) are effective treatment for "on-off" fluctuations in Parkinson's disease, but the frequency of adverse effects limits the number of patients who can be treated successfully with this technique.
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PMID:Continuous subcutaneous lisuride infusions in Parkinson's disease. 296 53

We investigated the effect of systemic administration of gamma-glutamyl L-3,4-dihydroxyphenylalanine (gamma-Glu-DOPA) on catecholamine contents in the brain. gamma-Glu-DOPA was transformed to dopamine (DA) in vitro with brain homogenate by the sequential action of gamma-glutamyl transpeptidase and aromatic L-amino acid decarboxylase. Intraperitoneal injection of gamma-Glu-DOPA to mice increased DA markedly and noradrenaline (NA) moderately in the brain. The increase of endogenous DA was followed by elevation of the main DA metabolites (3,4-dihydroxyphenyl-acetic acid and homovanillic acid). These increases were in a dose-dependent manner. The maximal elevation of DA was observed within 30 min after administration of gamma-Glu-DOPA, but a substantial increase of NA was observed 2 h after the administration. These results suggest that gamma-Glu-DOPA may be applicable to the treatment of Parkinson's disease.
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PMID:Increase of catecholamines in mouse brain by systemic administration of gamma-glutamyl L-3,4-dihydroxyphenylalanine. 311 8

The combinations of benserazide and levodopa (1:4, Madopar) and of carbidopa and levodopa (1:10 and 1:4, Sinemet) are currently the most effective treatment of Parkinson's disease. In the present comparative study some effects of the peripheral aromatic L-amino acid decarboxylase (AADC) inhibitors benserazide and carbidopa administered alone or in combination with levodopa by the oral route were investigated in two animal species (rat and mouse) and in healthy volunteers. Benserazide is about 10 times more potent than carbidopa as inhibitor of peripheral AADC both in animals and man. Even at relatively high doses (up to 60 mumol/kg p.o.) benserazide is shown in animals to inhibit the decarboxylation of levodopa only in the extracerebral tissues, thus permitting the formation of dopamine in the striatum and in the hypothalamus. As benserazide is the most potent peripheral AADC inhibitor presently available, is well tolerated and relatively nontoxic even when used chronically, it appears to be the peripheral AADC inhibitor of choice for the development of controlled-release formulations in which Dopa is combined with a peripheral AADC inhibitor. When administered to healthy subjects the pharmacokinetics of the new drug delivery system named Madopar HBS (hydrodynamically balanced system) was characterized by lower and delayed plasma peak concentrations but a longer-lasting concentration of Dopa than after Madopar standard. Therefore, this new controlled-release system may reduce the clinical fluctuations occurring in patients with 'wearing-off' and 'on-off' phenomena.
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PMID:Inhibition of decarboxylase and levels of dopa and 3-O-methyldopa: a comparative study of benserazide versus carbidopa in rodents and of Madopar standard versus Madopar HBS in volunteers. 312 42

DL-threo-3,4-Dihydroxyphenylserine (DOPS) is increasingly being investigated for treatment of disorders involving defects of the sympathetic nervous system, such as Parkinson's disease, Shy-Drager syndrome and congenital dopamine-beta-hydroxylase deficiency. Whilst L-DOPS is converted by aromatic L-amino acid decarboxylase into natural norepinephrine in vitro, D-DOPS inhibits this process. There are no data on the interaction between D- and L-DOPS in vivo because a reliable method for the measurement of the D- and L-enantiomers in plasma and urine is lacking. We describe here such a method based on reversed-phase chromatography after derivatization with o-phthaldialdehyde and N-acetyl-L-cysteine. Good separation was achieved with this procedure (resolution factor 2.33). Two simple and sensitive methods are also presented for total D,L-DOPS estimation, based on reversed-phase chromatography with electrochemical detection after either deproteinization (DP) or liquid-liquid extraction (LE) as sample preparation steps. The two methods gave identical results (regression line DOPS (DP) = 1.026 DOPS (LE) + 33.28; r = 0.997; n = 52). Excellent agreement was found between the sum of the D- and L-DOPS concentrations and the measured total D,L-DOPS concentration (regression line DOPS (D + L) = 0.955 DOPS (total, LE) + 116.65; r = 0.992; n = 100).
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PMID:Determination of D,L-threo-3,4-dihydroxyphenylserine and of the D- and L-enantiomers in human plasma and urine. 313 37

1. Selective inhibitors of the monoamine oxidase (MAO) isoenzymes, types A and B, are of potential therapeutic utility. Brain selectivity would overcome the risk of tyramine interactions which have been shown to occur with selective MAO-A but not MAO-B inhibitors. 2. (E)-3-Fluoroallylamines of general structure, FHC = C(R)CH2NH2 have been designed as enzyme-activated, irreversible inhibitors of these enzymes. Two compounds, MDL 72145 (R = 3,4 dimethoxyphenyl) and MDL 72974 (R = 4-fluorophenethyl), are selective and irreversible inhibitors of MAO type B which in vivo show high inhibitory potency against the rat brain enzyme (ED50 0.35 and 0.18 mg/kg p.o., respectively). In animals, these inhibitors do not potentiate the cardiovascular effects of tyramine and have no amphetamine-like effects. However, they do potentiate the central effects of L-Dopa and prevent the neurotoxic effects of MPTP in both mice and monkeys. 3. In early clinical studies, MDL 72145 has been shown to be a potent, long-acting inhibitor of MAO type B. Doses of 16 mg per patient totally inhibit platelet enzyme without potentiating the cardiovascular effects of oral tyramine. Compounds of this type should prove useful in Parkinson's disease. 4. Selective inhibition of brain MAO-A can be achieved by using the bioprecursor amino acid MDL 72394 (E-beta-fluoromethylene-m-tyrosine). This amino acid is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to liberate MDL 72392 (R = 3-hydroxyphenyl), a potent irreversible inhibitor of MAO-A. Combination of MDL 72394 with a peripherally selective inhibitor of AADC (e.g., carbidopa) restricts MAO inhibition to the brain. Consequently, under these conditions, there is a greatly reduced propensity to potentiate the cardiovascular effects of tyramine. 5. This has been confirmed in human volunteers; MDL 72394 (8 mg), combined with carbidopa, substantially decreased urinary MHPG and plasma DHPG concentrations with minimal potentiation of the cardiovascular effects of i.v. tyramine. These results predict that such therapy has potential in the treatment of affective disorders.
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PMID:Design and early clinical evaluation of selective inhibitors of monoamine oxidase. 326 32

Loss of efficacy and response fluctuations develop in many patients with Parkinson's disease after long-term levodopa therapy. This may be due in part to near-total degeneration of the surviving nigrostriatal dopaminergic neurons during disease progression, with massive decreases in the capacity of the striatum to form and store dopamine from exogenous levodopa. It was recently suggested that intracerebral grafting of fetal nigral or adrenal chromaffin cells may be beneficial in advanced Parkinson's disease by reestablishing spontaneous dopaminergic neurotransmission or by secretion of trophic factors that promote sprouting of residual dopaminergic nerve-terminals. It is now hypothesized that intrastriatal transplantation of such cellular elements that contain the enzyme dopa decarboxylase and dopamine storage sites may significantly increase synthesis, storage, and release of dopamine from exogenous levodopa. It may therefore reverse loss of responsiveness and restore the initial smooth and stable beneficial effect of levodopa therapy.
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PMID:Brain grafting may reverse loss of responsiveness to levodopa therapy in Parkinson's disease. 328 Jan 29

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been reported to cause chronic Parkinsonism in humans, primates, and long lasting striatal dopamine depletion in mice. Acute animal models thus produced closely resemble Parkinson's disease. There are, however, two major differences. The one is a lack of Lewy bodies and the other is that norepinephrine system is relatively well preserved in the model. So the acute animal model is better considered a nigrostriatal dopamine deficiency model. We have produced another model by adding N-2-chloroethyl-N-ethyl-2-bromobenzyl-amine (DSP4) to MPTP. This material is known to produce selective destruction of norepinephrine terminal in the central nervous system as well as in the periphery. Both norepinephrine system and dopamine system are severely depressed in this model, and the functional role of norepinephrine system was investigated by comparing two models. 90 male C57 black mice weighing 20-25 grams were used. MPTP (Aldrich) was dissolved in sterile distilled water with 5% ethanol solution. Experimental animals were divided into three groups. i) control group; in this group animals received vehicles alone. ii) MPTP group; in this group, mice received daily i.p. doses of MPTP 30 mg/kg for consecutive 10 days, thus total doses of MPTP was 300 mg/kg. iii) MPTP & DSP4 group; in this group animals received daily i.p. doses of MPTP 30 mg/kg for consecutive 10 days and at the last day of MPTP injection they received DSP4 50 mg/kg i.p.. 7 to 14 days after the last injection of MPTP both treated and control mice received an intraperitoneal injection of L-DOPA (200 mg/kg & aromatic L-amino acid decarboxylase mg/kg) and the effect of this drug on three groups were investigated by using behavioral, biochemical and histofluorescence method. Histofluorescence studies by GA-FAS method revealed severe reduction of nigrostriatal dopamine in MPTP treated mice. Mesolimbic and mesocortical dopamine systems seemed relatively preserved. There was no apparent changes in locus coeruleus norepinephrine system. In MPTP & DSP4 treated mice marked reduction of norepinephrine terminal fluorescence as well as nigrostriatal dopamine system was observed. Chemical analysis of norepinephrine and dopamine by HPLC confirmed histofluorescence studies. Behavioral studies were analyzed by Automex locomotor activity meter. Marked increase of locomotor activity was observed in MPTP treated mice after L-DOPA administration.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[A mouse model of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced parkinsonism: effect of norepinephrine terminal destruction]. 331 16

Rats with unilateral 6-hydroxydopamine lesions of the substantia nigra (SN) were challenged with L-DOPA (25 mg/kg, i.p.). One hour later, during the peak of rotational behavior, the animals were killed and the striatum and the SN were dissected and assayed for dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) content. While L-DOPA treatment elevated DA levels in the lesioned striatum by only 10%, DA levels in the lesioned SN were completely restored to normal levels. DOPAC levels showed similar changes. In order to establish whether the large DA increase in the lesioned SN contributed to L-DOPA-induced contralateral circling, animals were implanted with chronic in-dwelling cannulas in the lesioned SN. Infusion of the DOPA decarboxylase inhibitor carbidopa (5 micrograms in 1 microliter) 30 min prior to peripheral L-DOPA injection not only reduced contralateral circling but reversed the direction of turning 20 min after the L-DOPA injection. The results are discussed in terms of dopaminergic regulation of the striatonigral pathway, their clinical relevance to Parkinson's disease and the suggestion that the SN is an important site for the action of L-DOPA.
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PMID:Evidence that the substantia nigra is a site of action for L-DOPA. 339 96

Seventeen years after its introduction, L-dopa, now administered in combination with a peripheral dopa decarboxylase inhibitor remains the most effective palliative remedy for Lewy body Parkinson's disease. A therapeutic effect to large doses is so consistent that alternative diagnoses should be considered in any patient with a Parkinsonian syndrome who fails completely to respond. Despite improving the quality of life, it probably does not influence appreciably the reduced life expectancy in Parkinson's disease and the long-term therapeutic response is frequently marred by drug-induced oscillations in motor performance, dyskinesias and psychotoxicity. Experimental studies using continuous intravenous infusions of L-dopa in order to obtain constant plasma levels suggests that additional refinements in management may be achieved by the design of a practical controlled delivery system, and prototype pumps and sustained release formulations are already under evaluation.
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PMID:L-dopa treatment and Parkinson's disease. 352 59

The etiology, pathophysiology, diagnosis and clinical presentation, and clinical management of Parkinson's disease are reviewed. The cause of Parkinson's disease, a progressive, degenerative neurologic motor disorder, is unknown. Both endogenous and environmental factors appear to play a role. The clinical features of parkinsonism result from a depletion in dopaminergic transmission in the corpus striatum; the dopamine deficiency is caused by a loss of melanin-containing nerve cells within the substantia nigra and locus ceruleus. In the remaining neurons, hyalin-like masses called Lewy bodies increase in number, but the importance of this is unclear. The diagnosis of Parkinson's disease is based on the clinical presentation of the patient, which initially includes sensory complaints of aching pains, paresthesias, numbness, and coldness. As the disease progresses, the four classic symptoms become prominent: tremor, rigidity, bradykinesia, and postural difficulties. Drug therapy is the cornerstone of clinical management of Parkinson's disease, but no treatment has been found that will retard or reverse the disease. Therapy is usually initiated with anticholinergic agents such as biperiden hydrochloride or trihexyphenidyl hydrochloride with or without amantadine. The mainstay of therapy is levodopa, which is used in combination with dopa decarboxylase inhibitors to decrease the peripheral conversion of levodopa to dopamine. Bromocriptine is a dopamine agonist useful in treating Parkinson's disease. Therapy, which must continue for life, eventually becomes less effective or completely ineffective in all patients. Drug therapy has improved greatly the functional ability of patients with Parkinson's disease, but new agents that can extend the length of effective treatment or reverse the disease are needed.
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PMID:Current concepts in clinical therapeutics: Parkinson's disease. 353 Jun 16


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