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Brain & Development Jun 2015Patients suffering Dopa-Responsive Dystonia present dystonia, abnormal postural balance and gait impairment. Treatment with levodopa typically improves these three...
INTRODUCTION
Patients suffering Dopa-Responsive Dystonia present dystonia, abnormal postural balance and gait impairment. Treatment with levodopa typically improves these three symptoms. The present study provides an extensive analysis of gait and posture in a patient with Dopa-Responsive Dystonia, prior to and during levodopa therapy.
METHOD
The patient was assessed with the Unified Dystonia Rating Scale, underwent motion analysis with an optoelectronic system and postural analysis with force plates.
RESULTS
This study provides a detailed quantification of gait parameters in a Dopa-Responsive Dystonia patient. Prior to treatment, mean walking speed was severely reduced, gait cadence and step length were decreased and stride width was increased. Right lower limb and pelvis showed kinematic defects, trunk and Centre of Mass were backwards. During levodopa therapy, the walking speed was doubled, gait cadence and step length were increased and stride width was reduced. Nearly all kinematic parameters of lower limbs were significantly improved. The patient's Centre of Mass during gait and Centre of pressure in static position both shifted forward.
CONCLUSION
Levodopa dramatically decreased dystonia and improved spatio-temporal, kinematic and posture parameters. Our main pathophysiological hypothesis is that trunk tilt and its consequences on the Centre of Mass position have a pivotal influence on gait and balance, explaining both the initial impairments and the therapeutic effects. Gait analysis proves to be an effective tool to understand the pathophysiology of this patient, the therapeutic effects and mild residual gait defects in order to plan further rehabilitation strategy for this DRD patient. We propose that it will also prove to be useful for the exploration of other dystonic patients.
Topics: Adult; Biomechanical Phenomena; Dystonic Disorders; Female; Gait; Humans; Levodopa; Posture; Treatment Outcome; Young Adult
PubMed: 25282485
DOI: 10.1016/j.braindev.2014.09.005 -
The Journal of Pharmacy and Pharmacology Aug 1987Intraperitoneal administration of the 2-tetrahydropyranylmethyl, phenoxyethyl, ethyl, 2-hydroxypropyl and methyl ester prodrugs of L-dopa produced locomotor activity in...
Intraperitoneal administration of the 2-tetrahydropyranylmethyl, phenoxyethyl, ethyl, 2-hydroxypropyl and methyl ester prodrugs of L-dopa produced locomotor activity in reserpine-pretreated mice with equal intensity and duration to that observed following administration of L-dopa itself. Administration of the 2-(1-methoxy)propyl ester produced a more prolonged effect while the p-methoxyphenylethyl, n-propyl, phenylethyl, m-trifluoromethylbenzyl, cyclohexyl, p-chlorophenylethyl and benzyl ester prodrugs were less active than L-dopa itself. On oral administration, the ethyl and methyl ester prodrugs were more effective than L-dopa in reversing reserpine-induced akinesia in mice. The 2-tetrahydropyranylmethyl, 2-(1-methoxy)propyl, 2-hydroxypropyl, n-propyl, benzyl and phenoxyethyl ester prodrugs produced effects comparable with those of L-dopa. In contrast, the cyclohexyl, m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs were less effective than L-dopa on oral administration. Intraperitoneal administration of L-dopa and the ester prodrugs of L-dopa to rats with a prior 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB) produced contraversive circling responses. Rotation observed following administration of the n-propyl, 2-tetrahydropyranylmethyl, methyl and ethyl ester prodrugs was more intense than that observed following administration of L-dopa itself. Rotation produced by the administration of L-dopa and the cyclohexyl, 2-(1-methoxy)propyl, phenylethyl, p-chlorophenylethyl, p-methoxyphenylethyl, benzyl, 2-hydroxypropyl, phenoxyethyl and m-trifluoromethylbenzyl ester prodrugs was identical. Ester prodrugs of L-dopa may be as effective as L-dopa itself in producing motor activity but overall none of the compounds tested was markedly more potent or of longer duration than L-dopa itself.
Topics: Animals; Behavior, Animal; Disease Models, Animal; Female; Hydroxydopamines; Levodopa; Male; Mice; Movement Disorders; Oxidopamine; Parkinson Disease; Rats; Rats, Inbred Strains; Reserpine; Stereotyped Behavior
PubMed: 2888854
DOI: 10.1111/j.2042-7158.1987.tb03441.x -
Clinica Chimica Acta; International... Mar 2015L-dopa (l-3,4-dihydroxyphenylalanine) is commonly used for treating Parkinson's disease (PD). However, regardless of its prominent effect, therapeutic range of L-dopa...
BACKGROUND
L-dopa (l-3,4-dihydroxyphenylalanine) is commonly used for treating Parkinson's disease (PD). However, regardless of its prominent effect, therapeutic range of L-dopa narrows down with disease progression, which leads to development of motor complications including wearing off and dyskinesias. In addition, intestinal absorption of L-dopa is inversely correlated with the amount of oral protein intake, and shows intra- and inter-day variability. Hence, frequent monitoring of plasma L-dopa concentrations is beneficial, but frequent venipuncture imposes physical and psychological burdens on patients with PD.
METHODS
We investigated the usefulness of sweat samples instead of plasma samples for monitoring L-dopa concentrations. With a monolithic silica disk-packed spin column and the high-performance liquid chromatography-electrochemical detection system, L-dopa in sweat samples was successfully quantified and analyzed in 23 PD patients.
RESULTS
We found that the Pearson's correlation coefficient of the plasma and sweat l-dopa concentrations was 0.678. Although the disease durations and severities were not correlated with the deviation of the actual sweat L-dopa concentrations from the fitted line, acquisition of the sweat samples under a stable condition was technically difficult in severely affected patients. The deviations may also be partly accounted for by skin permeability of L-dopa.
CONCLUSIONS
Measuring L-dopa concentrations in sweat is suitable to get further insights into the L-dopa metabolism.
Topics: Blood Chemical Analysis; Humans; Levodopa; Parkinson Disease; Sweat
PubMed: 25591966
DOI: 10.1016/j.cca.2014.12.032 -
BMC Neuroscience Jul 2016We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of L-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and...
BACKGROUND
We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of L-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and neuroprotective effects of L-DOPA in striatal astrocytes. We examined changes in the numbers of dopaminergic neurons after treatment with L-DOPA and 3-OMD or entacapone, a peripheral COMT inhibitor, using primary cultured mesencephalic neurons and striatal astrocytes.
RESULTS
The number of tyrosine hydroxylase-positive dopaminergic neurons was not affected by L-DOPA treatment in mesencephalic neurons alone. However, the increase in viability of dopaminergic neurons in the presence of astrocytes was further enhanced after methyl-L-DOPA treatment (25 µM) in mixed cultured mesencephalic neurons and striatal astrocytes. The neuroprotective effect of 25 µM L-DOPA was almost completely inhibited by simultaneous treatment with 3-OMD (10 or 100 µM), and was enhanced by concomitant treatment with entacapone (0.3 µM). The uptake of L-DOPA into and the release of glutathione from striatal astrocytes after L-DOPA treatment (100 µM) were inhibited by simultaneous exposure to 3-OMD (100 µM).
CONCLUSIONS
These data suggest that L-DOPA exerts its neuroprotective effect on dopaminergic neurons via astrocytes and that 3-OMD competes with L-DOPA by acting on target molecule(s) (possibly including glutathione) released from astrocytes. Since some amount of entacapone can cross the blood-brain barrier, this reagent may enhance L-DOPA transportation by inhibiting COMT and increase the astrocyte-mediated neuroprotective effects of L-DOPA on dopaminergic neurons.
Topics: Animals; Astrocytes; Catechol O-Methyltransferase Inhibitors; Catechols; Cells, Cultured; Corpus Striatum; Dihydroxyphenylalanine; Dopamine Agents; Dopaminergic Neurons; Dose-Response Relationship, Drug; Glutathione; Levodopa; Mesencephalon; Neuroprotection; Neuroprotective Agents; Nitriles; Rats, Sprague-Dawley; Tyrosine
PubMed: 27456338
DOI: 10.1186/s12868-016-0289-0 -
The International Journal of... Dec 2019In Parkinson's disease (PD), as in many other neurodegenerative disorders, mitochondrial dysfunction, protein misfolding, and proteotoxic stress underly the disease...
In Parkinson's disease (PD), as in many other neurodegenerative disorders, mitochondrial dysfunction, protein misfolding, and proteotoxic stress underly the disease process. For decades, the primary symptomatic treatment for PD has been the dopamine precursor L-DOPA (Levodopa). L-DOPA however can initiate protein misfolding through its ability to mimic the protein amino acid L-tyrosine, resulting in random errors in aminoacylation and L-DOPA becoming mistakenly inserted into the polypeptide chain of proteins in place of L-tyrosine. In the present study we examined the impact that the generation of DOPA-containing proteins had on human neuroblastoma cell (SH-SY5Y) function in vitro. We showed that even in the presence of antioxidants there was a significant accumulation of cytosolic ubiquitin in DOPA-treated cells, an upregulation in the endosomal-lysosomal degradation system, deleterious changes to mitochondrial morphology and a marked decline in mitochondrial function.The effects of L-DOPA on mitochondrial function were not observed with D-DOPA, the stereoisomer of L-DOPA that cannot be inserted into proteins so did not result from oxidative stress. We could fully protect against these effects by co-treatment with L-tyrosine, supporting the view that misincorporation of L-DOPA into proteins contributed to these cytotoxic effects, leading us to suggest that co-treatment with L-tyrosine could be beneficial therapeutically.
Topics: Humans; Levodopa; Mitochondria; Parkinson Disease
PubMed: 31654750
DOI: 10.1016/j.biocel.2019.105624 -
Molecules (Basel, Switzerland) Jun 2019l-3,4-dihydroxyphenylalanine (l-DOPA) is a medically relevant compound in Parkinson's disease therapy. Several extraction methods of l-DOPA from beans, including velvet...
l-3,4-dihydroxyphenylalanine (l-DOPA) is a medically relevant compound in Parkinson's disease therapy. Several extraction methods of l-DOPA from beans, including velvet and faba beans, have been described in the literature. However, these methods require the use of strong acids, long extraction times, or complex downstream processing, which makes the extraction of l-DOPA expensive and energy-demanding, limiting its industrial application. In addition, the stability of l-DOPA during the extraction process is critical, further complicating the extraction of adequate amounts of this amino acid. This work is the first report on a simple, rapid, greener, and robust extraction method of l-DOPA. The developed method consists of a quick homogenization step followed by a double extraction with 0.2% / acetic acid for 20 min and was applied to faba bean at a ratio of 1:25 with respect to the extracting solvent. This study also investigated the stability of l-DOPA during extraction and thermal treatment. The proposed method demonstrated to be robust and extraordinarily efficient for numerous cultivars of faba bean, velvet bean, and food products containing faba beans.
Topics: Chemical Fractionation; Decision Trees; Hydrogen-Ion Concentration; Levodopa; Molecular Structure; Reproducibility of Results; Solvents; Workflow
PubMed: 31238569
DOI: 10.3390/molecules24122325 -
Pharmaceutical Research Jul 2017When levodopa (L-DOPA) is administered orally, it is eliminated from the body very quickly resulting in a series of sharp fluctuations in its blood concentrations. These...
PURPOSE
When levodopa (L-DOPA) is administered orally, it is eliminated from the body very quickly resulting in a series of sharp fluctuations in its blood concentrations. These frequent changes in blood levels are considered to be responsible for the development of late motor complications and dyskinesias, which are troubling clinical and treatment issues in Parkinson's disease. Transdermal drug delivery is a patient-compliant method for delivering therapeutics into the systemic circulation in a continuous and controlled manner. Transdermal delivery of L-DOPA can achieve continuous dopaminergic stimulation (CDS), thus reducing motor fluctuations.
METHODS
However, there are two technical difficulties in the development of a transdermal patch for L-DOPA: (a) L-DOPA is poorly soluble in most pharmaceutically-acceptable solvents, and (b) L-DOPA has a limited permeability through the skin even from saturated solutions. We have, therefore, investigated the transdermal delivery of L-DOPA using an innovative self-assembling nano-micellar system (SANS), loaded with 2% L-DOPA and 1% carbidopa.
RESULTS
In vitro testing as well as in vivo pharmacokinetic studies (multiple-dose regimen) in rabbits have demonstrated for the first time a significantly increased percutaneous permeation and systemic absorption of L-DOPA.
CONCLUSIONS
It has therefore been proposed that either a once-daily or a twice-daily regimen could be therapeutically effective depending on the severity of the disease.
Topics: Administration, Cutaneous; Animals; Antiparkinson Agents; Carbidopa; Drug Carriers; Drug Combinations; Drug Liberation; Levodopa; Male; Micelles; Nanoparticles; Permeability; Rabbits; Rats, Sprague-Dawley; Skin Absorption; Surface Properties; Swine; Transdermal Patch
PubMed: 28405912
DOI: 10.1007/s11095-017-2162-y -
The New Phytologist Apr 2016
Topics: Betalains; Levodopa; Oxygenases
PubMed: 26919693
DOI: 10.1111/nph.13901 -
Journal of Nuclear Medicine : Official... Mar 1986The radiofluorination of L-dopa with [18F]F2 was investigated with the purpose of improving the yield of 6-[18F]fluoro-L-dopa. When boron trifluoride was added to the...
The radiofluorination of L-dopa with [18F]F2 was investigated with the purpose of improving the yield of 6-[18F]fluoro-L-dopa. When boron trifluoride was added to the reaction mixture in hydrogen fluoride (HF), the yield was increased threefold. Nine millicuries of 6-[18F]fluoro-L-dopa were produced from 100 mCi [18F]F2 routinely and reliably after 2 hr of preparation. If acetonitrile or water were substituted for HF, little or no 6-fluoro-L-dopa was made.
Topics: Arsenic; Arsenicals; Boranes; Chromatography, High Pressure Liquid; Dihydroxyphenylalanine; Fluorides; Fluorine; Isomerism; Isotope Labeling; Levodopa; Radioisotopes; Silanes; Silicon Compounds; Solvents
PubMed: 3086520
DOI: No ID Found -
Farmakologiia I Toksikologiia 1977
Review
Topics: Amination; Animals; Catecholamines; Decarboxylation; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Humans; In Vitro Techniques; Levodopa; Methylation; Methyldopa; Parkinson Disease; Protein Binding; Pyridoxine
PubMed: 340258
DOI: No ID Found