• Journal of Pharmaceutical Investigation
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• v.38 no.1
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• pp.31-38
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• 2008

The objective of this work is to study transdermal delivery of levodopa using iontophoresis and evaluate various factors which affect the transdermal transport. Levodopa is unstable in aqueous solution, and, in order to establish a stable condition for levodopa for the duration of experiment, we investigated the stability of levodopa in aqueous solutions of different pHs with/without the addition of dextrose or the application of current. Using stable aqueous solution, we have studied the effect of pH, polarity and penetration enhancer (ethanol) on transdermal flux and compared the results. We also investigated the iontophoretic flux from hydroxypropyl cellulose (HPC) hydrogel. In vitro flux study was performed at $33^{\circ}C$, using side-by-side diffusion cell. Full thickness hairless mouse skin and rat skin were used for this work. Current densities applied were 0.4 or $0.6mA/cm^2$ and current was off after 6 hour application. Stability study showed that levodopa solution with a pH 2.5 or 4.5 maintained the initial concentration of levodopa for 24 hours with the addition of 5% dextrose. However, at pH 9.5, levodopa was unstable and 30 to 40% of levodopa degraded within 24 hours, even with the addition of 5% dextrose. Hydrogel swollen with dextrose added levodopa solution maintained about 97% of the initial concentration of levodopa for 13 days, when stored in $4^{\circ}C$. The application of current did not affect the stability of levodopa in hydrogel. Flux study from levodopa solution with pH 2.5 showed that cathodal delivery of levodopa was higher than passive or anodal delivery. When the pH of the donor solution was 4.5, anodal delivery of levodopa was higher than passive or cathodal delivery. These results seem to indicate that electroosmosis plays more dominant role than electrorepulsion in the flux of levodopa at pH 2.5, and the reverse situation applies for pH 4.5. The passive flux was unexpectedly high for the ionized levodopa. Similar to the results from aqueous solution, cumulative amount of levodopa transported trom HPC hydrogel by cathodal delivery was significantly higher than passive or anodal delivery. The treatment of 70% ethanol cotton ball by scrubbing increased passive, anodal and cathodal flux, with the largest increase for anodal flux. These results indicate that iontophoretic delivery of zwitterion such as levodopa is much complicated than that can be expected from small ionic molecules with single charge. The results also indicate that the balance between electroosmosis and electrorepulsion plays a very important role in the transport through skin.

• Korean Journal of Clinical Pharmacy
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• v.28 no.4
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• pp.285-292
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• 2018

Background: Long-term levodopa therapy relieves the motor dysfunction associated with Parkinson's disease (PD), but has various effects on non-motor symptoms, including cognitive dysfunction, hallucinations, and affective disorders, and can exacerbate certain aspects of dementia-like cognitive dysfunction. Here, we investigated the relationship between levodopa treatment and development of dementia in patients with PD. Methods: This retrospective study analyzed 76 consecutive patients with PD who had taken levodopa between 2011 and 2015. The participants were initially free of dementia and had initial daily levodopa doses of below 600 mg. Patients who did and did not develop comorbid dementia were compared in terms of potential predictor variables, including PD onset age, sex, levodopa doses, and non-dementia comorbidities. Results: Of the 76 patients, 21 (27.6%) developed dementia, which was followed by hallucinations and insomnia. The independent predictors of incident dementia were PD onset age and second-year and third-year average levodopa doses that were higher than the first-year average levodopa dose. Patients who developed dementia had significantly higher average daily levodopa doses and levodopa dose increases over the 6-year treatment period than those who did not develop dementia. In addition, patients with higher levodopa doses were more likely to experience hallucinations. Conclusion: These results suggest that increases in levodopa doses may be associated with a greater risk of cognitive impairment in patients with PD. Therefore, motor and cognitive functions and levodopa dose increases should be evaluated regularly during long-term levodopa therapy in patients with PD.

• Journal of Pharmaceutical Investigation
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• v.40 no.1
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• pp.23-31
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• 2010

In our previous work on levodopa delivery at pH 2.5 using iontophoresis, we found that cathodal delivery showed higher permeation than anodal delivery and electroosmosis plays more dominant role than electrorepulsion. In this work, we studied the transdermal transport of levodopa at very low pH (pH=1.0) where all levodopa molecules are cations, and evaluated some factors which affect the transdermal transport. The transport study at pH 2.5 was also conducted for comparison. The contribution of electrorepulsion and electroosmosis on flux was also evaluated. Using stable aqueous solution, the effect of electrode polarity, current density, current type and drug concentration on transport through skin were studied and the results were compared. We also investigated the iontophoretic flux from hydroxypropyl cellulose (HPC) hydrogel containing levodopa. In vitro flux study was performed at $33^{\circ}C$, using side-by-side diffusion cell. Full thickness hairless mouse skin were used. Current densities applied were 0.2, 0.4 or $0.6\;mA/cm^2$. Contrary to the pH 2.5 result, anodal delivery showed higher flux, indicating that electrorepulsion is the dominant force for the transport, overcoming the electroosmotic flow which is acting against the direction of electrorepulsion. Cumulative amount of levodopa transported was increased as the current density or drug concentration was increased. When amount of current dose was constant, continuous current was more beneficial than pulsed current in promoting levodopa permeation. Similar transport results were obtained when hydrogel was used as the donor phase. These results indicate that iontophoretic delivery of zwitterion such as levodopa is much complicated than that can be expected from small ionic molecules. The results also indicate that, only at very low pH like pH 1.0, electrorepulsion can be the dominant force over the electroosmosis in the levodopa transport.

• Journal of Pharmaceutical Investigation
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• v.38 no.6
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• pp.373-380
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• 2008

In order to develop optimal formulation and iontophoresis condition for the transdermal delivery of levodopa, we have evaluated the effect of two permeation enhancers, ethanol and oleic acid in microemulsion, on transdermal delivery of levodopa. In vitro flux studies were performed at $33^{\circ}C$, using side-by-side diffusion cell and full thickness hairless mouse skin. Current density applied was $0.4\;mA/cm^2$ and current was off after 6 hours application. Levodopa was analysed by HPLC at 280 nm. The o/w microemulsions of oleic acid in buffer solution (pH 2.5 & 4.5) were prepared using oleic acid, Tween 80 and ethanol. The existence of microemulsion regions were investigated in pseudo-ternary phase diagrams. Contrary to our expectation, cumulative amount of levodopa transported from microemulsion (pH 2.5) for 10 hours was similar to that from aqueous solution in all delivery methods (passive, anodal and cathodal). When pH of the micro-emulsion was pH 4.5, cumulative amount of levodopa transported for 10 hours increased about 40% (anodal) to 50% (cathodal), when compared to that from aqueous solution. Flux from pH 4.5 microemulsion showed higher value than that from pH 2.5 in all delivery methods. These results seem to indicate that electroosmosis plays more dominant role than electrorepulsion in the flux of levodopa at pH 2.5. The effect of ethanol on iontophoretic flux was studied using pH 2.5 phosphate buffer solution containing 3% or 5% (v/v) ethanol. Flux enhancement was observed in passive and anodal delivery as the concentration of the ethanol increased. Without ethanol, cathodal delivery showed higher flux than anodal delivery. Anodal delivery increased the cumulative amount of levodopa transported 1.6 fold by 5% ethanol after 10 hours. However, in cathodal delivery, no flux enhancement of levodopa was observed during current application and only marginal increase in cumulative amount transported after 10 hours was observed by 5% ethanol. These results seem to be related to the decrease in dielectric constant of the medium and the lipid extraction of the ethanol, which decrease the electroosmotic flow, and thus decrease the flux. Overall, the results provide important insights into the role of electroosmosis and electrorepulsion in the transport of levodopa through skin, and provide some useful informations for optimal formulation for levodopa.

• Korean Journal of Biological Psychiatry
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• v.4 no.1
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• pp.132-135
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• 1997

Current treatment strategies for levodopa-induced psychosis in advanced Parkinson's disease have had limited success. Reduction or discontinuation of levodopa and coadministration with dopamine-blocking neuroleptics may attenuate the psychotic symptoms, but these strategies are associated with worsening of parkinsonian symptoms. Administration of 5-HT3 receptor antagonist ; ondansetron, a newer strategy to attenuate psychosis of Parkinson'disease without motor deterioration was introduced. A 41-year-old young-onset male, who was diagnosed as Parkinson's disease 7 years ago, was treated with levodopa therapy, and had levodopa-induced psychosis(delusion, hallucination, paranoid, insomnia). After trial of ondansetron, he showed improvement in the Brief Psychiatric Rating Scale(from 21 points to 9 points) in spite of increasing the dosage of levodopa. With ondansetron, we could increase the dosage of levodopa without psychotic complications(esp, hallucination), and he showed improvement in the motor fluctuation.

• Journal of Acupuncture Research
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• v.27 no.6
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• pp.11-21
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• 2010

Objective : This study was aimed at investigating the therapeutic effects of acupuncture on gastrointestinal side effect of Levodopa on idiopathic Pakinson's disease patients. Methods : The subjects of this study were 42 patients with idiopathic Parkinson's disease. We divided them into two groups; acupuncture treatment group, no treatment group. We treated the former group with acupuncture therapy focusing on gastrointestinal side effect of Levodopa while administering Levodopa as well. And the latter group was also dosed up with Levodopa without acupuncture therapy. To see the effect of acupuncture treatment clearly, we used gastrointestinal syndrome rating scale (GSRS) and visual analog scale (VAS) and compared the GSRS grade and VAS score of two groups statistically, after 1, 2, 3, 4 weeks since they have been under the treatment. Results : This study suggests that the group who has been treated with acupuncture on gastrointestinal side effect of Levodopa on idiopathic pakinson's disease patients showed higher GSRS grade and VAS score than the one that has not. But, We could't find statistical significance between the two groups on improvement of GSRS grade and VAS score. Conclusions : These results proved that acupucture theraphy might be available for re lieving symptoms related with gastrointestinal side effect of Levodopa than the one that has not. But further studies are necessary.

• Applied Chemistry
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• v.15 no.1
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• pp.25-28
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• 2011

A highly sensitive spectrofluorimetric method was developed for the determination of levodopa based on the formation of a ternary complex with Eu³⁺ in the presence of ethylenediaminetetraacetic acid. It was found that this complex manifests intense fluorescence at 591 and 613 nm with excitation at 372 nm and maximum intensity was obtained at 613 nm. Under the optimum conditions, the enhanced fluorescence intensity was proportional to the concentration of levodopa over the range of 3×10^-9-2.5×10^-7 mol L^-1 with limit of detection (LOD) of 4.37×10^-10 mol L^-1. The method offers higher sensitivity and selectivity which could be effectively applied for the determination of levodopa in pharmaceutical and biological samples.

• Bulletin of the Korean Chemical Society
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• v.25 no.12
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• pp.1764-1768
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• 2004

The present work reports on the investigations based on the interaction of sodium hydroxide with catechol derivatives. The first derivative spectra allowed the simultaneous determination of levodopa and carbidopa. The calibration graph was constructed from the first derivative signals by measuring $^1D$ at 350 nm for standard samples containing between 3 and 30 mg $L^{-1}$ of levodopa and at 305 nm for standard samples containing between 3 and 80 mg $L^{-1}$ of carbidopa. This method offers the advantages of simplicity, rapidity, selectivity and higher sensitivity than most of the existing spectophotometric methods.

• Annals of Clinical Neurophysiology
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• v.7 no.2
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• pp.107-109
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• 2005

Neuroleptic malignant syndrome is a serious complication of levodopa withdrawal in patients with Parkinson's disease. We report a patient with advanced parkinsonism who developed neuroleptic malignant syndrome in setting of withdrawal of levodopa intake.

• Journal of Korean Neurosurgical Society
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• v.54 no.2
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• pp.118-124
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• 2013

Objective : Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment of choice for patients with advanced idiopathic Parkinson's disease (PD) who have motor complication with medication. The objectives of this study are to analyze long-term follow-up data of STN DBS cases and to identify the factors related to outcomes. Methods : Fifty-two PD patients who underwent STN DBS were followed-up for more than 3 years. The Unified Parkinson's Disease Rating Scale (UPDRS) and other clinical profiles were assessed preoperatively and during follow-up. A linear regression model was used to analyze whether factors predict the results of STN DBS. We divided the study individuals into subgroups according to several factors and compared subgroups. Results : Preoperative activity of daily living (ADL) and the magnitude of preoperative levodopa response were shown to predict the improvement in UPDRS part II without medication, and preoperative ADL and levodopa equivalent dose (LED) were shown to predict the improvement in UPDRS part II with medication. In UPDRS part III with medication, the magnitude of preoperative levodopa response was a predicting factor. Conclusion : The intensity of preoperative levodopa response was a strong factor for motor outcome. And preoperative ADL and LED were strong factors for ADL improvement. More vigorous studies should be conducted to elucidate how levodopa-induced motor complications are ameliorated after STN DBS.