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Sten-magnus Aquilonius - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of Levodopa carbidopa microtablets versus Levodopa benserazide and Levodopa carbidopa in healthy volunteers
Clinical Neuropharmacology, 2012Co-Authors: Dag Nyholm, Tommy Lewander, Tobias Bäckström, Georgios Panagiotidis, Mats Ehrnebo, Christer Nyström, Cecilia Gomestrolin, Sten-magnus AquiloniusAbstract:OBJECTIVES: To compare bioavailability and pharmacokinetics of single doses of 3 different Levodopa formulations given orally in healthy volunteers. Two marketed formulations, standard Levodopa/carbidopa, 100/25 mg (LC-100), and dispersible Levodopa/benserazide, 100/25 mg (LB-100), were used as reference formulations for a newly developed dispersible microtablet formulation of Levodopa/carbidopa, 5/1.25 mg (LC-5). The microtablets are intended for individualized dosing of Levodopa/carbidopa in Parkinson disease by means of an electronic dose dispenser with a built-in diary for symptom registration. METHODS: A single-dose, open, randomized, 3-way crossover study was performed in 19 healthy subjects. Concentrations of Levodopa, carbidopa, and the metabolite 3-O-MD in plasma were determined after intake of 100 mg of Levodopa, that is, one tablet of reference formulations and 20 microtablets of the new formulation. RESULTS: The LC-5 microtablets were bioequivalent to the LC-100 tablets in area under the curve (AUC) and maximum concentration in plasma (Cmax) for Levodopa, and to the LB-100 tablets in AUC. The dispersible Levodopa/benserazide formulation showed earlier time to Cmax and significantly higher Cmax for Levodopa in plasma compared to the microtablets. Carbidopa showed larger interindividual variation in AUC and Cmax than Levodopa, and the bioequivalence comparison LC-5/LC-100 for this compound did not reach the target. Nevertheless, comparison of 3-O-MD levels for LC-5/LC-100, assuming proportionality to Levodopa levels, demonstrated bioequivalence. CONCLUSIONS: The new Levodopa/carbidopa microtablets had a pharmacokinetic profile that would allow for a convenient switch of therapy from standard tablets. Frequent dose administration of Levodopa/carbidopa microtablets with an electronic dose dispenser might offer an optimal oral drug delivery in Parkinson disease.
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long term intraduodenal infusion of a water based Levodopa carbidopa dispersion in very advanced parkinson s disease
Acta Neurologica Scandinavica, 2009Co-Authors: Dag Nilsson, Christer Nyström, L E Hansson, K Johansson, Lennart Paalzow, Sten-magnus AquiloniusAbstract:Objective - To evaluate the effects of continuous duodenal infusion of Levodopa over time on the disabling fluctuations in motor performance in advanced parkinsonian patients. It has earlier been demonstrated that these fluctuations can be reduced by keeping the plasma concentration of Levodopa constant. Material and methods - In view of the low water solubility of Levodopa a stable dispersion of the drug was developed and used for continuous intraduodenal infusion in patients with advanced Parkinson's disease. Nine patients were evaluated with respect to an optimal oral treatment, during nasoduodenal infusion by a portable pump and then followed for 6 months to 2 1/2 years when treated via transabdominal infusion. Upon each test occasion, over 2 non-consecutive days, objective movement analysis by means of an opto-electronic system was applied every 15-20 min and video recordings performed twice every h. On several test occasions plasma Levodopa concentrations were analysed every 15 min. Results - The patients showed improvement and decreased variance of their motor function. In the 2 patients followed over a period of 2 1/2 years Levodopa plasma concentration showed reduced fluctuations on infusion and the Levodopa consumption as well as mean Levodopa plasma concentration decreased. Conclusion - Continuous duodenal infusion of Levodopa is an alternative treatment strategy for patients with advanced Parkinson's disease when conventional therapy has failed.
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enteral Levodopa carbidopa infusion in advanced parkinson disease long term exposure
Clinical Neuropharmacology, 2008Co-Authors: Dag Nyholm, Tommy Lewander, Anders Johansson, Peter A Lewitt, Christofer Lundqvist, Sten-magnus AquiloniusAbstract:Objectives: In patients with advanced Parkinson disease, Levodopa/carbidopa formulated as a gel suspension (Duodopa) permits continuous delivery into the small intestine using a portable pump, resulting in less variability in Levodopa concentrations and fewer motor fluctuations and dyskinesias than with oral Levodopa administration. This is a retrospective analysis of the long-term clinical experience with this agent. Methods: All but 1 of the patients who had received enteral Levodopa infusion treatment between January 1, 1991, and June 30, 2002, consented to a review of their hospital charts. Results: Of the 65 patients with initial testing of the treatment, 86% opted for continued treatment via percutaneous endoscopic gastrostomy or gastrojejunostomy. Total exposure to Levodopa infusion was 216 patient-years (mean, 3.7 years). Maximum treatment duration was 10.7 years. Fifty-two patients were treated for 1 year or longer. The adverse effect profile of Levodopa/carbidopa infusion was similar to that observed with oral administration of Levodopa. Seven deaths occurred, all considered unrelated to the treatment. Intestinal tube problems, including dislocation of the intestinal tube to the stomach, were the most common technical problem, occurring in 69% of the patients during the first year. The optimal daily dose of Levodopa decreased by an average of 5% during follow-up. Conclusions: The safety of enteral infusion of Levodopa/ carbidopa formulated as a gel suspension was found acceptable. For most patients, the technical challenges posed by the enteral infusion system were offset by the improvement in motor fluctuations and dyskinesias offered by this technique.
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wireless real time electronic data capture for self assessment of motor function and quality of life in parkinson s disease
Movement Disorders, 2004Co-Authors: Dag Nyholm, Jan Kowalski, Sten-magnus AquiloniusAbstract:Pharmacotherapy for Parkinson’s disease (PD) is based on Levodopa, the most effective dopaminergic drug. The development of motor complications constitutes the major challenge for new or refined therapies.To evaluate the impact of Levodopa pharmacokinetics on motor function, an observational study in the patients’ home environment was carried out. A high variability in plasma Levodopa levels was found in all patients, irrespective of treatment regimen. The impact of Levodopa pharmacokinetics was further studied in a crossover trial comparing sustained-release tablets and continuous daytime intestinal infusion. Infusion produced significantly decreased variability in plasma levels of Levodopa, resulting in significantly normalised motor function. A permanent system for long-term Levodopa infusion has been developed and 28 patients have been followed for 87 patient-years. Motor response was generally preserved during the long-term observation period, implying that there is no development of tolerance to infusion therapy. Levodopa tablets are normally used in multiples of 50 or 100 mg, thus a rough estimate of individual dosage. A new concept for individualising Levodopa/carbidopa doses with microtablets of 5/1.25 mg is under development. An electronic drug-dispensing device for administering the microtablets was tested on patients with PD. All were able to handle the dispenser and most were interested in future use of the concept. Self-assessment of symptoms is accurate in PD, but traditional paper diaries are associated with low compliance. A wireless electronic diary was compared with a corresponding paper diary. The time-stamped and thus completely reliable patient compliance was 88% with the electronic diary.To conclude, pharmacokinetics of Levodopa is the major determinant for motor fluctuations in PD. Every effort to individualise dosage and to smooth out the fluctuations in Levodopa concentrations should be made, e.g. by means of microtablets or enteral infusion. Electronic patient diaries for real-time data capture are suitable for PD studies.
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optimizing Levodopa pharmacokinetics intestinal infusion versus oral sustained release tablets
Clinical Neuropharmacology, 2003Co-Authors: Dag Nyholm, Christer Nyström, Cecilia Gomestrolin, Hakan Askmark, Tina W Knutson, Hans Lennernas, Sten-magnus AquiloniusAbstract:Continuous duodenal infusion of carbidopa/Levodopa has been shown to control motor fluctuations in advanced Parkinson's disease (PD). The authors compared the pharmacokinetics of Levodopa and 3-O-methyldopa in patients with advanced PD after administration of an oral sustained-release Levodopa preparation and after continuous intestinal Levodopa infusion with a new formulation as a gel suspension. A randomized crossover trial was carried out in 12 patients. Carbidopa/Levodopa was administered as an oral sustained-release tablet and by nasoduodenal continuous infusion for 3-week periods for each treatment. Plasma Levodopa concentrations and motor performance were evaluated every 30 minutes during 3 test days of each treatment period. The average intraindividual coefficient of variation for the plasma Levodopa concentrations after oral therapy was 34% and was significantly lower (14%, p < 0.01) during continuous infusion. Hourly video evaluations showed a significant increase in ON time during infusion and a significant decrease in OFF time and dyskinesia. Continuous intraduodenal delivery of a new carbidopa/Levodopa formulation offers a means for markedly improved control of motor fluctuations in late stages of PD.
Dag Nyholm - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of Levodopa, Carbidopa, and 3-O-Methyldopa Following 16-hour Jejunal Infusion of Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson's Disease Patients
The AAPS journal, 2012Co-Authors: Dag Nyholm, Sandeep Dutta, Krai Chatamra, Per Odin, Anders Johansson, Charles Locke, Ahmed A OthmanAbstract:Motor complications of Parkinson’s disease (PD) are a consequence of pulsatile dopaminergic stimulation from standard oral Levodopa therapy. Levodopa–carbidopa intestinal gel (LCIG) is infused continuously via an intrajejunal percutaneous gastrostomy tube. This was the first study designed to characterize the full pharmacokinetic profiles of Levodopa, carbidopa, and Levodopa metabolite, 3-O-methyldopa (3-OMD) with 16-h LCIG infusion. Nineteen advanced PD patients (mean age, 65 years) who were on LCIG therapy for ≥30 days were enrolled. Patients received their individualized LCIG infusion doses, and serial pharmacokinetic samples were collected. Eighteen patients completed the study; 19 were assessed for safety. Mean (SD) total Levodopa and carbidopa doses were 1,580 (403) and 395 (101) mg, respectively. Mean (SD) Cavg (μg/mL) were 2.9 (0.84) for Levodopa, 17.1 (4.99) for 3-OMD, and 0.22 (0.08) for carbidopa. The degree of fluctuation [defined as (Cmax − Cmin)/Cavg] in Levodopa, 3-OMD, and carbidopa plasma concentrations was very low (0.52, 0.21, and 0.96, respectively) during hours 2–16 of infusion. Accordingly, the within-subject coefficients of variation in Levodopa, 3-OMD, and carbidopa concentrations were low (13%, 6%, and 19%, respectively). Three patients (16%) reported ≥1 treatment-emergent adverse event; none were considered severe. Continuous intrajejunal LCIG infusion maintained stable plasma Levodopa levels over 16 h. Consistent exposure has been shown to reduce motor and nonmotor complications associated with oral medications. LCIG was well tolerated, consistent with previous reports.
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pharmacokinetics of Levodopa carbidopa microtablets versus Levodopa benserazide and Levodopa carbidopa in healthy volunteers
Clinical Neuropharmacology, 2012Co-Authors: Dag Nyholm, Tommy Lewander, Tobias Bäckström, Georgios Panagiotidis, Mats Ehrnebo, Christer Nyström, Cecilia Gomestrolin, Sten-magnus AquiloniusAbstract:OBJECTIVES: To compare bioavailability and pharmacokinetics of single doses of 3 different Levodopa formulations given orally in healthy volunteers. Two marketed formulations, standard Levodopa/carbidopa, 100/25 mg (LC-100), and dispersible Levodopa/benserazide, 100/25 mg (LB-100), were used as reference formulations for a newly developed dispersible microtablet formulation of Levodopa/carbidopa, 5/1.25 mg (LC-5). The microtablets are intended for individualized dosing of Levodopa/carbidopa in Parkinson disease by means of an electronic dose dispenser with a built-in diary for symptom registration. METHODS: A single-dose, open, randomized, 3-way crossover study was performed in 19 healthy subjects. Concentrations of Levodopa, carbidopa, and the metabolite 3-O-MD in plasma were determined after intake of 100 mg of Levodopa, that is, one tablet of reference formulations and 20 microtablets of the new formulation. RESULTS: The LC-5 microtablets were bioequivalent to the LC-100 tablets in area under the curve (AUC) and maximum concentration in plasma (Cmax) for Levodopa, and to the LB-100 tablets in AUC. The dispersible Levodopa/benserazide formulation showed earlier time to Cmax and significantly higher Cmax for Levodopa in plasma compared to the microtablets. Carbidopa showed larger interindividual variation in AUC and Cmax than Levodopa, and the bioequivalence comparison LC-5/LC-100 for this compound did not reach the target. Nevertheless, comparison of 3-O-MD levels for LC-5/LC-100, assuming proportionality to Levodopa levels, demonstrated bioequivalence. CONCLUSIONS: The new Levodopa/carbidopa microtablets had a pharmacokinetic profile that would allow for a convenient switch of therapy from standard tablets. Frequent dose administration of Levodopa/carbidopa microtablets with an electronic dose dispenser might offer an optimal oral drug delivery in Parkinson disease.
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enteral Levodopa carbidopa infusion in advanced parkinson disease long term exposure
Clinical Neuropharmacology, 2008Co-Authors: Dag Nyholm, Tommy Lewander, Anders Johansson, Peter A Lewitt, Christofer Lundqvist, Sten-magnus AquiloniusAbstract:Objectives: In patients with advanced Parkinson disease, Levodopa/carbidopa formulated as a gel suspension (Duodopa) permits continuous delivery into the small intestine using a portable pump, resulting in less variability in Levodopa concentrations and fewer motor fluctuations and dyskinesias than with oral Levodopa administration. This is a retrospective analysis of the long-term clinical experience with this agent. Methods: All but 1 of the patients who had received enteral Levodopa infusion treatment between January 1, 1991, and June 30, 2002, consented to a review of their hospital charts. Results: Of the 65 patients with initial testing of the treatment, 86% opted for continued treatment via percutaneous endoscopic gastrostomy or gastrojejunostomy. Total exposure to Levodopa infusion was 216 patient-years (mean, 3.7 years). Maximum treatment duration was 10.7 years. Fifty-two patients were treated for 1 year or longer. The adverse effect profile of Levodopa/carbidopa infusion was similar to that observed with oral administration of Levodopa. Seven deaths occurred, all considered unrelated to the treatment. Intestinal tube problems, including dislocation of the intestinal tube to the stomach, were the most common technical problem, occurring in 69% of the patients during the first year. The optimal daily dose of Levodopa decreased by an average of 5% during follow-up. Conclusions: The safety of enteral infusion of Levodopa/ carbidopa formulated as a gel suspension was found acceptable. For most patients, the technical challenges posed by the enteral infusion system were offset by the improvement in motor fluctuations and dyskinesias offered by this technique.
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wireless real time electronic data capture for self assessment of motor function and quality of life in parkinson s disease
Movement Disorders, 2004Co-Authors: Dag Nyholm, Jan Kowalski, Sten-magnus AquiloniusAbstract:Pharmacotherapy for Parkinson’s disease (PD) is based on Levodopa, the most effective dopaminergic drug. The development of motor complications constitutes the major challenge for new or refined therapies.To evaluate the impact of Levodopa pharmacokinetics on motor function, an observational study in the patients’ home environment was carried out. A high variability in plasma Levodopa levels was found in all patients, irrespective of treatment regimen. The impact of Levodopa pharmacokinetics was further studied in a crossover trial comparing sustained-release tablets and continuous daytime intestinal infusion. Infusion produced significantly decreased variability in plasma levels of Levodopa, resulting in significantly normalised motor function. A permanent system for long-term Levodopa infusion has been developed and 28 patients have been followed for 87 patient-years. Motor response was generally preserved during the long-term observation period, implying that there is no development of tolerance to infusion therapy. Levodopa tablets are normally used in multiples of 50 or 100 mg, thus a rough estimate of individual dosage. A new concept for individualising Levodopa/carbidopa doses with microtablets of 5/1.25 mg is under development. An electronic drug-dispensing device for administering the microtablets was tested on patients with PD. All were able to handle the dispenser and most were interested in future use of the concept. Self-assessment of symptoms is accurate in PD, but traditional paper diaries are associated with low compliance. A wireless electronic diary was compared with a corresponding paper diary. The time-stamped and thus completely reliable patient compliance was 88% with the electronic diary.To conclude, pharmacokinetics of Levodopa is the major determinant for motor fluctuations in PD. Every effort to individualise dosage and to smooth out the fluctuations in Levodopa concentrations should be made, e.g. by means of microtablets or enteral infusion. Electronic patient diaries for real-time data capture are suitable for PD studies.
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optimizing Levodopa pharmacokinetics intestinal infusion versus oral sustained release tablets
Clinical Neuropharmacology, 2003Co-Authors: Dag Nyholm, Christer Nyström, Cecilia Gomestrolin, Hakan Askmark, Tina W Knutson, Hans Lennernas, Sten-magnus AquiloniusAbstract:Continuous duodenal infusion of carbidopa/Levodopa has been shown to control motor fluctuations in advanced Parkinson's disease (PD). The authors compared the pharmacokinetics of Levodopa and 3-O-methyldopa in patients with advanced PD after administration of an oral sustained-release Levodopa preparation and after continuous intestinal Levodopa infusion with a new formulation as a gel suspension. A randomized crossover trial was carried out in 12 patients. Carbidopa/Levodopa was administered as an oral sustained-release tablet and by nasoduodenal continuous infusion for 3-week periods for each treatment. Plasma Levodopa concentrations and motor performance were evaluated every 30 minutes during 3 test days of each treatment period. The average intraindividual coefficient of variation for the plasma Levodopa concentrations after oral therapy was 34% and was significantly lower (14%, p < 0.01) during continuous infusion. Hourly video evaluations showed a significant increase in ON time during infusion and a significant decrease in OFF time and dyskinesia. Continuous intraduodenal delivery of a new carbidopa/Levodopa formulation offers a means for markedly improved control of motor fluctuations in late stages of PD.
Y Agid - One of the best experts on this subject based on the ideXlab platform.
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Treatment of end-of-dose wearing-off in parkinson's disease: stalevo (Levodopa/carbidopa/entacapone) and Levodopa/DDCI given in combination with Comtess/Comtan (entacapone) provide equivalent improvements in symptom control superior to that of tradit
European neurology, 2005Co-Authors: David J. Brooks, Y Agid, Karla Eggert, Håkan Widner, Karen Østergaard, A HolopainenAbstract:The aim of this study was to evaluate the efficacy of the new optimised Levodopa, Stalevo (Levodopa, carbidopa and entacapone) in patients with Parkinson's disease experiencing end-of-dose wearing-off. Treatment with Stalevo was compared to treatment with traditional immediate-release Levodopa and dopa-decarboxylase inhibitor (DDCI) formulations along with adjunct entacapone (Comtess/Comtan). A European, open, parallel-group, active treatment-controlled phase IIIb study evaluating 176 patients randomised to switch from their current regimen of Levodopa/DDCI to either an equivalent dose of Stalevo or Levodopa/DDCI plus entacapone. After 6 weeks, treatments were assessed using the Clinical Global Impression of Change, the Unified Parkinson's Disease Rating Scale and a Motor Fluctuations Questionnaire. Over 70% of patients in both the Stalevo and adjunct entacapone arms felt that they were clinically improved and over 80% experienced a reduction in fluctuations. Although there was no significant difference between Stalevo and Levodopa/DDCI plus entacapone with regard to motor improvement and side effects, 81% of patients stated that they preferred treatment with Stalevo compared with taking two separate tablets (i.e. Levodopa/DDCI and entacapone). Stalevo was well tolerated and safe when substituted for Levodopa DDCI preparations.
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treatment of end of dose wearing off in parkinson s disease stalevo Levodopa carbidopa entacapone and Levodopa ddci given in combination with comtess comtan entacapone provide equivalent improvements in symptom control superior to that of traditional
European Neurology, 2005Co-Authors: David J. Brooks, Y Agid, Karla Eggert, Håkan Widner, Karen Østergaard, A HolopainenAbstract:The aim of this study was to evaluate the efficacy of the new optimised Levodopa, Stalevo (Levodopa, carbidopa and entacapone) in patients with Parkinson's disease experiencing end-of-dose wearing-off. Treatment with Stalevo was compared to treatment with traditional immediate-release Levodopa and dopa-decarboxylase inhibitor (DDCI) formulations along with adjunct entacapone (Comtess/Comtan). A European, open, parallel-group, active treatment-controlled phase IIIb study evaluating 176 patients randomised to switch from their current regimen of Levodopa/DDCI to either an equivalent dose of Stalevo or Levodopa/DDCI plus entacapone. After 6 weeks, treatments were assessed using the Clinical Global Impression of Change, the Unified Parkinson's Disease Rating Scale and a Motor Fluctuations Questionnaire. Over 70% of patients in both the Stalevo and adjunct entacapone arms felt that they were clinically improved and over 80% experienced a reduction in fluctuations. Although there was no significant difference between Stalevo and Levodopa/DDCI plus entacapone with regard to motor improvement and side effects, 81% of patients stated that they preferred treatment with Stalevo compared with taking two separate tablets (i.e. Levodopa/DDCI and entacapone). Stalevo was well tolerated and safe when substituted for Levodopa DDCI preparations.
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Levodopa in the treatment of parkinson s disease current controversies
Movement Disorders, 2004Co-Authors: Warren C Olanow, Y Agid, Y Mizuno, Alberto Albanese, U Bonucelli, Philip Damier, Justo Garcia De Yebenes, Oscar S Gershanik, Mark Guttman, Francisco GrandasAbstract:Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether Levodopa is toxic, and (2) whether Levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that Levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of Levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.
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ly293558 an ampa glutamate receptor antagonist prevents and reverses Levodopa induced motor alterations in parkinsonian rats
Synapse, 2001Co-Authors: Concepcio Marin, Y Agid, Anna Jimenez, Merce Bonastre, M Vila, E Hirsch, Eduardo TolosaAbstract:To evaluate the possible involvement of glutamate AMPA receptor-mediated mechanisms in Levodopa-induced motor fluctuations, we investigated the effects of LY293558, a competitive AMPA receptor antagonist, on Levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of LY293558 was studied to evaluate the possible reversion or prevention of these Levodopa effects. In the first set of experiments, rats were treated with Levodopa (25 mg/kg with benserazide, twice daily, i.p.) for 22 days and on day 23 LY293558 (5 mg/kg, i.p.) was administered immediately before Levodopa. In the second set of experiments, rats were treated daily for 22 days with Levodopa and LY293558 (5 mg/kg, twice daily, i.p.). In the third set of experiments, the effect of LY293558 (5 mg/kg, i.p.) administration on selective dopamine D-1 (SKF38393, 1.5 mg/kg, s.c.) and D-2 agonist (quinpirole, 0.1 mg/kg, i.p.)-induced rotational behavior after daily Levodopa treatment was studied. The duration of the rotational behavior induced by chronic Levodopa decreased by 30% after 22 days. Acute administration of LY293558 on day 23 reversed this effect. The group of animals that were chronically treated with Levodopa and LY293558 did not show the decrease in this motor response duration. Chronic Levodopa treatment attenuated the rotational response to the D-1 agonist SKF38393 and increased the response to the D-2 agonist quinpirole. LY293558 did not reverse the effect of Levodopa on rotational behavior induced by the D-1 agonist but significantly reduced the rotational response to the D-2 agonist in Levodopa-treated animals by 40%. Our results demonstrate that an AMPA receptor antagonist reverses and prevents Levodopa-induced motor alterations in parkinsonian rats and that this effect on motor fluctuations induced by chronic Levodopa is probably due to a modulation of the indirect output pathway of the basal ganglia. Synapse 42:40–47, 2001. © 2001 Wiley-Liss, Inc.
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axial parkinsonian symptoms can be improved the role of Levodopa and bilateral subthalamic stimulation
Journal of Neurology Neurosurgery and Psychiatry, 2000Co-Authors: Boulospaul Bejjani, David Gervais, Isabelle Arnulf, Savas Papadopoulos, Sophie Demeret, A M Bonnet, Philippe Cornu, Philippe Damier, Y AgidAbstract:OBJECTIVE To assess the effects of high frequency stimulation of the subthalamic nucleus (STN) on axial symptoms occurring in advanced stages of Parkinson9s disease (PD). METHODS The efficacy of STN stimulation on total motor disability score (unified Parkinson9s disease rating scale (UPDRS) part III) were evaluated in 10 patients with severe Parkinson9s disease. The subscores were then studied separately for limb akinesia, rigidity, and tremor, which are known to respond to Levodopa, and axial signs, including speech, neck rigidity, rising from a chair, posture, gait, and postural stability, which are known to respond less well to Levodopa. Patients were clinically assessed in the “off” and “on” drug condition during a Levodopa challenge test performed before surgical implantation of stimulation electrodes and repeated 6 months after surgery under continuous STN stimulation. A complementary score for axial symptoms from the “activities of daily living” (ADL)—that is, speech, swallowing, turning in bed, falling, walking, and freezing—was obtained from each patient9s questionnaire (UPDRS, part II). RESULTS Improvements in total motor disability score (62%), limb signs (62%), and axial signs (72%) obtained with STN stimulation were statistically comparable with those obtained with Levodopa during the preoperative challenge (68%, 69%, and 59%, respectively). When Levodopa and STN stimulation were combined there was a further improvement in total motor disability (80%) compared with preoperative Levodopa administration. This consisted largely of an additional improvement in axial signs (84%) mainly for posture and postural stability, no further improvement in Levodopa responsive signs being found. Axial symptoms from the ADL showed similar additional improvement when Levodopa and STN stimulation were combined. CONCLUSION These findings suggest that bilateral STN stimulation improves most axial features of Parkinson9s disease and that a synergistic effect can be obtained when stimulation is used in conjunction with Levodopa treatment.
Ahmed A Othman - One of the best experts on this subject based on the ideXlab platform.
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jejunal infusion of Levodopa carbidopa intestinal gel versus oral administration of Levodopa carbidopa tablets in japanese subjects with advanced parkinson s disease pharmacokinetics and pilot efficacy and safety
Clinical Pharmacokinectics, 2015Co-Authors: Ahmed A Othman, Sandeep Dutta, Krai Chatamra, Janet Benesh, Mohamed-eslam F. Mohamed, Masayoshi Yanagawa, Masahiro NagaiAbstract:Background and Objective Oral Levodopa-carbidopa (LC-oral) treatment in advanced Parkinson’s disease (PD) is associated with motor complications due to large fluctuations in Levodopa plasma concentrations. Levodopa–carbidopa intestinal gel (LCIG) provides individualized continuous Levodopa–carbidopa delivery through intrajejunal infusion. This study evaluated the pharmacokinetics, safety, and efficacy of LCIG relative to LC-oral in Japanese subjects with advanced PD.
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population pharmacokinetics of Levodopa in subjects with advanced parkinson s disease Levodopa carbidopa intestinal gel infusion vs oral tablets
British Journal of Clinical Pharmacology, 2014Co-Authors: Ahmed A Othman, Sandeep DuttaAbstract:Aims Levodopa-carbidopa intestinal gel (LCIG) provides continuous Levodopa-carbidopa delivery through intrajejunal infusion. This study characterized the population pharmacokinetics of Levodopa following a 16 h jejunal infusion of LCIG or frequent oral administration of Levodopa-carbidopa tablets (LC-oral) in subjects with advanced Parkinson's disease (PD).
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Pharmacokinetics of Levodopa, Carbidopa, and 3-O-Methyldopa Following 16-hour Jejunal Infusion of Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson's Disease Patients
The AAPS journal, 2012Co-Authors: Dag Nyholm, Sandeep Dutta, Krai Chatamra, Per Odin, Anders Johansson, Charles Locke, Ahmed A OthmanAbstract:Motor complications of Parkinson’s disease (PD) are a consequence of pulsatile dopaminergic stimulation from standard oral Levodopa therapy. Levodopa–carbidopa intestinal gel (LCIG) is infused continuously via an intrajejunal percutaneous gastrostomy tube. This was the first study designed to characterize the full pharmacokinetic profiles of Levodopa, carbidopa, and Levodopa metabolite, 3-O-methyldopa (3-OMD) with 16-h LCIG infusion. Nineteen advanced PD patients (mean age, 65 years) who were on LCIG therapy for ≥30 days were enrolled. Patients received their individualized LCIG infusion doses, and serial pharmacokinetic samples were collected. Eighteen patients completed the study; 19 were assessed for safety. Mean (SD) total Levodopa and carbidopa doses were 1,580 (403) and 395 (101) mg, respectively. Mean (SD) Cavg (μg/mL) were 2.9 (0.84) for Levodopa, 17.1 (4.99) for 3-OMD, and 0.22 (0.08) for carbidopa. The degree of fluctuation [defined as (Cmax − Cmin)/Cavg] in Levodopa, 3-OMD, and carbidopa plasma concentrations was very low (0.52, 0.21, and 0.96, respectively) during hours 2–16 of infusion. Accordingly, the within-subject coefficients of variation in Levodopa, 3-OMD, and carbidopa concentrations were low (13%, 6%, and 19%, respectively). Three patients (16%) reported ≥1 treatment-emergent adverse event; none were considered severe. Continuous intrajejunal LCIG infusion maintained stable plasma Levodopa levels over 16 h. Consistent exposure has been shown to reduce motor and nonmotor complications associated with oral medications. LCIG was well tolerated, consistent with previous reports.
Robert A. Hauser - One of the best experts on this subject based on the ideXlab platform.
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Extended-release carbidopa-Levodopa (IPX066) compared with immediate-release carbidopa-Levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial
The Lancet. Neurology, 2013Co-Authors: Robert A. Hauser, Kapil D. Sethi, Ann Hsu, Sherron Kell, Alberto J. Espay, Mark Stacy, William G. Ondo, Martin O'connell, Suneel GuptaAbstract:Summary Background IPX066 is an oral, extended-release, capsule formulation of carbidopa-Levodopa. We aimed to assess this extended-release formulation versus immediate-release carbidopa-Levodopa in patients with Parkinson's disease and motor fluctuations. Methods We did a phase 3, randomised, double-blind, double-dummy study at 68 academic and clinical centres in North America and Europe. Patients with Parkinson's disease who had at least 2·5 h per day of off-time underwent 3 weeks of open-label immediate-release carbidopa-Levodopa dose adjustment followed by 6 weeks of open-label extended-release carbidopa-Levodopa dose conversion. These patients were then randomly allocated (1:1), by use of an interactive web-response system, to 13 weeks of double-blind treatment with extended-release or immediate-release carbidopa-Levodopa plus matched placebos. The primary efficacy measure was off-time as a percentage of waking hours in all patients randomly allocated to treatment groups, adjusted for baseline value. This study is registered with ClinicalTrials.gov, number NCT00974974. Findings Between Sept 29, 2009, and Aug 16, 2010, we enrolled 471 participants, of whom 393 (83%) were randomly allocated in the double-blind maintenance period and were included in the main efficacy analyses. As a percentage of waking hours, 201 patients treated double-blind with extended-release carbidopa-Levodopa (mean 3·6 doses per day [SD 0·7]) had greater reductions in off-time than did 192 patients treated double-blind with immediate-release carbidopa-Levodopa (mean 5·0 doses per day [1·2]). Covariate-adjusted end-of-study means were 23·82% (SD 14·91) for extended-release carbidopa-Levodopa and 29·79% (15·81) for immediate-release carbidopa-Levodopa (mean difference −5·97, 95% CI −9·05 to −2·89; p vs two [1%] of 192 patients allocated immediate-release carbidopa-Levodopa), nausea (six [3%] vs three [2%]), and falls (six [3%] vs four [2%]). Interpretation Extended-release carbidopa-Levodopa might be a useful treatment for patients with Parkinson's disease who have motor fluctuations, with potential benefits including decreased off-time and reduced Levodopa dosing frequency. Funding Impax Laboratories.
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crossover comparison of ipx066 and a standard Levodopa formulation in advanced parkinson s disease
Movement Disorders, 2011Co-Authors: Robert A. Hauser, Ann Hsu, Sherron Kell, Aaron Ellenbogen, Leo Verhagen Metman, Martin Oconnell, Nishit B Modi, Hsuanming Yao, Suneel K GuptaAbstract:The objective of the study was to compare the pharmacokinetics, motor effects, and safety of IPX066, a novel extended-release formulation of carbidopa-Levodopa, with an immediate-release carbidopa-Levodopa formulation in advanced Parkinson's disease. We performed an open-label crossover study in 27 subjects with advanced Parkinson's disease experiencing motor fluctuations on Levodopa therapy. Subjects were randomized 1:1 to 8 days' treatment with either immediate-release carbidopa-Levodopa followed by IPX066 or IPX066 followed by immediate-release carbidopa-Levodopa. Pharmacokinetic and motor assessments were undertaken on day 1 for 8 hours (following a single dose) and on day 8 for 12 hours (during multiple-dose administration). Following a single dose of IPX066 or immediate-release carbidopa-Levodopa, plasma Levodopa concentrations increased at a similarly rapid rate and were sustained above 50% of peak concentration for 4 hours with IPX066 versus 1.4 hours with immediate-release carbidopa-Levodopa (P < .0001). Multiple-dose data showed IPX066 substantially reduced variability in plasma Levodopa concentrations despite a lower dosing frequency (mean, 3.5 vs 5.4 administrations per day). In addition, total Levodopa exposure during IPX066 treatment was approximately 87% higher, whereas the increase in Levodopa C(max) was approximately 30% compared with immediate-release carbidopa-Levodopa. Both products were well tolerated. IPX066 provided more sustained plasma Levodopa concentrations than immediate-release carbidopa-Levodopa. Larger, longer-term, well-controlled studies should be conducted to provide rigorous assessment of the clinical effects of IPX066.
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Levodopa carbidopa entacapone 200 50 200 mg stalevo 200 in the treatment of parkinson s disease a case series
Cases Journal, 2009Co-Authors: Kapil D. Sethi, Robert A. Hauser, Stuart Isaacson, Terry McclainAbstract:Levodopa continues to be the most efficacious and widely used treatment for Parkinson's disease. Levodopa dosing is understood to be critical for the optimal control of symptoms, and increasing the Levodopa dose is a common method to treat advancing disease. Escalating Levodopa dosages coupled with disease progression is associated with increasing likelihood of developing Levodopa-induced dyskinesia. Moreover, frequent and complicated dosing schemes, combined with limited dose availability, leads to increasing pill burden and its associated impairment of patient adherence issues. Levodopa/carbidopa/entacapone has been shown to improve the pharmacokinetic profile of Levodopa and provide superior symptomatic control compared with conventional Levodopa/dopa decarboxylase inhibitor therapy. We report four case histories describing clinical experience of using Levodopa/carbidopa/entacapone 200/50/200 mg, one of the latest doses of this formulation, in a range of patients with Parkinson's disease. These cases illustrate that Levodopa/carbidopa/entacapone 200/50/200 mg provides improvements in symptomatic control and convenience, and that switching to this dose was not associated with safety concerns.
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Levodopa carbidopa entacapone stalevo
Neurology, 2004Co-Authors: Robert A. HauserAbstract:A Levodopa/carbidopa/entacapone combination product (Stalevo) was recently approved to treat patients with idiopathic Parkinson’s disease (PD) who experience end-of-dose “wearing-off.” Stalevo is available in dose combinations of Levodopa/carbidopa/entacapone 50/12.5/200 mg (Stalevo 50), 100/25/200 mg (Stalevo 100), and 150/37.5/200 mg (Stalevo 150). A series of pharmacokinetic studies demonstrated bioequivalence between Stalevo and corresponding dosages of Levodopa/carbidopa plus entacapone. A clinical advantage of Stalevo is that patients can take one pill rather than two (or more) separate tablets. In addition, Stalevo 50 and 100 tablets are smaller than entacapone tablets. These advantages may be particularly beneficial for patients taking many pills, those who have difficulty following complex medication regimens, and those with swallowing difficulty. Most PD patients taking Levodopa/carbidopa immediate-release (IR) plus entacapone can be directly switched to the corresponding dose Stalevo product. For fluctuating PD patients taking Levodopa/carbidopa IR without entacapone, switching to the corresponding Stalevo tablet is analogous to adding entacapone. In switching patients who are receiving Levodopa/carbidopa controlled-release (CR), it should be noted that the bioavailability of Levodopa from Levodopa/carbidopa CR is approximately 70–75% that of Levodopa/carbidopa IR products, including Stalevo.