- Email: [email protected]
P2.199 The national deep brain stimulation brain tissue network (DBS-BTN): preliminary results
Poster presentations / Parkinsonism and Related Disorders 15S2 (2009) S29–S199
P2.196 STN high frequency stimulation is effective in Parkinson’s disease with camptocormia: a case report 2 I. Galazky1 , L. Buntjen ¨ , T. Trottenberg3 , L. Niehaus3 , J. Voges4 . 1 Clinic for Neurology, 2 Clinic for Stereotactic Neurosurgery, University of Magdeburg, Magdeburg, 3 Clinic for Neurology, Center for Psychiatry, Winnenden, 4 Clinic for Stereotactic Neurosurgery, University of Magdeburg, Magdeburg, Germany
Introduction: Camptocormia is an increasingly recognized feature of Parkinson’s disease (PD). Underlying pathologies are not fully understood yet. Two non-dopaminergic mechanisms are discussed: (1) Off dystonia causes an over-activity of abdominal muscles. In some cases botulinum toxin injections may be effective. (2) The abnormal posture is caused by weakness of paravertebral muscles. Evidence for this theory is provided by MRI and histopathological findings of myopathic changes. Objective: Deep brain stimulation (DBS) is effective to treat Parkinsonian symptoms with positive response to dopaminergic medication. Some cases of camptocormia are reported to be sensitive to DBS. Choosen targets have been the internal pallidum or the subthalamic nucleus (STN). Case: We report a 54 years old patient who was referred for DBS to treat Parkinson’s disease with camptocormia. She suffered from PD since 10 years and camptocormia first presented after introduction of levodopa to her prior medication 2 years ago. Camptocormia then persisted also without medication and administration of levodopa led to an intensification of painful abdominal cramps additionally. Method: Electrodes for DBS were implanted stereotactically into the bilateral STN. Chronic high frequency stimulation was put on 130 Hz, 60 ms and Voltage was adapted over weeks. Result: Camptocormia improved dramatically by microlesioning effect directly after implantation. Stimulation also led to a marked improvement but to a less extent. Conclusion: STN high frequency stimulation may relieve camptocormia in Parkinson’s disease under defined conditions. Modulation of camptocormia by levodopa and STN DBS in this case lets suggest dopaminergic as well as non-dopaminergic underlying pathologies. P2.197 Essential tremor and spasmodic dysphonia response to bilateral thalamic deep brain stimulation: review of experience and possible mechanism M. Lyons1 , V. Evidente2 . 1 Neurological Surgery, 2 Neurology, Mayo Clinic Arizona, Phoenix, AZ, USA The co-existence of essential tremor and spasmodic dysphonia has been reported in the literature. A patient with symptomatic essential tremor and coincidental spasmodic dysphonia presented to our institution. Her essential tremor was her major disability for which she presented, but the spasmodic dysphonia also caused her symptoms. Spasmodic dysphonia is a primary focal dystonia manifested by loss of control of the vocal muscles during speech secondary to laryngeal muscle spasms. The pathophysiology is not well understood. Deep brain stimulation surgery (DBS) for other focal dystonias has been well reported. Our patient underwent DBS for her essential tremor. We report the first case of bilateral thalamic DBS improving spasmodic dysphonia (SD) in a patient with essential tremor. The potential pathophysiologic mechanisms of this finding are discussed. There have not been previous reports of deep brain stimulation of any target resulting in improvement in spasmodic dysphonia. Reports have noted the effect on midline tremor with bilateral thalamic DBS, but not specific to dysphonia. Findings suggest that the high frequency electrical impulses to the thalamus with deep brain stimulation in patients with multiple sclerosis affected the phonation subsystems differently. In addition, investigators have reported that thalamic DBS appears to activate cerebellothalamocortical pathways rather than suppressing the
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target. This case demonstrates the potential beneficial effects of bilateral thalamic DBS for essential tremor of the upper extremities as well as improvement as a secondary effect for AdSD of the vocal cords. We postulate a possible mechanism of excitatory effect of thalamic stimulation of the cerebello–striatal–thalamo–cortical pathways. P2.198 Bilateral thalamic deep brain stimulation for orthostatic tremor M. Lyons1 , V. Evidente2 , J. Caviness2 , B. Falk2 , R. Hillman2 . 1 Neurological Surgery, 2 Neurology, Mayo Clinic Arizona, Phoenix, AZ, USA Introduction: Orthostatic tremor (OT) was first described in 1984 by Heilman in three patients presenting with leg and trunk tremor on standing that was relieved by walking, sitting, lying, and leaning against a wall. OT affects middle-aged and elderly people who commonly describe unsteadiness in the legs and a fear of falling upon standing, with a latency of several seconds or rarely, a few minutes. Case report: A 75 year old man has had a 10-year history of progressive OT. He had tried various medications for his OT, including clonazepam, valproate, gabapentin, topiramate, and acetazolamide without significant benefits. Before DBS, he would have immediate onset of fine tremors of both legs upon standing. He could only stand in place for 20 seconds at most before needing to sit, lean, or hold on to something. Bilateral thalamic DBS was performed. Results: Three months after DBS, he continued to be able to stand in place at least 7 minutes before needing to sit. Repeat surface EMG study done 3 months post-DBS. On standing from a seated position, there was immediate onset of tremor in the lower extremities on surface EMG, though the tremor bursts were less continuous, less rhythmic, and showing bursts of slower frequency than the previous 13 Hz tremor seen pre-operatively. Conclusions: DBS does not eradicate the tremor completely, but modulates the tremor making it slower in frequency, consistency, and rhythmicity. This ultimately leads to functional improvement of the patient’s ability to stand despite persistence of the tremor. P2.199 The national deep brain stimulation brain tissue network (DBS-BTN): preliminary results V. Vedam-Mai1 , N. Krock2 , M. Ullman2 , W. Shain3 , K. Smith3 , A. Yachnis4 , D. Steindler5 , B. Reynolds1 , S. Merritt2 , J. Wojcieszek6 , C. Vanamburg6 , F. Pagan7 , P. Hogarth8 , J. Marjama-Lyons9 , A. Resnick2 , M. Okun1,2 . 1 Neurosurgery, 2 Neurology, University of Florida, Gainesville, FL, 3 Wadsworth Center, New York State Department of Health, Albany, NY, 4 Pathology, University of Florida, 5 Neuroscience, University of Florida, Gainesville, FL, 6 Indiana University School of Medicine, Indianapolis, IN, 7 Georgetown University Medical Center, Washington, DC, 8 University of Oregon, Portland, OR, 9 University of New Mexico, Albuquerque, NM, USA Background: Over 50,000 DBS devices have been implanted worldwide; however, there remains a paucity of well-characterized post-mortem DBS brains available to researchers. We propose that the overall understanding of DBS can be improved though the establishment of a Deep Brain Stimulation-Brain Tissue Network (DBS-BTN), providing well-documented tissue samples to the research community. Objective: To create a DBS-BTN to preserve high-quality specimens for clinical and basic research. Methods: Standard operating procedures for processing DBS brains were developed. Complete data files were created for individual patients including demographic, clinical, imaging, pathology, and stimulation locations/settings. In select cases post-mortem MRI was performed.
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Poster presentations / Parkinsonism and Related Disorders 15S2 (2009) S29–S199
Results: Eighteen DBS brains were collected from 11 geographically dispersed centers across the U.S. The average age at the time of death was 69.2 years (51–92). The male:female ratio was 7:2. The average post-mortem interval was 10.6 hours. The brain areas targeted included: subthalamic nucleus (STN; n = 19 leads, 12 patients), globus pallidus interna (GPi; n = 8 leads, 5 patients), and ventral, intermediate thalamus (Vim; n = 2 leads, 2 patients). One patient had targets in both STN and Vim. In 16.7% of cases clinical diagnosis failed to match the pathological diagnosis. Detailed information will be presented on this cohort. Conclusions: Preliminary results demonstrate the feasibility and utility of creating a National DBS-BTN resource for the scientific community. Based on these results we plan to expand the Network to include a larger donor pool and enhance sample preparation methods to enable molecular studies and progenitor cell retrieval. P2.200 Cognitive deficits in drug induced parkinsonism J.-S. Kim1 , Y.-D. Kim1 , K.-S. Lee1 , I.-U. Song1 , H.-T. Kim2 . 1 Neurology, The Catholic University of Korea, 2 Neurology, Hanyang University Hospital, Seoul, Republic of Korea Backgroud: Drug-induced parkinsonism (DIP) is the second most common cause of parkinsonism in older population. Older age and female gender, dose and duration of treatment, potency of agent used, cognitive impairment and tardive dyskinesia were reported as risk factor for DIP. However, few studies have been performed on the relationship between the DIP and cognitive impairment. Methods: The cohort for this study comprised 13 consecutive patients with DIP, 85 patients with Parkinson’s disease (PD) and controls, all of who completed an Unified Parkinson’s Disease Rating Score (UPDRS), brain MRI, and underwent a detailed neuropsychological investigation. The white matter intensities were rated using the semiquantitative visual rating system proposed by Scheltens et al. Results: The DIP group was significantly older than other groups, and the DIP and IPD groups had less education than controls. After controlling age and educational duration, DIP and IPD groups significantly impaired than controls in most neuropsychological test domains except language function test. The DIP group showed significantly more hyperintensities in periventricular white matter than IPD group, however, there was no difference in another brain region. The cerebro-vascular risk factors were more prevalent in DIP group than IPD group. The linear regression analysis in DIP group revealed that initial UPDRS independently associated with some of cognitive domains. Conclusion: This study suggests that cognitive impairment is common observed in patients with DIP. In addition, our results also provide the finding that severe motor manifestations are an indicator associated with cognitive deficits in patients with DIP. P2.201 PYM50028 (Cogane™) is a small molecule inducer of GDNF and BDNF that reverses behavioural impairment in MPTP-lesioned macaques T.H. Johnston1 , J.B. Koprich1 , S.H. Fox1 , P.A. Howson2 , J.M. Brotchie1 . Toronto Western Research Institute, Toronto, ON, Canada; 2 Phytopharm plc, Huntingdon, UK 1
Background: An extensive body of scientific data supports a role for neurotrophic factors, including GDNF and BDNF, in the restoration of dopaminergic function in Parkinson’s disease (PD). PYM50028 is a novel small molecule, non-peptide drug that elevates brain GDNF and BDNF levels after oral administration and protects against loss of dopaminergic phenotype in MPTP-mice, a model of PD (Visanji et al. 2008). The effect of PYM50028 in MPTP-lesioned macaques remains unknown. Objective: This study investigated the ability of PYM50028 to reverse MPTP-induced parkinsonism in macaques.
Methods: Fourteen female macaques received MPTP (0.2 mg/kg/day, s.c.) until marked, stable, parkinsonian symptoms developed. Animals (N = 7/group) were randomly assigned to two groups; PYM50028 20 mg/kg/day, p.o.) or vehicle control (HPMC, 0.5% w/v containing Tween 80, 0.2% v/v). Assessments of parkinsonian disability were made at baseline, after MPTP administration and following 18 weeks of PYM50028 administration. Parkinsonian disability was evaluated by post hoc analysis of DVD-recordings by a neurologist blinded to treatment. Results: Administration of PYM50028 for 18 weeks significantly reduced median parkinsonian disability by 43% (P < 0.001) and was most apparent for bradykinesia (P < 0.01), compared to post MPTP administration. No significant change in parkinsonian disability was observed in the MPTP-lesioned macaques treated with vehicle (P > 0.05). Conclusions: Oral administration of PYM50028 over 18 weeks significantly reduced parkinsonian disability supporting the continued development of PYM50028 as both a symptomatic and potentially disease-modifying treatment for PD. This work was supported by the Michael J Fox Foundation. Reference(s) Visanji et al. (2008). FASEB J. 22(7): 2488–97.
P2.202 Levodopa pharmacokinetics following administration of novel gastric retentive extended-release formulations compared to a reference extended-release tablet in Parkinson’s disease patients I.D. Stolyarov1 , S.N. Illarioshkin2 , C. Chen3 , S.Y.E. Hou3 , V.E. Cowles3 , M. Sweeney3 . 1 Institute of Russian Academy of Sciences “Institute of Human Brain of RAS, St. Petersburg, 2 State Institution “Scientific Center of Neurology of RAMS, Moscow, Russia; 3 Product Development, Depomed, Inc, Menlo Park, CA, USA The objective of this study was to compare the pharmacokinetic (PK) profiles of LD delivered from two gastric retentive extended-release (ER) formulations of LD/carbidopa (CD) versus a comparator LD/CD controlled-release (CR) tablet, in 18 patients at least 30 years of age with a diagnosis of idiopathic Parkinson’s disease. The patients had stable disease and a modified Hoehn & Yahr stage ≤3. The study was designed as a randomized, open-label, single-dose, six-sequence, threetreatment, three-period crossover study. Following a fast of at least 4 h the patients were fed a standardized meal and then dosed with one of the test formulations, LD/CD ER 4 h single layer tablet (SL-4H) or LD/CD ER 6 h bilayer tablet (BL-6H) or with the comparator (C-CR). All dosage forms contained 200 mg LD & 50 mg CD. Plasma samples for LD analysis were obtained at various times post-dose. The SL-4H tablet significantly extended the median tmax (4.0 h vs 2.8 h) and the last time above the efficacious threshold of 300 ng/mL (8.4 h vs 6.5 h), while reducing the Cmax (1336 vs 1664) and maintaining bioavailability compared to C-CR. BL-6H exhibited a lower relative bioavailability and a more variable absorption profile compared to the SL-4H or C-CR. These data indicate that a gastric retentive extended-release formulation of LD may achieve a more constant concentration–time profile of LD upon multiple dosing, consequently decreasing the occurrence of dyskinesia which may be associated with peak levodopa concentrations and/or a rapid rise or fall in blood levels.
P2.196 STN high frequency stimulation is effective in Parkinson’s disease with camptocormia: a case report 2 I. Galazky1 , L. Buntjen ¨ , T. Trottenberg3 , L. Niehaus3 , J. Voges4 . 1 Clinic for Neurology, 2 Clinic for Stereotactic Neurosurgery, University of Magdeburg, Magdeburg, 3 Clinic for Neurology, Center for Psychiatry, Winnenden, 4 Clinic for Stereotactic Neurosurgery, University of Magdeburg, Magdeburg, Germany
Introduction: Camptocormia is an increasingly recognized feature of Parkinson’s disease (PD). Underlying pathologies are not fully understood yet. Two non-dopaminergic mechanisms are discussed: (1) Off dystonia causes an over-activity of abdominal muscles. In some cases botulinum toxin injections may be effective. (2) The abnormal posture is caused by weakness of paravertebral muscles. Evidence for this theory is provided by MRI and histopathological findings of myopathic changes. Objective: Deep brain stimulation (DBS) is effective to treat Parkinsonian symptoms with positive response to dopaminergic medication. Some cases of camptocormia are reported to be sensitive to DBS. Choosen targets have been the internal pallidum or the subthalamic nucleus (STN). Case: We report a 54 years old patient who was referred for DBS to treat Parkinson’s disease with camptocormia. She suffered from PD since 10 years and camptocormia first presented after introduction of levodopa to her prior medication 2 years ago. Camptocormia then persisted also without medication and administration of levodopa led to an intensification of painful abdominal cramps additionally. Method: Electrodes for DBS were implanted stereotactically into the bilateral STN. Chronic high frequency stimulation was put on 130 Hz, 60 ms and Voltage was adapted over weeks. Result: Camptocormia improved dramatically by microlesioning effect directly after implantation. Stimulation also led to a marked improvement but to a less extent. Conclusion: STN high frequency stimulation may relieve camptocormia in Parkinson’s disease under defined conditions. Modulation of camptocormia by levodopa and STN DBS in this case lets suggest dopaminergic as well as non-dopaminergic underlying pathologies. P2.197 Essential tremor and spasmodic dysphonia response to bilateral thalamic deep brain stimulation: review of experience and possible mechanism M. Lyons1 , V. Evidente2 . 1 Neurological Surgery, 2 Neurology, Mayo Clinic Arizona, Phoenix, AZ, USA The co-existence of essential tremor and spasmodic dysphonia has been reported in the literature. A patient with symptomatic essential tremor and coincidental spasmodic dysphonia presented to our institution. Her essential tremor was her major disability for which she presented, but the spasmodic dysphonia also caused her symptoms. Spasmodic dysphonia is a primary focal dystonia manifested by loss of control of the vocal muscles during speech secondary to laryngeal muscle spasms. The pathophysiology is not well understood. Deep brain stimulation surgery (DBS) for other focal dystonias has been well reported. Our patient underwent DBS for her essential tremor. We report the first case of bilateral thalamic DBS improving spasmodic dysphonia (SD) in a patient with essential tremor. The potential pathophysiologic mechanisms of this finding are discussed. There have not been previous reports of deep brain stimulation of any target resulting in improvement in spasmodic dysphonia. Reports have noted the effect on midline tremor with bilateral thalamic DBS, but not specific to dysphonia. Findings suggest that the high frequency electrical impulses to the thalamus with deep brain stimulation in patients with multiple sclerosis affected the phonation subsystems differently. In addition, investigators have reported that thalamic DBS appears to activate cerebellothalamocortical pathways rather than suppressing the
S143
target. This case demonstrates the potential beneficial effects of bilateral thalamic DBS for essential tremor of the upper extremities as well as improvement as a secondary effect for AdSD of the vocal cords. We postulate a possible mechanism of excitatory effect of thalamic stimulation of the cerebello–striatal–thalamo–cortical pathways. P2.198 Bilateral thalamic deep brain stimulation for orthostatic tremor M. Lyons1 , V. Evidente2 , J. Caviness2 , B. Falk2 , R. Hillman2 . 1 Neurological Surgery, 2 Neurology, Mayo Clinic Arizona, Phoenix, AZ, USA Introduction: Orthostatic tremor (OT) was first described in 1984 by Heilman in three patients presenting with leg and trunk tremor on standing that was relieved by walking, sitting, lying, and leaning against a wall. OT affects middle-aged and elderly people who commonly describe unsteadiness in the legs and a fear of falling upon standing, with a latency of several seconds or rarely, a few minutes. Case report: A 75 year old man has had a 10-year history of progressive OT. He had tried various medications for his OT, including clonazepam, valproate, gabapentin, topiramate, and acetazolamide without significant benefits. Before DBS, he would have immediate onset of fine tremors of both legs upon standing. He could only stand in place for 20 seconds at most before needing to sit, lean, or hold on to something. Bilateral thalamic DBS was performed. Results: Three months after DBS, he continued to be able to stand in place at least 7 minutes before needing to sit. Repeat surface EMG study done 3 months post-DBS. On standing from a seated position, there was immediate onset of tremor in the lower extremities on surface EMG, though the tremor bursts were less continuous, less rhythmic, and showing bursts of slower frequency than the previous 13 Hz tremor seen pre-operatively. Conclusions: DBS does not eradicate the tremor completely, but modulates the tremor making it slower in frequency, consistency, and rhythmicity. This ultimately leads to functional improvement of the patient’s ability to stand despite persistence of the tremor. P2.199 The national deep brain stimulation brain tissue network (DBS-BTN): preliminary results V. Vedam-Mai1 , N. Krock2 , M. Ullman2 , W. Shain3 , K. Smith3 , A. Yachnis4 , D. Steindler5 , B. Reynolds1 , S. Merritt2 , J. Wojcieszek6 , C. Vanamburg6 , F. Pagan7 , P. Hogarth8 , J. Marjama-Lyons9 , A. Resnick2 , M. Okun1,2 . 1 Neurosurgery, 2 Neurology, University of Florida, Gainesville, FL, 3 Wadsworth Center, New York State Department of Health, Albany, NY, 4 Pathology, University of Florida, 5 Neuroscience, University of Florida, Gainesville, FL, 6 Indiana University School of Medicine, Indianapolis, IN, 7 Georgetown University Medical Center, Washington, DC, 8 University of Oregon, Portland, OR, 9 University of New Mexico, Albuquerque, NM, USA Background: Over 50,000 DBS devices have been implanted worldwide; however, there remains a paucity of well-characterized post-mortem DBS brains available to researchers. We propose that the overall understanding of DBS can be improved though the establishment of a Deep Brain Stimulation-Brain Tissue Network (DBS-BTN), providing well-documented tissue samples to the research community. Objective: To create a DBS-BTN to preserve high-quality specimens for clinical and basic research. Methods: Standard operating procedures for processing DBS brains were developed. Complete data files were created for individual patients including demographic, clinical, imaging, pathology, and stimulation locations/settings. In select cases post-mortem MRI was performed.
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Poster presentations / Parkinsonism and Related Disorders 15S2 (2009) S29–S199
Results: Eighteen DBS brains were collected from 11 geographically dispersed centers across the U.S. The average age at the time of death was 69.2 years (51–92). The male:female ratio was 7:2. The average post-mortem interval was 10.6 hours. The brain areas targeted included: subthalamic nucleus (STN; n = 19 leads, 12 patients), globus pallidus interna (GPi; n = 8 leads, 5 patients), and ventral, intermediate thalamus (Vim; n = 2 leads, 2 patients). One patient had targets in both STN and Vim. In 16.7% of cases clinical diagnosis failed to match the pathological diagnosis. Detailed information will be presented on this cohort. Conclusions: Preliminary results demonstrate the feasibility and utility of creating a National DBS-BTN resource for the scientific community. Based on these results we plan to expand the Network to include a larger donor pool and enhance sample preparation methods to enable molecular studies and progenitor cell retrieval. P2.200 Cognitive deficits in drug induced parkinsonism J.-S. Kim1 , Y.-D. Kim1 , K.-S. Lee1 , I.-U. Song1 , H.-T. Kim2 . 1 Neurology, The Catholic University of Korea, 2 Neurology, Hanyang University Hospital, Seoul, Republic of Korea Backgroud: Drug-induced parkinsonism (DIP) is the second most common cause of parkinsonism in older population. Older age and female gender, dose and duration of treatment, potency of agent used, cognitive impairment and tardive dyskinesia were reported as risk factor for DIP. However, few studies have been performed on the relationship between the DIP and cognitive impairment. Methods: The cohort for this study comprised 13 consecutive patients with DIP, 85 patients with Parkinson’s disease (PD) and controls, all of who completed an Unified Parkinson’s Disease Rating Score (UPDRS), brain MRI, and underwent a detailed neuropsychological investigation. The white matter intensities were rated using the semiquantitative visual rating system proposed by Scheltens et al. Results: The DIP group was significantly older than other groups, and the DIP and IPD groups had less education than controls. After controlling age and educational duration, DIP and IPD groups significantly impaired than controls in most neuropsychological test domains except language function test. The DIP group showed significantly more hyperintensities in periventricular white matter than IPD group, however, there was no difference in another brain region. The cerebro-vascular risk factors were more prevalent in DIP group than IPD group. The linear regression analysis in DIP group revealed that initial UPDRS independently associated with some of cognitive domains. Conclusion: This study suggests that cognitive impairment is common observed in patients with DIP. In addition, our results also provide the finding that severe motor manifestations are an indicator associated with cognitive deficits in patients with DIP. P2.201 PYM50028 (Cogane™) is a small molecule inducer of GDNF and BDNF that reverses behavioural impairment in MPTP-lesioned macaques T.H. Johnston1 , J.B. Koprich1 , S.H. Fox1 , P.A. Howson2 , J.M. Brotchie1 . Toronto Western Research Institute, Toronto, ON, Canada; 2 Phytopharm plc, Huntingdon, UK 1
Background: An extensive body of scientific data supports a role for neurotrophic factors, including GDNF and BDNF, in the restoration of dopaminergic function in Parkinson’s disease (PD). PYM50028 is a novel small molecule, non-peptide drug that elevates brain GDNF and BDNF levels after oral administration and protects against loss of dopaminergic phenotype in MPTP-mice, a model of PD (Visanji et al. 2008). The effect of PYM50028 in MPTP-lesioned macaques remains unknown. Objective: This study investigated the ability of PYM50028 to reverse MPTP-induced parkinsonism in macaques.
Methods: Fourteen female macaques received MPTP (0.2 mg/kg/day, s.c.) until marked, stable, parkinsonian symptoms developed. Animals (N = 7/group) were randomly assigned to two groups; PYM50028 20 mg/kg/day, p.o.) or vehicle control (HPMC, 0.5% w/v containing Tween 80, 0.2% v/v). Assessments of parkinsonian disability were made at baseline, after MPTP administration and following 18 weeks of PYM50028 administration. Parkinsonian disability was evaluated by post hoc analysis of DVD-recordings by a neurologist blinded to treatment. Results: Administration of PYM50028 for 18 weeks significantly reduced median parkinsonian disability by 43% (P < 0.001) and was most apparent for bradykinesia (P < 0.01), compared to post MPTP administration. No significant change in parkinsonian disability was observed in the MPTP-lesioned macaques treated with vehicle (P > 0.05). Conclusions: Oral administration of PYM50028 over 18 weeks significantly reduced parkinsonian disability supporting the continued development of PYM50028 as both a symptomatic and potentially disease-modifying treatment for PD. This work was supported by the Michael J Fox Foundation. Reference(s) Visanji et al. (2008). FASEB J. 22(7): 2488–97.
P2.202 Levodopa pharmacokinetics following administration of novel gastric retentive extended-release formulations compared to a reference extended-release tablet in Parkinson’s disease patients I.D. Stolyarov1 , S.N. Illarioshkin2 , C. Chen3 , S.Y.E. Hou3 , V.E. Cowles3 , M. Sweeney3 . 1 Institute of Russian Academy of Sciences “Institute of Human Brain of RAS, St. Petersburg, 2 State Institution “Scientific Center of Neurology of RAMS, Moscow, Russia; 3 Product Development, Depomed, Inc, Menlo Park, CA, USA The objective of this study was to compare the pharmacokinetic (PK) profiles of LD delivered from two gastric retentive extended-release (ER) formulations of LD/carbidopa (CD) versus a comparator LD/CD controlled-release (CR) tablet, in 18 patients at least 30 years of age with a diagnosis of idiopathic Parkinson’s disease. The patients had stable disease and a modified Hoehn & Yahr stage ≤3. The study was designed as a randomized, open-label, single-dose, six-sequence, threetreatment, three-period crossover study. Following a fast of at least 4 h the patients were fed a standardized meal and then dosed with one of the test formulations, LD/CD ER 4 h single layer tablet (SL-4H) or LD/CD ER 6 h bilayer tablet (BL-6H) or with the comparator (C-CR). All dosage forms contained 200 mg LD & 50 mg CD. Plasma samples for LD analysis were obtained at various times post-dose. The SL-4H tablet significantly extended the median tmax (4.0 h vs 2.8 h) and the last time above the efficacious threshold of 300 ng/mL (8.4 h vs 6.5 h), while reducing the Cmax (1336 vs 1664) and maintaining bioavailability compared to C-CR. BL-6H exhibited a lower relative bioavailability and a more variable absorption profile compared to the SL-4H or C-CR. These data indicate that a gastric retentive extended-release formulation of LD may achieve a more constant concentration–time profile of LD upon multiple dosing, consequently decreasing the occurrence of dyskinesia which may be associated with peak levodopa concentrations and/or a rapid rise or fall in blood levels.