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Comparison of the antiparkinsonian and antidyskinetic effects of hemantane and amantadine
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Abstracts / Parkinsonism and Related Disorders 22 (2016) e87ee141
currently approved in all 30 countries of the European Economic Area and this therapy is available in Italy since 2005. The study was aimed at: 1) quantifying the level of diffusion of LCIG in Italy and 2) assessing treatment management practice in different movement disorders centres. Methods: 32 centres in Italy completed a survey covering LCIG issues. The questionnaire included questions about clinical, practical, and reimbursements aspects. Results: Clinical features of 653 patients were evaluated. The majority of respondents reported uniform criteria about practical management: involvement of multidisciplinary team, biochemical, EMG and neuropsychological test execution. On the contrary, selection criteria are not standardized and many centres (60%) use internal guidelines. The mode of drug’s dispensing and reimbursement is not homogeneous. The rate of overall non-serious adverse events is of 48%: weight decrease and chronic polyneuropathy were the most frequently reported. 41% of centres use replacement therapy with Vitamin B12 and Folate since LCIG start and for all treatment duration. 81% of the centres presented at least 1 case of discontinuation of therapy (primarily because of device or infusion-related adverse events). Conclusions: Data from this survey may improve knowledge about the implementation of LICG therapy in Italy and can be the starting point to develop uniform national guidelines in order to guide health care staff and administrators in optimizing therapeutic management for PD patients. References 1. Angelo Antonini et al. on behalf of the GLORIA study investigators and coordinators. Global long-term study on motor and non-motor symptoms and safety of levodopa carbidopa intestinal gel in routine care of advanced Parkinson’s disease patients; 12 month interim outcomes. Parkinsonism and Related Disorders 2015;21:231-235. 2. Stephen Wørlich Pedersen et al. Practical Guidance on How to Handle Levodopa/Carbidopa Intestinal Gel Therapy of Advanced PD in a Movement Disorder Clinic. The Open Neurology Journal, 2012;6:37-50. 3. Daniela Calandrella et al. Causes of withdrawal of duodenal levodopa infusion in advanced Parkinson disease. Neurology 2015 84:1e 4. 4. Francesca Mancini et al. Prevalence and features of peripheral neuropathy in Parkinson’s disease patients under different therapeutic regimens Parkinsonism and Related Disorders 2013;21. 5. Zibetti M. Levodopa/carbidopa intestinal gel infusion in advanced Parkinson’s disease: a 7-year experience.European Journal of Neurology 2014;21:312-318. P 2.070. COMPARISON OF THE ANTIPARKINSONIAN AND ANTIDYSKINETIC EFFECTS OF HEMANTANE AND AMANTADINE Elena Ivanova, Inga Kapitsa, Elena Valdman, Tatyana Voronina. Laboratory of Psychopharmacology, Zakusov Institute of Pharmacology, Moscow, Russian Federation Objectives: antiparkinsonian drug hemantane is an uncompetitive, low affinity NMDA receptor open-channel blocker. Its closest analog is an antiparkinsonian and antidyskinetic drug amantadine. The aim of this study is to compare antiparkinsonian and antidyskinetic effects of hemantane and amantadine. Methods: male outbred rats were given injections of 6-hydroxydopamine (6-OHDA) into the left medial forebrain bundle 12mg/4ml to induce hemiparkinsonism. Two weeks later rats were intraperitonially (i.p.) administered hemantane (5 mg/kg), amantadine (20 mg/kg), saline (6-OHDA and sham operated groups) for 21 days. On days 21, 28 and 35 after 6-OHDA injections the rats’ behavior was evaluated in ‘cylinder test’ and ‘footstep test’. To achieve levodopa-induced dyskinesia (LID), rats were started on daily injections of levodopa (10 mg/kg i.p.) three weeks after 6-OHDA injections. Abnormal involuntary movements (AIMs) for limb, axial, orolingual and rotatory movements were rated on a scale from 0 to 4. Treatment with hemantane (10 mg/kg i.p.) and amantadine (20 mg/kg i.p.) was initiated one week before levodopa therapy. Results: in the model of hemiparkinsonism, the antiparkinsonian effect of hemantane does not differ from amantadine (Table 1). In the model of LID, hemantane showed significant antidyskinetic activity comparable to amantadine (Table 2). Conclusions: hemantane demonstrates an antiparkinsonian (5 mg/kg)
and antidyskinetic (10 mg/kg) effect similar to amantadine (20 mg/kg).
Table 1Effects of hemantane and amantadine on forelimb akinesia as a characteristic of hemiparkinsonian lesion in ʻFootstep testʼ and ʻCylinder testʼ (Mean±SEM). Groups
ʻFootstep testʼ: right forelimb steps - % of all steps with the left and right forepaws day 21
day 28
day 35
Sham-operated 6-OHDA Hemantane Amantadine
46.9±3.50 20.0±7.45# 46.2±2.28* 40.9±6.27*
45.7±3.12 26.8±5.81# 50.9±1.65* 50.9±4.19*
51.7±1.67 21.1±4.95# 52.6±2.13* 60.9±4.33*
ʻCylinder testʼ on day 35: right forelimb use, % 49.4±0.6 21.7±3.9# 43.7±2.6* 50.5±2.7*
*Significant relative to the 6-OHDA group, p<0.05 (Mann-Whitney) #Significant relative to the Sham-operated group, p<0.05 (Mann-Whitney)
Table 2 Effect of hemantane and amantadine on levodopa-induced dyskinesia (AIMs score, Mean±SEM). Groups
Day of levodopa treatment Day 7
Day 14
Limb AIMs Levodopa 14.4±0.52 13.1±1.15 Hemantane + Levodopa 9.5±3.42* 7.5±2.8* Amantadine + Levodopa 8.3±4.6* 4.3±4.38 Axial AIMs Levodopa 13.6±0.7 14.1±0.91 Hemantane + Levodopa 10.3±3.54 9.3±3.25 Amantadine + Levodopa 9.3±4.81 4.7±4.67* Orolingual AIMs Levodopa 12.1±0.8 8.8±1.33 Hemantane + Levodopa 9.0±0.71* 5.3±2.75 Amantadine + Levodopa 5.0±0.58* 5.7±2.19 Total score for forelimb, axial and orolingual AIMs Levodopa 28.0±1.12 27.2±2.0 Hemantane + Levodopa 19.8±6.96 16.8±5.89* Amantadine + Levodopa 18.0±9.07 9.7±8.69* Rotations Levodopa 13.6±0.88 15.8±0.2 Hemantane + Levodopa 6.0±2.74* 8.8±3.09* Amantadine + Levodopa 11.3±2.41 6.0±4.51*
Day 21 13.5±0.48 7.0±3.2* 3.3±3.3* 14.6±0.45 7.5±3.28* 3.3±3.33* 10.2±1.62 8.5±2.72 5.7±0.88 28.1±0.8 14.5±6.51* 6.7±6.67* 15.2±0.29 7.5±2.88* 3.3±3.33*
*Significant relative to the Levodopa group, p<0.05 (Mann-Whitney).
P 2.071. FAVOURABLE EFFECT OF SAFINAMIDE ON MOOD OVER 2-YEAR TREATMENT OF FLUCTUATING PARKINSON’S DISEASE PATIENTS Carlo Cattaneo 1, Roberto La Ferla 1, Elvira Müller 2, Marco Sardina 3. 1 Medical Department, Zambon SpA, Bresso, Italy; 2 Laser €rrach, Germany; 3 R&D Department, Zambon SpA, Bresso, Italy Analytica, Lo Objective: Safinamide (Xadago®, Zambon SpA, Italy), a new drug with dopaminergic and non-dopaminergic actions, was studied in late stage PD patients in two double-blind, placebo-controlled trials (016 and 018), showing an increase in “ON” time without increasing troublesome dyskinesia. The objective of this post-hoc analysis of studies 016 and 018 is to evaluate the efficacy of safinamide (100 mg/day oral tablets) vs placebo on mood in fluctuating PD patients over 2-year treatment. Methods: The effects of safinamide on mood were investigated on the “emotional well-being” domain of the Parkinson’s Disease Quality of life questionnaire (PDQ-39), the grid version of the Hamilton rating scale for depression (GRID-HAMD) and the percentage of patients reporting depression as an adverse event. Results: Safinamide significantly improved the emotional well-being domain
Abstracts / Parkinsonism and Related Disorders 22 (2016) e87ee141
currently approved in all 30 countries of the European Economic Area and this therapy is available in Italy since 2005. The study was aimed at: 1) quantifying the level of diffusion of LCIG in Italy and 2) assessing treatment management practice in different movement disorders centres. Methods: 32 centres in Italy completed a survey covering LCIG issues. The questionnaire included questions about clinical, practical, and reimbursements aspects. Results: Clinical features of 653 patients were evaluated. The majority of respondents reported uniform criteria about practical management: involvement of multidisciplinary team, biochemical, EMG and neuropsychological test execution. On the contrary, selection criteria are not standardized and many centres (60%) use internal guidelines. The mode of drug’s dispensing and reimbursement is not homogeneous. The rate of overall non-serious adverse events is of 48%: weight decrease and chronic polyneuropathy were the most frequently reported. 41% of centres use replacement therapy with Vitamin B12 and Folate since LCIG start and for all treatment duration. 81% of the centres presented at least 1 case of discontinuation of therapy (primarily because of device or infusion-related adverse events). Conclusions: Data from this survey may improve knowledge about the implementation of LICG therapy in Italy and can be the starting point to develop uniform national guidelines in order to guide health care staff and administrators in optimizing therapeutic management for PD patients. References 1. Angelo Antonini et al. on behalf of the GLORIA study investigators and coordinators. Global long-term study on motor and non-motor symptoms and safety of levodopa carbidopa intestinal gel in routine care of advanced Parkinson’s disease patients; 12 month interim outcomes. Parkinsonism and Related Disorders 2015;21:231-235. 2. Stephen Wørlich Pedersen et al. Practical Guidance on How to Handle Levodopa/Carbidopa Intestinal Gel Therapy of Advanced PD in a Movement Disorder Clinic. The Open Neurology Journal, 2012;6:37-50. 3. Daniela Calandrella et al. Causes of withdrawal of duodenal levodopa infusion in advanced Parkinson disease. Neurology 2015 84:1e 4. 4. Francesca Mancini et al. Prevalence and features of peripheral neuropathy in Parkinson’s disease patients under different therapeutic regimens Parkinsonism and Related Disorders 2013;21. 5. Zibetti M. Levodopa/carbidopa intestinal gel infusion in advanced Parkinson’s disease: a 7-year experience.European Journal of Neurology 2014;21:312-318. P 2.070. COMPARISON OF THE ANTIPARKINSONIAN AND ANTIDYSKINETIC EFFECTS OF HEMANTANE AND AMANTADINE Elena Ivanova, Inga Kapitsa, Elena Valdman, Tatyana Voronina. Laboratory of Psychopharmacology, Zakusov Institute of Pharmacology, Moscow, Russian Federation Objectives: antiparkinsonian drug hemantane is an uncompetitive, low affinity NMDA receptor open-channel blocker. Its closest analog is an antiparkinsonian and antidyskinetic drug amantadine. The aim of this study is to compare antiparkinsonian and antidyskinetic effects of hemantane and amantadine. Methods: male outbred rats were given injections of 6-hydroxydopamine (6-OHDA) into the left medial forebrain bundle 12mg/4ml to induce hemiparkinsonism. Two weeks later rats were intraperitonially (i.p.) administered hemantane (5 mg/kg), amantadine (20 mg/kg), saline (6-OHDA and sham operated groups) for 21 days. On days 21, 28 and 35 after 6-OHDA injections the rats’ behavior was evaluated in ‘cylinder test’ and ‘footstep test’. To achieve levodopa-induced dyskinesia (LID), rats were started on daily injections of levodopa (10 mg/kg i.p.) three weeks after 6-OHDA injections. Abnormal involuntary movements (AIMs) for limb, axial, orolingual and rotatory movements were rated on a scale from 0 to 4. Treatment with hemantane (10 mg/kg i.p.) and amantadine (20 mg/kg i.p.) was initiated one week before levodopa therapy. Results: in the model of hemiparkinsonism, the antiparkinsonian effect of hemantane does not differ from amantadine (Table 1). In the model of LID, hemantane showed significant antidyskinetic activity comparable to amantadine (Table 2). Conclusions: hemantane demonstrates an antiparkinsonian (5 mg/kg)
and antidyskinetic (10 mg/kg) effect similar to amantadine (20 mg/kg).
Table 1Effects of hemantane and amantadine on forelimb akinesia as a characteristic of hemiparkinsonian lesion in ʻFootstep testʼ and ʻCylinder testʼ (Mean±SEM). Groups
ʻFootstep testʼ: right forelimb steps - % of all steps with the left and right forepaws day 21
day 28
day 35
Sham-operated 6-OHDA Hemantane Amantadine
46.9±3.50 20.0±7.45# 46.2±2.28* 40.9±6.27*
45.7±3.12 26.8±5.81# 50.9±1.65* 50.9±4.19*
51.7±1.67 21.1±4.95# 52.6±2.13* 60.9±4.33*
ʻCylinder testʼ on day 35: right forelimb use, % 49.4±0.6 21.7±3.9# 43.7±2.6* 50.5±2.7*
*Significant relative to the 6-OHDA group, p<0.05 (Mann-Whitney) #Significant relative to the Sham-operated group, p<0.05 (Mann-Whitney)
Table 2 Effect of hemantane and amantadine on levodopa-induced dyskinesia (AIMs score, Mean±SEM). Groups
Day of levodopa treatment Day 7
Day 14
Limb AIMs Levodopa 14.4±0.52 13.1±1.15 Hemantane + Levodopa 9.5±3.42* 7.5±2.8* Amantadine + Levodopa 8.3±4.6* 4.3±4.38 Axial AIMs Levodopa 13.6±0.7 14.1±0.91 Hemantane + Levodopa 10.3±3.54 9.3±3.25 Amantadine + Levodopa 9.3±4.81 4.7±4.67* Orolingual AIMs Levodopa 12.1±0.8 8.8±1.33 Hemantane + Levodopa 9.0±0.71* 5.3±2.75 Amantadine + Levodopa 5.0±0.58* 5.7±2.19 Total score for forelimb, axial and orolingual AIMs Levodopa 28.0±1.12 27.2±2.0 Hemantane + Levodopa 19.8±6.96 16.8±5.89* Amantadine + Levodopa 18.0±9.07 9.7±8.69* Rotations Levodopa 13.6±0.88 15.8±0.2 Hemantane + Levodopa 6.0±2.74* 8.8±3.09* Amantadine + Levodopa 11.3±2.41 6.0±4.51*
Day 21 13.5±0.48 7.0±3.2* 3.3±3.3* 14.6±0.45 7.5±3.28* 3.3±3.33* 10.2±1.62 8.5±2.72 5.7±0.88 28.1±0.8 14.5±6.51* 6.7±6.67* 15.2±0.29 7.5±2.88* 3.3±3.33*
*Significant relative to the Levodopa group, p<0.05 (Mann-Whitney).
P 2.071. FAVOURABLE EFFECT OF SAFINAMIDE ON MOOD OVER 2-YEAR TREATMENT OF FLUCTUATING PARKINSON’S DISEASE PATIENTS Carlo Cattaneo 1, Roberto La Ferla 1, Elvira Müller 2, Marco Sardina 3. 1 Medical Department, Zambon SpA, Bresso, Italy; 2 Laser €rrach, Germany; 3 R&D Department, Zambon SpA, Bresso, Italy Analytica, Lo Objective: Safinamide (Xadago®, Zambon SpA, Italy), a new drug with dopaminergic and non-dopaminergic actions, was studied in late stage PD patients in two double-blind, placebo-controlled trials (016 and 018), showing an increase in “ON” time without increasing troublesome dyskinesia. The objective of this post-hoc analysis of studies 016 and 018 is to evaluate the efficacy of safinamide (100 mg/day oral tablets) vs placebo on mood in fluctuating PD patients over 2-year treatment. Methods: The effects of safinamide on mood were investigated on the “emotional well-being” domain of the Parkinson’s Disease Quality of life questionnaire (PDQ-39), the grid version of the Hamilton rating scale for depression (GRID-HAMD) and the percentage of patients reporting depression as an adverse event. Results: Safinamide significantly improved the emotional well-being domain