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† Compared to placebo
1. Xadago (safinamide). Summary of product characteristics. 2. Kulisevsky J. Safinamide - A Unique Treatment Targeting Both Dopaminergic and Non-Dopaminergic Systems. Eur Neurol Rev 2016;11(2):101-5. 3. Borgohain R, et al. Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations. Mov Disord. 2014;29(2):229-37. 4. Borgohain R, et al. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson’s disease. Mov Disord. 2014;29(10):1273-80. 5. Schapira AH, et al. Assessment of Safety and Efficacy of Safinamide as a levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurol. 2017;74(2):216-224.
The pathophysiology of Parkinson's disease
Parkinson’s disease is a slow, progressive, degenerative disorder largely characterised by striatal dopaminergic depletion. However, alterations in other neurochemical pathways are also implicated (Calabresi et al, 2017).
The degeneration of nigrostriatal dopaminergic neurons causes chain reactions, resulting in the overstimulation of glutamate (Jenner et al, 2019). Parkinson’s disease is associated with elevated levels of glutamate within the basal ganglia (Zhang et al, 2016).
Motor implications of glutamatergic overstimulation include:
(Jenner et al, 2019)
Apoptosis of dopaminergic neurons, contributing to levodopa-induced dyskinesia
Non-motor implications of glutamatergic overstimulation include:
(Jenner et al, 2019)
Pain
Cognitive impairment
Mood disturbances
Mechanism of action
Xadago has a unique dual mechanism of action (Kulisevsky et al, 2016):
Dopaminergic mechanism
MAO-B, alongside COMT, is responsible for dopamine metabolism, and is found localised in glial cells (Caccia et al, 2006). Xadago selectively and reversibly inhibits MAO-B, which prolongs the lifetime activity of dopamine in the synaptic cleft (Calabresi et al, 2017).
Non-dopaminergic mechanism
Parkinson’s Disease is associated with elevated levels of glutamate within the basal ganglia (Zhang et al, 2016). Xadago inhibits sodium and calcium voltage-dependent channels, modulating glutamate release (Calabresi et al, 2017).
To what extent the non-dopaminergic effects contribute to the overall effect has not been established (Xadago (safinamide), Summary of Product Characteristics).
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Watch Professor Peter Jenner, Emeritus Professor of Pharmacology at King’s College London, provide an overview of the pathophysiology of Parkinson's disease and the mechanism of action of Xadago.
The SYNAPSES study
The SYNAPSES trial was a European, multicenter, retrospective-prospective cohort StudY to observe the safiNAmide safety profile and pattern of use in clinical Practice during the firSt post commErcialisation phaSe.
The study was designed to investigate the use of safinamide in routine clinical practice, as recommended by the European Medicines Agency.
The trial reinforced the previously documented safety profile of safinamide even in special groups of patients, and showed clinically significant improvements in motor complications and motor scores in the UPDRS scale (Abbruzzese et al, 2021).
Extending Choice is our flagship annual event bringing together a range of expert speakers who present on current and pertinent topics in Parkinson's disease.
Check out the session content available at the link here and subscribe now to ensure you receive your invite to the next educational event and other promotional updates.
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Expert speaker sessions
A number of expert healthcare professionals discuss relevant topics in Parkinson's disease.
Parkinson's Academy webinars
A series of educational webinars hosted by Neurology Academy, sponsored by Zambon UK.
References
Abbruzzese et al., 2021: A European Observational Study to Evaluate the Safety and the Effectiveness of Safinamide in Routine Clinical Practice: The SYNAPSES Trial. Journal of Parkinsons Disease. 2021;11(1):187-198
Borgohain R, et al. Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations. Mov Disord. 2014;29(2):229-37.
Borgohain R, et al. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson’s disease. Mov Disord. 2014;29(10):1273-80.
Caccia C, Maj R, Calabresi M, et al. Safinamide: from molecular targets to a new anti-Parkinson drug. Neurology. 2006;67:S18-23
Calabresi P, Kulisevsky J. Safinamide as Add-on Therapy – Moving Beyond Dopamine for a Multifaceted Approach in Parkinson’s Disease European Neuro Review. 2017; 12(Suppl. 5):2-6
Kulisevsky J. Safinamide - A Unique Treatment Targeting Both Dopaminergic and Non-Dopaminergic Systems. Eur Neurol Rev 2016;11(2):101-5.
Jenner P., Caccia C. The Role of Glutamate in the Healthy Brain and in the Pathophysiology of Parkinson’s Disease. Eur. Neurol. Rev. 2019; 14,2–12
Schapira AH, et al. Assessment of Safety and Efficacy of Safinamide as a levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurol. 2017;74(2):216-224.
Xadago (safinamide). Summary of Product Characteristics.
Zhang Y, Tan F, Xu P, Qu S. Recent advance in the relationship between excitatory amino acid transporters and Parkinson’s disease. Neural Plasticity. 2016
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June 2023