Abstract:The aim of this study was to evaluate the pressor response to oral tyramine during repeated administration of oral safinamide in healthy volunteers. Twelve females and eight males aged 52.7 ± 4.9 years entered the study. An oral tyramine screening test was conducted to select subjects sensitive to the tyramine pressor effect on systolic blood pressure (SBP) in the dose range of 200-400 mg. Safinamide 300 mg was then administered once daily under fasting conditions. Starting on day 5 (safinamide pharmacokinetic… Show more
“…volunteers safinamide 300 mg administered o.d. under fasting conditions did not change the tyramine pressorresponse at steady state after 6-7 days of treatment 31. …”
Parkinson’s disease is associated with motor complications, especially dyskinesias, which limit dopaminergic replacement therapy. Safinamide is a water-soluble, orally active a-aminoamide derivative that modulates dopaminergic and glutamatergic neurotransmission with a unique dual mechanism of action. It improves motor symptoms, motor complications, quality of life and ‘on’ and ‘off’ time even in combination with other Parkinson’s disease (PD) medications, such as dopamine agonists and levodopa (LD). Safinamide reduces ‘off’ time and extends ‘on’ time without troublesome dyskinesia. Furthermore, safinamide maintains its effects after long-term treatment and has a favourable pharmacokinetic and side-effect profile. It therefore has the potential to become an important drug in PD management. This review will summarise data from animals, healthy human subjects and patients with PD on the long-term efficacy and safety of safinamide.
“…volunteers safinamide 300 mg administered o.d. under fasting conditions did not change the tyramine pressorresponse at steady state after 6-7 days of treatment 31. …”
Parkinson’s disease is associated with motor complications, especially dyskinesias, which limit dopaminergic replacement therapy. Safinamide is a water-soluble, orally active a-aminoamide derivative that modulates dopaminergic and glutamatergic neurotransmission with a unique dual mechanism of action. It improves motor symptoms, motor complications, quality of life and ‘on’ and ‘off’ time even in combination with other Parkinson’s disease (PD) medications, such as dopamine agonists and levodopa (LD). Safinamide reduces ‘off’ time and extends ‘on’ time without troublesome dyskinesia. Furthermore, safinamide maintains its effects after long-term treatment and has a favourable pharmacokinetic and side-effect profile. It therefore has the potential to become an important drug in PD management. This review will summarise data from animals, healthy human subjects and patients with PD on the long-term efficacy and safety of safinamide.
Heterogeneous expression of neurotransmitter deficits results from onset and progression of Parkinson’s disease. Intervals, characterized by reappearance of motor and associated certain nonmotor symptoms, determine the end of good tolerability and efficacy of oral levodopa therapy. These “OFF” states result from levodopa pharmacokinetics and disease progression-related deterioration of the central buffering capacity for fluctuations of dopamine levels. This review discusses safinamide as an add-on therapeutic agent in orally levodopa-treated patients with “OFF” phenomena. Safinamide provided beneficial effects on “OFF” symptoms in pivotal trials with doses of 50 or 100 mg once daily. Safinamide reversibly inhibits mono-amine oxidase B and declines abnormal glutamate release by modulation of potassium- and sodium ion channels. An ideal candidate for combination with safinamide is opicapone. This inhibitor of peripheral catechol-O-methyltransferase supports continuous brain delivery of levodopa and, thus, the continuous dopaminergic stimulation concept. Both compounds with their once-daily application and good tolerability may complement each other by reduction of necessary oral levodopa intakes and “OFF” times. Thus, a promising, future option will be combination of safinamide and opicapone in one formulation. It will reduce adherence issues and may complement levodopa treatment. It will probably cause less nausea and edema than a dopamine agonist/levodopa regimen.
“… 17 Therefore, while it is still contraindicated in combination with other MAO inhibitors or sympathomimetic drugs, the “cheese effect” has not been demonstrated in safinamide and in theory the risk is much lower. 18 – 20 …”
Safinamide (Xadago®) is a novel medication with both dopaminergic and non-dopaminergic effects, approved first by the European Commission and more recently by the US Food and Drug Administration (FDA) as an adjunctive treatment to carbidopa/levodopa in patients with mid- to late-stage Parkinson’s disease (PD) and motor fluctuations. It works through multiple mechanisms, namely as a reversible selective monoamine oxidase-B inhibitor and through modulation of glutamate release. Safinamide is extensively metabolized via oxidation to several inactive metabolites that are excreted primarily through the urine. Several large Phase III clinical trials of patients with advanced PD with motor fluctuations have shown that safinamide, administered orally at doses of 50–100 mg daily, increased ON time with no or non-troublesome dyskinesia, decreased daily OFF time, improved overall motor function (as measured by Unified Parkinson’s Disease Rating Scale [UPDRS] part III total score), and quality of life (as measured by Clinical Global Impression-Change and 39-item Parkinson’s Disease Questionnaire). In large clinical trials of patients with early PD on a single dopamine agonist, safinamide administered orally at a dose of 100 mg daily improved overall motor function as measured by UPDRS part III total score; however, some of the results reported were exploratory. Safinamide is generally well-tolerated and safe, with few to no treatment-related adverse events. Safinamide does not cause new or worsening dyskinesia and may be able to reduce this symptom in patients reporting it at baseline. Evidence suggests that safinamide is a good option for add-on therapy to carbidopa/levodopa in patients with advanced PD with motor complications, but there is still insufficient evidence to recommend it as monotherapy or add-on therapy in patients with early PD.
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