BACKGROUND: Sleep problems commonly occur in Parkinson\'s disease (PD) and significantly affect patients\' quality of life. A possible effect on subjective sleep disturbances of monoamine oxidase-B inhibitors (MAOB-Is) has been described.
METHODS: This prospective, observational, single-centre study involved 45 fluctuating PD patients complaining sleep problems as documented by the PD Sleep Scale -2nd version (PDSS-2 ≥18) starting rasagiline 1 mg/daily or safinamide 100 mg/daily, according to common clinical practice, and maintaining antiparkinsonian therapy unchanged. Polysomnography (PSG), sleep questionnaires (PDSS-2, Epworth Sleepiness Scale - ESS), and motor function were evaluated at baseline (T0) and after 4 months of treatment (T1).
RESULTS: Safinamide was prescribed in thirty patients and rasagiline in fifteen patients. Both drugs induced a significant improvement in Movement Disorder Society Unified PD Rating Scale III scores. Patients treated with rasagiline showed a significant increase in stage 1 (N1) Non-REM sleep compared to T0, with no significant effects on sleep scales. Patients treated with safinamide showed a significant increase in stage 3 of Non-REM sleep and sleep efficiency and a reduction in the rate of periodic limb movements, matching a significant reduction in PDSS-2 and ESS scales compared to T0.
CONCLUSIONS: This study showed that safinamide, in addition to having a significant effect on PD motor symptoms, like the other MAOB-Is, may exert a specific beneficial effect on subjective and objective sleep, probably driven by its dual mechanism of action, which involves both dopaminergic and glutamatergic neurotransmission.

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BACKGROUND: Safinamide is an effective adjunctive therapy for wearing-off in Parkinson\'s disease (PD); however, evidence is lacking in older patients and those in the early stages of wearing-off. This study evaluated the efficacy and safety of safinamide as adjunctive therapy in patients with PD treated with levodopa monotherapy in clinical practice.
METHODS: This multicentre, open-label observational study was conducted at five sites in Japan. Patients diagnosed with PD and wearing-off initiated safinamide as adjunctive therapy with levodopa monotherapy. Efficacy endpoints were mean changes in Movement Disorder Society-Unified Parkinson\'s Disease Rating Scale (MDS-UPDRS) Part I, III, and IV scores; daily ON-time without dyskinesia using 24-h patient symptom diaries; and 39-item Parkinson\'s Disease Questionnaire (PDQ-39) scores at 18 weeks of treatment.
RESULTS: In total, 24 patients initiated safinamide (66.7% were aged ≥75 years); the mean duration of wearing-off was 1.2 years. MDS-UPDRS Part III total score, Part IV total score, and PDQ-39 summary index decreased significantly from baseline (mean change -7.0 [p = 0.012], -2.4 [p = 0.007] and - 5.3 [p = 0.012], respectively). There was a non-statistically significant increase of 1.55 h in mean daily ON-time without dyskinesia. Numerical Rating Scale total score for pain (p = 0.015), and scores for OFF-period pain (p = 0.012) and nocturnal pain (p = 0.021) subdomains were significantly improved in the subgroup with pain. Most reported adverse events were classified as mild.
CONCLUSIONS: Safinamide improved motor and non-motor symptoms and quality of life-related measures in older patients with PD in the early stages of wearing-off without new safety concerns.
BACKGROUND: University Hospital Medical Information Network in Japan; study ID: UMIN000044341.

OBJECTIVE: The aim of this study was to assess the possible pharmacological interactions between safinamide and antidepressants, and in particular the appearance of serotonin syndrome with data from real life.
METHODS: We conducted a retrospective observational study of patients with Parkinson\'s disease from our Movement Disorders Unit, who were under treatment with any antidepressant drug and safinamide. Specifically, symptoms suggestive of serotonin syndrome were screened for. Also, we collected time of simultaneous use, doses of levodopa and other antiparkinsonian drugs.
RESULTS: Clinical records were reviewed for the study period of September 2018 to September 2019. Seventy-eight PD patients who were treated with safinamide of which 25 (32.05%) had a concomitant treatment with an antidepressant drug, being sertraline and escitalopram the most frequent. Mean age was 80 years±8.43 and H&Y stage was 3 [2-4]. Mean dose of levodopa used was 703.75mg±233.15. Median duration of concomitant treatment with safinamide and antidepressant drug was 6 months (IQR 20.5), and over eighteen months in 5 cases. No case of serotonin syndrome was recorded, neither was any of its typical manifestations combined or in isolation.
CONCLUSIONS: Our real clinical practice study suggests that concomitant use of safinamide with antidepressant drugs in PD patients seemed to be safe and well tolerated, even in the long term. However, caution is warranted, individualizing treatment regimens and monitoring the potential appearance of adverse effects.

BACKGROUND: Traumatic spinal cord injury (SCI) is the most common preventable cause of morbidity. Despite rapid advances in medicine, effective pharmacological treatment against SCI has not yet been confirmed. This study aimed to investigate the possible anti-inflammatory, antiapoptotic, and neuroprotective effects of safinamide after SCI in a rat model.
METHODS: A total of 40 male Wistar albino rats were randomly divided into four groups. Group 1 underwent only laminectomy. Group 2 underwent SCI after laminectomy. In group 3, SCI was performed after laminectomy, and immediately afterward, intraperitoneal physiological saline solution was administered. In group 4, SCI was performed after laminectomy, and 90 mg/kg of safinamide was given intraperitoneally immediately afterward. Moderate spinal cord damage was induced at the level of thoracic vertebra nine (T9). Neuromotor function tests were performed and levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) were measured. In both serum and spinal cord tissue, immunohistochemistry and histopathology studies were also conducted.
RESULTS: TNF-α, IL-1β, and IL-6 levels were found to be significantly increased in group 2 and group 3. In group 4, these levels were statistically significantly decreased. Group 4 also exhibited significant improvement in neuromotor function tests compared to the other groups. Histopathologically, it was found that group 4 showed significantly reduced inflammation and apoptosis compared to the other groups.
CONCLUSIONS: This study revealed that safinamide has neuroprotective effects against SCI due to its anti-inflammatory, antiapoptotic, and antioxidant activities.

BACKGROUND: Safinamide (SAF), an α-aminoamide derivative and a selective, reversible monoamine oxidase (MAO)-B inhibitor, has both dopaminergic and nondopaminergic (glutamatergic) properties. Several studies have explored the potential of SAF against various neurological disorders; however, to what extent SAF modulates the magnitude, gating, and voltage-dependent hysteresis [Hys(V)] of ionic currents remains unknown.
METHODS: With the aid of patch-clamp technology, we investigated the effects of SAF on voltage-gated sodium ion (NaV) channels in pituitary GH3 cells.
RESULTS: SAF concentration-dependently stimulated the transient (peak) and late (sustained) components of voltage-gated sodium ion current (INa) in pituitary GH3 cells. The conductance-voltage relationship of transient INa [INa(T)] was shifted to more negative potentials with the SAF presence; however, the steady-state inactivation curve of INa(T) was shifted in a rightward direction in its existence. SAF increased the decaying time constant of INa(T) induced by a train of depolarizing stimuli. Notably, subsequent addition of ranolazine or mirogabalin reversed the SAF-induced increase in the decaying time constant. SAF also increased the magnitude of window INa induced by an ascending ramp voltage Vramp. Furthermore, SAF enhanced the Hys(V) behavior of persistent INa induced by an upright isosceles-triangular Vramp. Single-channel cell-attached recordings indicated SAF effectively increased the open-state probability of NaV channels. Molecular docking revealed SAF interacts with both MAO and NaV channels.
CONCLUSIONS: SAF may interact directly with NaV channels in pituitary neuroendocrine cells, modulating membrane excitability.

OBJECTIVE: Morning-off is a symptom experienced by patients with Parkinson\'s disease (PD), which markedly reduces patients\' quality of life. The present study evaluated the effect of safinamide on morning-off in elderly PD patients.
METHODS: This observational study included 30 PD patients treated with 50 or 100 mg/day of safinamide in the evening. Using patient-reported outcomes, we evaluated the effect of safinamide on daily/morning ON-time, daily/morning OFF-time, Unified Parkinson\'s Disease Rating Scale (UPDRS) Part III score, and non-motor symptoms. Data at baseline (treatment start) and at 4, 8, 12, and 16 weeks after baseline were recorded.
RESULTS: The PD patients (75.8±7.5 years old) in this study, who tended to be older than in previous phase 2/3 or 3 studies, may represent real-world Japanese PD patients. Compared with baseline, safinamide significantly increased the daily ON-time at eight weeks and morning ON-time at four weeks. Safinamide significantly reduced the daily OFF-time and morning OFF-time at four weeks. The UPDRS Part III score was significantly reduced by 1 point at 12 weeks. Safinamide showed a tendency to reduce non-motor symptoms, such as anxiety, pain, and depressive feelings. There was no marked difference in these parameters between patients treated with 50 and 100 mg of safinamide.
CONCLUSIONS: Our results suggest that safinamide administered in the evening can benefit elderly patients who experience wearing off, especially morning off, and non-motor symptoms.

BACKGROUND: Pain is often neglected in Parkinson\'s disease (PD), although it impacts most PD patients. While the mechanism of pain in PD is still being studied, various pharmacological, interventional, and alternative treatment options have been offered for pain relief. Safinamide, a recently approved drug for PD, has shown promising results in improving pain in patients with PD. Several clinical studies report changes in pain scores in PD patients treated with safinamide, but these have not been systematically summarized. Therefore, our main goal was to perform a systematic review and statistical analysis of relevant studies.
METHODS: A systematic search of studies was conducted using four databases: Pubmed, Cochrane Library, Google Scholar, and Scopus. The nine included randomized controlled trials did not provide sufficient data for a meta-analysis; therefore, we conducted a qualitative systematic review.
RESULTS: Our results suggest that safinamide at a daily dose of 100mg is more effective for treating PD pain than that of 50mg. Moreover, the reduction in fluctuation-related pain and pain from edema was more consistent when treated with safinamide compared to other PD pain types. We also attempted to suggest a mechanism of action for safinamide on pain processing in the brain, which should be explored in more detail in future studies.
CONCLUSIONS: Clinical evidence suggests that safinamide may be particularly beneficial for PD patients experiencing fluctuation-related pain and pain from edema, as these subtypes of pain showed greater improvement compared to other types of pain. Based on the findings of the included studies, safinamide appears to relieve the overall pain burden. However, the lack of sufficient data for conducting a meta-analysis highlights the need for future studies to report mean pain scores and their standard deviations.

Ethnicity differences are an important determinant in the clinical manifestation of Parkinson\'s disease (PD), but they are not yet widely recognized, particularly regarding the response to dopaminergic medications. The aim of this paper is to analyze the efficacy and safety of safinamide in Chinese patients with PD in the pivotal studies SETTLE and XINDI compared to the non-Chinese population of the SETTLE trial.
SETTLE (NCT00627640) and XINDI (NCT03881371) were phase III, randomized, double-blind, placebo-controlled, multicenter trials. Patients received safinamide or placebo as add-on to levodopa. The primary efficacy endpoint was the change in the mean total daily OFF time. Secondary efficacy endpoints included total daily ON time, ON time with no/non-troublesome dyskinesia, Unified Parkinson\'s Disease Rating Scale, and Parkinson\'s Disease Questionnaire-39 items. Safety was evaluated through the frequency of adverse events. Data from 440 non-Chinese and 109 Chinese patients in the SETTLE study, and 305 Chinese patients in the XINDI trial were considered for this post hoc analysis.
Significant positive results were seen in favor of safinamide in all populations for the primary and secondary endpoints, with no differences in terms of magnitude. No \"treatment by ethnicity\" interaction was detected for any parameters, confirming the homogeneity of treatment effects between different populations. The safety and tolerability of safinamide in Chinese patients were similar to those in the other ethnic groups, without unexpected adverse reactions.
Safinamide was shown to improve PD symptoms and quality of life in different ethnic populations, without any treatment by race interaction. Further studies are warranted to investigate potential differences in a real-life situation.
SETTLE (NCT00627640) and XINDI (NCT03881371).