Safinamide

Since the 1980s, the MAO-B inhibitors have gained considerable status in the therapy of the Parkinson's disease. In addition to the symptomatic effect in mono- and combination therapies, a neuroprotective effect has repeatedly been a matter of some discussion, which has unfortunately led to a good many misunderstandings. Due to potential interactions, selegiline has declined in significance in the field. For the MAO-B inhibitor safinamide, recently introduced to the market, an additional inhibition of pathological release of glutamate has been postulated. At present, rasagiline and selegiline are being administered in early therapy as well as in combination with levodopa. Safinamide has been approved only for combination therapy with levodopa when motor fluctuations have occurred. MAO-B inhibitors are a significant therapeutic option for Parkinson's disease, an option which is too often not appreciated properly. 

/pdf/a-critical-appraisal-of-mao-b-inhibitors-in-the-treatment-of-15iebndv.pdf

A critical appraisal of MAO-B inhibitors in the treatment of Parkinson’s disease

Abstract Non-motor symptoms (NMS) are common among patients with Parkinson’s disease and reduce patients’ quality of life (QOL). However, there remain considerable unmet needs for NMS management. Three monoamine oxidase B inhibitors (MAO-BIs), selegiline, rasagiline, and safinamide, have become commercially available in many countries. Although an increasing number of studies have reported potential beneficial effects of MAO-BIs on QOL and NMS, there has been no consensus. Thus, the primary objective of this study was to provide an up-to-date systematic review of the QOL and NMS outcomes from the available clinical studies of MAO-BIs. We conducted a literature search using the PubMed, Scopus, and Cochrane Library databases in November 2021. We identified 60 publications relevant to this topic. Overall, rasagiline and safinamide had more published evidence on QOL and NMS changes compared with selegiline. This was likely impacted by selegiline being introduced many years prior to the field embarking on the study of NMS. The impact of MAO-BIs on QOL was inconsistent across studies, and this was unlikely to be clinically meaningful. MAO-BIs may potentially improve depression, sleep disturbances, and pain. In contrast, cognitive and olfactory dysfunctions are likely unresponsive to MAO-BIs. Given the paucity of evidence and controlled, long-term studies, the effects of MAO-BIs on fatigue, autonomic dysfunctions, apathy, and ICD remain unclear. The effects of MAO-BIs on static and fluctuating NMS have never been investigated systematically. More high-quality studies will be needed and should enable clinicians to provide personalized medicine based on a non-motor symptom profile. 

https://www.nature.com/articles/s41531-022-00339-2.pdf

Effects of MAO-B inhibitors on non-motor symptoms and quality of life in Parkinson’s disease: A systematic review

/pdf/effects-of-mao-b-inhibitors-on-non-motor-symptoms-and-3mn7nhpr.pdf

The incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer's disease. 

/pdf/overcoming-undesirable-herg-affinity-by-incorporating-3hf77nqw.pdf

Overcoming undesirable hERG affinity by incorporating fluorine atoms: A case of MAO-B inhibitors derived from 1 H-pyrrolo-[3,2-c]quinolines.

Mood disorders are frequent in Parkinson’s disease (PD) and a favorable effect of safinamide on mood has been observed. We aimed to analyze the effectiveness of safinamide on mood as a secondary objective from the SAFINONMOTOR (an open-label study of the effectiveness of SAFInamide on NON-MOTOR symptoms in patients with Parkinson’s disease) study. SAFINONMOTOR is a prospective open-label single-arm study conducted in five centers from Spain. Patients with PD were required to have at baseline a Non-Motor Symptoms Scale (NMSS) total score of at least 40. In this analysis, the changes from V1 (baseline) to V4 (6 months ± 1 month) in the BDI-II (Beck Depression Inventory-II), NMSS mood/apathy domain, and PDQ-39 (Parkinson’s Disease Questionnaire-39) emotional well‐being domain were analyzed. Depression was identified and classified (DSM-IV and Judd criteria) at baseline and at the end of follow-up as major depression (MD), minor depression (mD), subthreshold depression (subD), and non-depression (nonD). Fifty patients with PD were included (age 68.5 ± 9.12 years; 58% women; 6.4 ± 5.1 years from diagnosis) and 44 patients (88%) completed the follow-up at 6 months. The BDI-II total score was reduced by 35.9% (from 15.88 ± 10.46 at V1 to 10.18 ± 6.76 at V4; p < 0.0001). A significant decrease in the NMSS mood/apathy domain and PDQ-39 emotional well‐being domain was observed as well (p < 0.0001). At baseline, 52% of the patients presented MD, 34% mD, 12% subD, and 2% nonD whereas at V4 the percentages were 31.8%, 34.1%, 22.7%, and 11.4%, respectively (p = 0.029). Safinamide improves mood in patients with PD at 6 months.

/pdf/effectiveness-of-safinamide-over-mood-in-parkinson-s-disease-4je1h9zf5y.pdf

Effectiveness of Safinamide over Mood in Parkinson's Disease Patients: Secondary Analysis of the Open-label Study SAFINONMOTOR.

Background and objective: Pain is a frequent and disabling symptom in Parkinson’s disease (PD) patients. Our aim was to analyze the effectiveness of safinamide on pain in PD patients from the SAFINONMOTOR (an open-label study of the effectiveness of SAFInamide on NON-MOTOR symptoms in Parkinson´s disease patients) study. Material and Methods: SAFINONMOTOR is a prospective open-label single-arm study conducted in five centers from Spain. In this analysis, a secondary objective of the study, the score in the KPPS (King´s Parkinson´s Disease Pain Scale) at V1 (baseline) and V4 (6 months ± 1 month) were compared. Wilcoxon´s rank sum test was performed to test the changes from V1 to V4. Results: Forty-four (88%) out of 50 PD patients (age 68.5 ± 9.12 years; 58% women; 6.4 ± 5.1 years from diagnosis) completed the study. The KPPS total score was reduced by 43.6% (from 40.04 ± 36.18 in V1 to 22.60 ± 21.42 in V4; p < 0.0001). By domains, improvement was observed in musculoskeletal (−35.9%; p = 0.009), fluctuation-related (−51.7%; p = 0.020), nocturnal (−46.1%; p = 0.001), discoloration and/or edema/swelling (−50.4%; p = 0.009) and radicular pain (−40.1%; p = 0.048). A total of 21 adverse events in 11 patients (22%) were reported, five being severe, but not related to safinamide. Conclusion: Safinamide is well tolerated and improves pain in PD patients at 6 months. Future studies are necessary to analyze the possible beneficial effect of safinamide on pain in PD patients.

Pain Improvement in Parkinson's Disease Patients Treated with Safinamide: Results from the SAFINONMOTOR Study.

Some studies observed a benefit of PD patients after treatment with safinamide in some non-motor symptoms. Our aim was to analyze the effectiveness of safinamide on sleep and daytime sleepiness in Parkinson’s disease (PD) patients. SAFINONMOTOR is a prospective open-label single-arm study conducted in 5 centers from Spain. In this analysis, a secondary objective of the study, the score in the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) at V1 (baseline) and V4 (6 months ± 1 month) were compared. Fifty patients were included between May/2019 and February/2020 (age 68.5 ± 9.12 years; 58% women; 6.4 ± 5.1 years from diagnosis). At 6 months, 44 patients completed the follow-up (88%). The PSQI total score was reduced by 19.8% (from 10.43 ± 4.02 at V1 to 8.36 ± 4.41 at V4; p = 0.001). By domains, improvement was observed in subjective sleep quality (PSQI-C1; − 23.9%; p = 0.009), sleep latency (PSQI-C2; − 25%; p = 0.025), sleep duration (PSQI-C3; − 40%; p = 0.001), and habitual sleep efficiency (PSQI-C4; − 25.9%; p = 0.023). A significant reduction (− 24.7%) in the ESS total score from V1 to V4 was observed as well (from 9.20 ± 5.64 to 6.93 ± 5.11; p = 0.012). Specifically, the improvement in daytime sleepiness was observed in sitting and reading (p = 0.024) and sitting inactive in a public space (p = 0.027). A total of 21 adverse events in 11 patients (22%) were reported, 5 of which were severe (not related to safinamide). Safinamide was well-tolerated and improved sleep and daytime sleepiness in PD patients at 6 months.

/pdf/safinamide-improves-sleep-and-daytime-sleepiness-in-2wq5cdox7d.pdf

Diego Santos García

Papers

Effectiveness of Safinamide over Mood in Parkinson's Disease Patients: Secondary Analysis of the Open-label Study SAFINONMOTOR.

Pain Improvement in Parkinson's Disease Patients Treated with Safinamide: Results from the SAFINONMOTOR Study.

Safinamide improves sleep and daytime sleepiness in Parkinson's disease: results from the SAFINONMOTOR study.