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Efficacy of Safinamide and Gender Differences During Routine Clinical Practice.

ABSTRACT: Background: There is increasing evidence of gender differences in the epidemiology and clinical manifestation of both motor and non-motor symptoms of Parkinson's disease (PD). Nevertheless, few data are available on gender differences in the response to antiparkinsonian drugs. Safinamide is a multimodal drug with positive effects on motor and non-motor fluctuations that might improve patients' care and quality of life. Objective: To analyze gender differences on clinical effects of safinamide in PD patients treated in real-life conditions during the SYNAPSES trial. Methods: SYNAPSES was a multinational, multicenter, observational study. At baseline, patients with PD diagnosis received safinamide as an add-on to levodopa and were followed up for 12 months, with visits performed every 4 months. A new statistical analysis was performed to describe the efficacy of safinamide in men and women on motor complications, motor symptoms, and adverse events. Results: Six hundred and sixteen (38%) out of 1,610 patients enrolled in the SYNAPSES study were women and 994 (62%) men. Safinamide improved motor symptoms and motor complications (fluctuations and dyskinesia) in both genders, with a good safety profile and without requiring any change in the concomitant dopaminergic therapy. Clinically significant improvements, according to the criteria developed by Shulman et al., were seen in 46% of male and female patients for the UPDRS motor score and 43.5% of men vs. 39.1% of women for the UPDRS total score. Conclusions: Safinamide was effective in improving motor fluctuations and dyskinesia and proved to be safe in both male and female patients with PD. Further prospective studies, specifically addressing potential gender differences in response to PD therapies, are needed to develop tailored management strategies.

SUBMITTER: Pellecchia MT

PROVIDER: S-EPMC8712933 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Proteomics has identified potential pathways involved in platelet storage lesions, which correlate with untoward effects in the recipient, including febrile non-haemolytic reactions. We hypothesize that an additional pathway involves protein mediators that accumulate in the platelet supernatants during routine storage in a donor gender-specific fashion. Apheresis platelet concentrates were collected from 5 healthy males and 5 females and routinely stored. The 14 most abundant plasma proteins were removed and the supernatant proteins from days 1 and 5 were analyzed via 1D-SDS-PAGE/nanoLC-MS/MS, before label-free quantitative proteomics analyses. Findings from a subset of 18 proteins were validated via LC-SRM analyses against stable isotope labeled standards. A total of 503 distinct proteins were detected in the platelet supernatants from the 4 sample groups: female or male donor platelets, either at storage day 1 or 5. Proteomics suggested a storage and gender-dependent impairment of blood coagulation mediators, pro-inflammatory complement components and cytokines, energy and redox metabolic enzymes. The supernatants from female donors demonstrated increased deregulation of structural proteins, extracellular matrix proteins and focal adhesion proteins, possibly indicating storage-dependent platelet activation. Routine storage of platelet concentrates induces changes in the supernatant proteome, which may have effects on the transfused patient, some of which are related to donor gender.The rationale behind this study is that protein components in platelet releasates have been increasingly observed to play a key role in adverse events and impaired homeostasis in transfused recipients. In this view, proteomics has recently emerged as a functional tool to address the issue of protein composition of platelet releasates from buffy coat-derived platelet concentrates in the blood bank. Despite early encouraging studies on buffy coat-derived platelet concentrates, platelet releasates from apheresis platelets have not been hitherto addressed by means of extensive proteomics technologies. Indeed, apheresis platelets are resuspended in donors' plasma, which hampers detection of less abundant proteins, owing to the overwhelming abundance of albumin (and a handful of other proteins), and the dynamic range of protein concentrations of plasma proteins. In order to cope with these issues, we hereby performed an immuno-affinity column-based depletion of the 14 most abundant plasma proteins. Samples were thus assayed via GeLC-MS, a workflow that allowed us to cover an unprecedented portion of the platelet supernatant proteome, in comparison to previous transfusion medicine-oriented studies in the literature. Finally, we hereby address the issue of biological variability, by considering the donor gender as a key factor influencing the composition of apheresis platelet supernatants. As a result, we could conclude that platelet supernatants from male and female donors are not only different in the first place, but they also store differently. This conclusion has been so far only suggested by classic transfusion medicine studies, but has been hitherto unsupported by actual biochemistry/proteomics investigations. In our opinion, the main strengths of this study are related to the analytical workflow (immunodepletion and GeLC-MS) and proteome coverage, the translational validity of the results (from a transfusion medicine standpoint) and the biological conclusion about the intrinsic (and storage-dependent) gender-related differences of platelet supernatants.

Project description:The incidence and prevalence of Parkinson's disease (PD) is expected to raise dramatically over the next decades. Gender-related differences are not yet widely recognized, particularly regarding the response to dopaminergic medications. To analyse gender differences in the clinical effects of safinamide, compared to placebo, in Chinese PD patients of the pivotal XINDI trial. The XINDI study was a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Patients were followed for 16 weeks receiving 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. A post-hoc analysis was performed to describe the efficacy of safinamide in both genders on motor symptoms, motor fluctuations and quality of life. 128 (42%) out of 305 patients enrolled were women and 177 (58%) men. Our additional analyses of the XINDI study have shown that safinamide, compared to placebo, was associated with improvements in motor symptoms, motor fluctuations and quality of life in both genders, with some differences in the response that did not reach statistical significance, possibly due to sample size limitation and post-hoc design of the study. The changes from baseline at week 16 were > 50% higher in the females compared to males for the total daily OFF time (- 1.149 h vs - 0.764 h in males), the total daily ON time (1.283 h vs 0.441 h in males), the UPDRS total score (- 8.300 points vs - 5.253 points in males) and the UPDRS part II score (- 2.574 points vs - 1.016 points in males). The changes from baseline at week 16 were higher in the females compared to males in the "ADL" domain (- 6.965 points vs - 5.772 points in males), the "Emotional well-being" domain (- 6.243 points vs - 4.203 in males), the "Stigma" domain (- 6.185 points vs - 4.913 points in males) and the "Bodily discomfort" domain (- 5.196 points vs 1.099 points in males), while were higher in males in the "Mobility" score (- 6.523 points vs - 4.961 points in females) and the "Communication" score (- 3.863 points vs - 1.564 points in females). Safinamide was shown to improve PD symptoms and quality of life in both male and female Chinese patients. Possible differences in the response between genders need to be further studied in larger and different ethnic populations.

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Efficacy of Safinamide and Gender Differences During Routine Clinical Practice.

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