CuidAME, the Spanish national registry for Spinal Muscular Atrophy (SMA), was created in 2020 to collect real-life data after the arrival of innovative therapies: Nusinersen (Ns, available in Spain since 2018), gene therapy Onasemnogene abeparvovec (GT, 2021) and Risdiplam (Rs, 2022). It includes all genetically confirmed SMA patients, treated or not, followed up in several Spanish hospitals (target population estimated at 450 patients, followed for five years). The objective is to describe the characteristics of the SMA population in Spain. Observational registry that collects retrospective and prospective data: epidemiology, natural history, effect of treatments and impact of the disease. 470 patients (246 children, 224 adults) from 24 centers. SMA type distribution is: 22% SMA1, 39% SMA2, 36% SMA3, 1% SMA4. 6 patients (1%) were diagnosed presymptomatically, three of them in the context of newborn screening. 413 patients (88%) received a disease-modifying therapy (DMT) during the follow-up: Ns 269 (70%), Rs 56 (15%) and GT 25 (6%). 13% received multiple treatments: 32 switched from Ns to Rs (1 AME1, 26 AME2, 5 AME3) and 12 AME1 patients received both GT and Ns. 4 presymptomatic patients were treated with GT and 2 with Ns (median age at treatment: 61 days of life, current median age: 2.6 y.o). Prospective data on the motor, respiratory, digestive and neurocognitive CuidAME is currently the platform containing Spanish largest, harmonized, and standardized SMA clinical lead database. The estimated population has already been recruited and is expected to increase due to the inclusion of new centers. It provides crucial data, allowing a better understanding of the disease, the efficacy and the adverse effects of innovative therapies. National and international collaborations among centers and registries are promoted, expanding SMA knowledge.

Safinamide has been recently approved as an add-on to levodopa therapy for Parkinson disease. In addition to inhibiting monoamine oxidase type B, it blocks sodium channels and modulates glutamate (Glu) release in vitro. Since this property might contribute to the therapeutic action of the drug, we undertook the present study to investigate whether safinamide inhibits Glu release also in vivo and whether this effect is consistent across different brain areas and is selective for glutamatergic neurons. To this aim, in vivo microdialysis was used to monitor the spontaneous and veratridine-induced Glu and GABA release in the hippocampus and basal ganglia of naive, awake rats. Brain levels of safinamide were measured as well. To shed light on the mechanisms underlying the effect of safinamide, sodium currents were measured by patch-clamp recording in rat cortical neurons. Safinamide maximally inhibited the veratridine-induced Glu and GABA release in hippocampus at 15 mg/kg, which reached free brain concentrations of 1.89–1.37 µM. This dose attenuated veratridine-stimulated Glu (but not GABA) release in subthalamic nucleus, globus pallidus, and substantia nigra reticulata, but not in striatum. Safinamide was ineffective on spontaneous neurotransmitter release. In vitro, safinamide inhibited sodium channels, showing a greater affinity at depolarized (IC50 = 8 µM) than at resting (IC50 = 262 µM) potentials. We conclude that safinamide inhibits in vivo Glu release from stimulated nerve terminals, likely via blockade of sodium channels at subpopulations of neurons with specific firing patterns. These data are consistent with the anticonvulsant and antiparkinsonian actions of safinamide and provide support for the nondopaminergic mechanism of its action.

Objectives: To evaluate efficacy, tolerability and safety of Monurelle Biogel vaginal gel for treatment of vaginal dryness. Methods: Multicenter, national, randomized, controlled vs. no-treatment, open-label study. Ninety-five postmenopausal women were randomized (48 to Monurelle Bioger and 47 to no treatment). Primary endpoint was the change of Verbal Rating Scale (VRS) total score of vaginal atrophy (VA) symptoms after 8-week treatment. The main secondary endpoints were VRS single-item score, Vaginal Health Index (VHI) score, Maturation Index (MI), Female Sexual Function Index (FSFI), and Female Sexual Distress Scale-Revised (FSDS-R). Results: The VRS total score was statistically significant in favor of the treatment group on day 28 (p = 0.001) but not on day 56 (p = 0.064). By excluding women who were not sexually active, the total VRS scores reached the criteria for clinical success in 27/43 subjects (62.8%) in the control arm and in 38/46 subjects (82.6%) in the treatment arm (p = 0.035) on day 56. The VHI score significantly changed in the active arm (4.71 +/- 4.85 vs. 0.28 +/- 1.71) (p < 0.001) on day 56. Even the MI significantly improved, with an increase in the percentage of superficial cells (p = 0.01). The improvements in both VHI and MI were still present at the follow-up visit after the discontinuation of the treatment (day 84). Sexual function and distress showed a statistical significant difference on day 56. Conclusions: Monurelle Biogel vaginal gel applied twice daily for 8 weeks is effective in relieving vaginal dryness and other VA symptoms. Such a clinical meaningful effect persists at least 4 weeks and is supported by an improvement in the vaginal environment.

Background: Pain, a frequent non-motor symptom in Parkinson's Disease (PD), significantly impacts on quality of life.Safinamide is a new drug with dopaminergic and non-dopaminergic properties, approved in Europe as adjunct therapy to levodopa for the treatment of fluctuating PD patients.Results from two 24-month, double-blind, placebo-controlled studies demonstrated that safinamide has positive effects on both motor functions and quality of life in PD patients.Objective: To investigate the effects of safinamide on pain management in PD patients with motor fluctuations using pooled data from studies 016 and SETTLE.Methods: This post-hoc analysis evaluated the reduction of concomitant pain treatments and the changes in the scores of the items related to pain of the Parkinson's Disease Quality of Life Questionnaire (PDQ-39).A path analysis was performed in order to examine direct and indirect associations between safinamide and PDQ-39 pain-related items assessed after 6-months of treatment.Results: The percentage of patients with no pain treatments at the end of the trials was significantly lower in the safinamide group compared to the placebo group.Safinamide 100 mg/day significantly reduced on average the individual use of pain treatments by ≈24% and significantly improved two out of three PDQ-39 pain-related items of the "Bodily discomfort" domain.Path analysis showed that the direct effect of safinamide on pain accounted for about 80% of the total effect.Conclusions: These results suggest that safinamide may have a positive effect on pain, one of the most underestimated non-motor symptoms.Prospective studies are warranted to investigate this potential benefit.

INTRODUCTION The Edry® spray dried particle engineering technique can be used to generate inhaled drugs using existing compounds and inhalers, yet with optimal size and de-agglomeration characteristics. For Z7200 (budesonide (BUD)/formoterol fumarate (FF) 80/2.25µg) it was demonstrated via in-vitro and in-silico testing that the Edry technology allows for comparable lung deposition with half the delivered dose compared to the reference product (Symbicort® Turbohaler®: 160/4.5µg). The aim of this work was to investigate if the pharmacodynamic effects of Z7200 are also comparable to the ones of its reference product. METHODS A double blind, double dummy, randomized, two way cross over study was performed to compare the acute effects of Z7200 and Symbicort in 20 asthma patients. Drug effects were analyzed by FRI changes in airway volumes and resistances, lung function and patient feeling. RESULTS Both products showed improved lung function for all measured variables; see figure1 for the FRI airway volume and FEV1. Patient feeling did not improve with either product. Also, no statistically significant differences in treatment effect were found between the test and reference product. CONCLUSIONS This work shows that there was no difference in efficacy parameters between Z7200 and Symbicort®, notably considering the delivered dose of the test product was half of the that of the reference product.

Safinamide is an orally administered α ‐aminoamide derivative with both dopaminergic and non‐dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic ( PK ) and pharmacokinetic–pharmacodynamic ( PKPD ) analyses were developed using records from, respectively, 623 and 668 patients belonging to two Phase 3, randomized, placebo‐controlled, double‐blind efficacy studies. The aim was to estimate safinamide population PK parameters in patients with Parkinson's disease ( PD ) on stable levodopa therapy, and to develop a model of safinamide effect on the PD phase of normal functioning ( ON ‐time). The final models were internally evaluated using visual predictive checks ( VPCs ), prediction corrected‐ VPC , and nonparametric bootstrap analysis. Safinamide profiles were adequately described by a linear one‐compartmental model with first‐order absorption and elimination. CL /F, Vd/F, and KA (95% confidence interval [ CI ]) were 4.96 (4.73–5.21) L/h, 166 (158–174) L, and 0.582 (0.335–0.829) h −1 , respectively. CL /F and Vd/F increased with body weight, while age, gender, renal function, and exposure to levodopa did not influence safinamide PK . The observed ON ‐time values were adequately described by a linear model, with time in the study period as dependent variable, and rate of ON ‐time change and baseline plus offset effect as slope and intercept parameters. Safinamide treatment resulted in an increase in ON ‐time of 0.73 h (week 4), with further ON ‐time increase with the same slope as placebo. The increase was not influenced by age, levodopa, or safinamide exposure. The population models adequately describe the population PK of safinamide and safinamide effect on ON ‐time. No dose adjustments in elderly and mild to moderate renally impaired patients are requested.

Objectives: Safinamide (Xadago®) is a novel drug approved as add-on therapy to levodopa in mid- to late-stage Parkinson's disease (PD). Safinamide has a dual mechanism of action: it inhibits monoamino oxidase type B and causes an use-dependent block of voltage-operated sodium channels which results in inhibition of glutamate release from overactive glutamatergic terminals. Therefore, we undertook the present microdialysis study in awake rats to investigate the impact of safinamide on veratridine-evoked glutamate (and GABA) release in four different nuclei of the basal ganglia, i.e. the dorsolateral striatum (DLS), globus pallidus (GP), substantia nigra reticulata (SNr) and subthalamic nucleus (STN).

OBJECTIVE:To prove the efficacy, tolerability and safety of Monurelle Biogel(®) (ZP-025) vaginal gel, which contains a purified, dialyzed, lyophilized bovine colostrum, in women of reproductive age suffering from vaginal dryness.DESIGN:Randomized clinical trial (RCT) (Z7213M01).SETTING:Five University Gynaecological Units.PATIENTS:Ninety-five subjects were allocated at random to receive either ZP-025 (n=48) for about 23 intermenstrual days (1 or 2 times/daily intra-vaginally) or no treatment (lubricants on demand were allowed).MAIN OUTCOME MEASURES:Change of Verbal Rating Scale (VRS) total and single score for vaginal symptoms, Vaginal Health Index (VHI) score, Female Sexual Function index (FSFI) and Female Sexual Distress Scale-revised (FSDS-R) scores.RESULTS:A total number of 85 subjects was evaluable for primary analyses. Symptoms (VRS) of vaginal discomfort improved significantly already after 11 days, as compared to the control arm (p<0.0001). The mean VHI score was also significantly higher in ZP-025 group (p<0.001) at the end of the study. The analysis of covariance with the baseline value as covariate carried out on the FSFI Total Score showed a statistically significant difference in favour of the ZP-025 arm (p<0.032). A shift from presence to absence of sexual distress (≤11 points) was more prominent in the ZP-025 arm [10 subjects (40%) in the ZP-025 arm (p<0.0001) and 6 subjects (21.4%) in the control arm (p=0.01)]. Women reported a compliance rate of 100% for one ZP-025 application/day. Local tolerability of ZP-025 was excellent or good in 82.9% of the subjects.CONCLUSIONS:The present multicentre RCT supports the use of Monurelle Biogel(®) in women of reproductive age reporting symptoms of vaginal dryness. A positive impact on vaginal health and sexual function was also evident.

Objectives: Safinamide (Xadago®) is a novel drug recently approved as add-on therapy to levodopa in mid- to late-stage Parkinson's disease. Xadago® shows a unique dual mechanism of action: it has both dopaminergic properties (highly selective, potent and reversible inhibition of monoamine oxidase-B) and non-dopaminergic properties (state and use-dependent sodium channel blockade causing inhibition of excessive glutamate release). The study aim was to evaluate the effect of safinamide on stimulated glutamate release in rat hippocampus at doses giving free brain concentrations able to block sodium channels and to provide a PK/PD approach to support its clinical relevance on overactive glutamate release inhibition.

BACKGROUND:Studies 016 and SETTLE showed that safinamide was safe and effective as adjunct therapy in patients with advanced Parkinson's disease (PD) and motor fluctuations. The addition of safinamide to a stable dose of levodopa alone or with other antiparkinsonian medications significantly increased ON time with no/non-troublesome dyskinesia, decreased OFF time and improved Parkinson's symptoms.OBJECTIVE:To evaluate the clinical effects of safinamide 100 mg/day on motor fluctuations and cardinal Parkinson's symptoms in specific patient subgroups using pooled data from Studies 016 and SETTLE.METHODS:Both studies were double blind, placebo-controlled, randomized, phase 3 trials which enrolled patients with mid- to late-stage PD experiencing motor fluctuations while receiving optimized and stable doses of levodopa, alone or with other dopaminergic treatments. The present post-hoc analyses assessed the change from baseline in ON time (with no or non-troublesome dyskinesia) and OFF time in subgroups of patients who were receiving only levodopa at baseline, who were classified as "mild fluctuators" (daily OFF time ≤4 h), and who were receiving concomitant dopaminergic therapy, with or without amantadine, and the effects of safinamide versus placebo on individual cardinal PD symptoms during ON time.RESULTS:Safinamide significantly increased mean ON time (with no or non-troublesome dyskinesia) and reduced mean OFF time when used as first adjunct therapy in levodopa-treated patients and patients with mild motor fluctuations. Mean daily ON time (with no or non-troublesome dyskinesia) and OFF time were favorably changed, compared with placebo, to similar extents regardless of whether patients were receiving concomitant dopamine agonists, catechol-O-methyltransferase inhibitors and amantadine. Additionally, safinamide improved bradykinesia, rigidity, tremor and gait.CONCLUSIONS:Safinamide was a safe and effective first adjunct therapy in levodopa-treated patients and improved 4/5 cardinal symptoms of PD while providing benefits to mild and non-mild fluctuators and patients receiving other concomitant dopaminergic therapies.

INTRODUCTION: Recent DPI development focussed on new inhalation devices and better chemicals. An little explored option is particle engineering. Edry is a spray drying platform to engineer powder particles with optimal size and deagglomeration characteristics. The aim of this work was to evaluate the Edry technology utilizing a new product candidate, Z7200 (budesonide (BUD)/formoterol fumarate (FF) 80/2.25µg) compared to its reference product (Symbicort 160/4.5µg). METHODS In vitro aerosol properties were tested using a Multi Stage Liquid Impinger (MSLI) at 4 different pressure drops (1-2-3-4kPa). FRI lung deposition calculations were based on CT scans of 5 asthmatic patients. The lower airways were coupled to 2 upper airway geometries (average and narrow) and DPI device. Deposition of BUD and FF was calculated via FRI at the above mentioned pressure drops by using the aerodynamic characterization from MSLI. RESULTS Results showed consistent aerosolization performances for each active moiety of Z7200 at every flow rate both in vitro and in silico. On the contrary, Symbicort requires an optimal inhalatory effort in order to deposit therapeutic amounts of drug in the lung. CONCLUSIONS This work indicates that Edry powders are potentialy offering significant benefits in lung deposition and inhalation flow rate independency with respect to a conventional reference product like Symbicort, both for BUD and FF.

Abstract Background: Safinamide is a novel α-aminoamide with dopaminergic and non-dopaminergic properties developed as adjunctive therapy for patients with PD. Results from a 24-month double-blind controlled study suggested that as add-on to levodopa (and other PD medications) the benefits of safinamide on dyskinesia may be related to severity of dyskinesia at baseline. Objective: This post-hoc analysis further characterized the effects of safinamide on dyskinesia in mid- to late-stage PD patients. Methods: Patients were stratified by the presence or absence of dyskinesia at baseline, and by whether or not the dose of levodopa had been changed during the 24-month treatment period. Differences between safinamide and placebo were evaluated using the Wilcoxon rank-sum test. Results: For the overall treated population (with or without baseline dyskinesia), safinamide 100 mg/day significantly improved the dyskinesia rating scale score, compared with placebo, in the subgroup of patients with no change in levodopa dose (p = 0.0488). For patients with baseline dyskinesia, improvements over placebo were also significant (p = 0.0153) in patients with or without changes in levodopa dose, and nearly significant (p = 0.0546) in patients with no change in levodopa dose, suggesting that these improvements were not due to levodopa dose reductions. Conclusions: While no statistically significant difference in mean DRS scores was seen between safinamide and placebo in the original study population, the present post-hoc analysis helps to provide a meaningful interpretation of the long-term effects of safinamide on dyskinesia. These results may be related to safinamide state- and use-dependent inhibition of sodium channels and stimulated glutamate release, and are unlikely due to reduced dopaminergic stimulation.

Objective: Safinamide (Xadago®, Zambon SpA, Italy), a new drug with dopaminergic and non-dopaminergic actions, was studied in late stage PD patients in two double-blind, placebo-controlled trials (016 and 018), showing an increase in “ON” time without increasing troublesome dyskinesia. The objective of this post-hoc analysis of studies 016 and 018 is to evaluate the efficacy of safinamide (100 mg/day oral tablets) vs placebo on mood in fluctuating PD patients over 2-year treatment.