Rasagiline and safinamide as a dopamine-sparing therapy for Parkinson's disease.

OBJECTIVES: To evaluate whether the prescription of monoamine oxidase B inhibitors (MAOB-I), rasagiline and safinamide, contributes to the reduction of levodopa and/or dopamine agonists (DA) dose in order to minimize adverse effects. MATERIALS AND METHODS: A total of 724 patients with Parkinson's disease (PD) have been prospectively included in our database since the year 2000, representing a total of 5124 visits. For each patient and visit, antiparkinsonian treatment was recorded. In the presence of rasagiline and safinamide, we analysed the evolution of levodopa equivalent dose (LED) and LED for DA (LED-DA). RESULTS: The data obtained from the 1664 visits between 2006 and 2010 (321 patients) and the 1709 visits between 2014 and 2018 (403 patients) were analysed in order to assess the impact of the introduction of rasagiline and safinamide, respectively. The annual mean LED remained stable without statistically significant differences. In the first period (impact of rasagiline), the annual mean LED-DA in 2010 was significantly higher than in 2006 (P = 0.001). In the second period (impact of safinamide), the annual mean LED-DA in 2018 was significantly lower than in 2014 (P = 0.002). A repeated-measure analyses of LED-DA including only patients who had taken safinamide showed a statistically significant decrease in LED-DA (P = 0.027). CONCLUSIONS: The introduction of MAOB-I in the overall treatment of PD as part of routine clinical practice has not helped to reduce annual mean LED. However, safinamide reduces annual mean LED-DA and may be linked to a reduction in dose-dependent adverse effects in the long term.

Agomelatine for Depression in Parkinson Disease: Additional Effect on Sleep and Motor Dysfunction.

Depression and sleep disorders are among the most prevalent nonmotor symptoms of Parkinson disease (PD). Because agomelatine acts as a MT1 and MT2 agonist and as a 5HT2c antagonist, this study was designed to assess the efficacy of agomelatine in treating depressive symptoms in PD patients, and the potential changes both in sleep quality and motor symptoms. Depressed patients with PD were treated with agomelatine for 6 months, and they were evaluated with an array of scales. Completed nocturnal video-polysomnography was performed at baseline and week 12. The efficacy analysis population included 24 patients (12 men). The mean (SD) age was 75.2 (8.3) years. The mean (SD) daily dose of agomelatine was 25.00 (10.43) mg at 24 weeks. No changes in dopamine replacement therapy were made. There was a significant decrease in the 17-item Hamilton Depression Scale score over the course of the study (P < 0.0005). The Scales for Outcomes in Parkinson disease Sleep Questionnaire showed a statistically significant improvement over time in each of its subscales: nighttime sleep (P < 0.005), last month nighttime sleep (P < 0.0005), and daytime sleepiness (P < 0.0005). Surprisingly, changes over time in the motor subscale of Unified Parkinson Disease Rating Scale were statistically significant (P < 0.0005). Periodic limb movements and awakenings measured by polysomnography improved significantly (P < 0.005 and P < 0.05, respectively). We concluded that the use of agomelatine in PD depressed patients may have a considerable therapeutic potential because of its dual action for treating both symptoms of depression and disturbed sleep given its secondary beneficial effects regarding the reduction of extrapyramidal symptoms.

Advances and challenges of CAR T therapy and suitability of animal models (Review).

Chimeric antigen receptors (CARs) recently gained momentum in cancer treatment due to their ability to promote T-cell mediated responses to a specific tumor-associated antigen. CARs are part of the adoptive cell transfer (ACT) strategies that utilize patients' T lymphocytes, genetically engineered to kill cancer cells. However, despite the therapy's success against blood-related malignancies, treating solid tumors has not reached its fullest potential yet. The reasons include the complex suppressive tumor microenvironment, mutations on cancer cells' target receptors, lethal side-effects, restricted trafficking into the tumor, suboptimal persistence in vivo and the lack of animal models that faithfully resemble human tumor's immunological responses. Currently, rodent models are used to investigate the safety and efficacy of CAR therapies. However, these models are limited in representing the human disease faithfully, fail to predict the adverse treatment events and overestimate the efficacy of the therapy. On the other hand, spontaneously developed tumors in dogs are more suited in CAR research and their efficacy has been demonstrated in a number of diseases, including lymphoma, osteosarcoma and mammary tumors. The present review discusses the design and evolution of CARs, challenges of CAR in solid tumors, human and canine clinical trials and advantages of the canine model.

Ductal Carcinoma In Situ Progression in Dog Model of Breast Cancer.

The mechanisms that drive ductal carcinoma in situ (DCIS) progression to invasive cancer are not clear. Studying DCIS progression in humans is challenging and not ethical, thus necessitating the characterization of an animal model that faithfully resembles human disease. We have characterized a canine model of spontaneous mammary DCIS and invasive cancer that shares histologic, molecular, and diagnostic imaging characteristics with DCIS and invasive cancer in women. The purpose of the study was to identify markers and altered signaling pathways that lead to invasive cancer and shed light on early molecular events in breast cancer progression and development. Transcriptomic studies along the continuum of cancer progression in the mammary gland from healthy, through atypical ductal hyperplasia (ADH), DCIS, and invasive carcinoma were performed using the canine model. Gene expression profiles of preinvasive DCIS lesions closely resemble those of invasive carcinoma. However, certain genes, such as SFRP2, FZD2, STK31, and LALBA, were over-expressed in DCIS compared to invasive cancer. The over-representation of myoepithelial markers, epithelial-mesenchymal transition (EMT), canonical Wnt signaling components, and other pathways induced by Wnt family members distinguishes DCIS from invasive. The information gained may help in stratifying DCIS as well as identify actionable targets for primary and tertiary prevention or targeted therapy.

Impulsive and compulsive behaviors in Parkinson's disease: a one-year follow-up study.

Impulsive and compulsive behaviors (ICBs) have been reported to occur frequently in Parkinson's disease (PD) and include impulse control disorders (ICDs), punding and dopamine dysregulation syndrome (SSD). We report on the outcomes of 25 PD patients who developed ICBs. Information was collected on changes in parkinsonian and psychiatric medication follow-up (median=12.1 months). At time 1, only 18 patients (72%) were taking dopamine agonists (DA). At time 2, fifteen patients (83.33%) either discontinued or decreased their DA treatment. Of these patients, thirteen (86.67%) reported experiencing full or partial remission of their ICBs symptoms. When analyzing separately the 11 patients with punding, these symptoms remained unchanged in 9 patients (81.82%) independently of changes in dopaminergic drugs. In conclusion, the current study suggests that there are clear similarities, but also important differences, between punding and ICDs over time. Pathological gambling, binge or compulsive eating, pathological hypersexuality and compulsive shopping in PD were robustly associated with the use of DA but the relationship between dopaminergic medications and punding is less clear. It is important to determine if other treatment strategies may be effective for punding in PD.

Does nefazodone improve both depression and Parkinson disease? A pilot randomized trial.

Some of the selective serotonin reuptake inhibitors (SSRI)-induced motor side effects are mediated by stimulating 5-HT2 receptors in the basal ganglia, probably because serotonin inhibits the subsequent neuronal dopamine release. We hypothesized that nefazodone, a serotonin 2 antagonist/reuptake inhibitor (SARI) that selectively blocks 5-HT2 receptors, could disrupt the aforementioned inhibitory pathway. Therefore, increased dopamine levels in the postsynaptic milieu and an improvement in the motor symptoms in depressed patients with Parkinson disease (PD) should be observed. This study was designed to determine whether nefazodone has a dual activity as an antidepressant and as an agent capable of reducing the extrapyramidal symptoms in depressed parkinsonian patients. Depressed patients with PD were randomly assigned to 2 therapeutic groups: nefazodone or fluoxetine. Patients were evaluated by a psychiatrist and were blindly assessed by a neurologist with an array of scales. Patients on nefazodone (n = 9) showed a significant improvement over time in the total Unified Parkinson Disease Rating Scale score (UPDRS) (part II + part III) (P = 0.004) and in the UPDRS subscore part III (P = 0.003). None of these scores changed over time in the fluoxetine group (n = 7). Both, nefazodone and fluoxetine were equally effective as antidepressants: Beck Depression Inventory scores significantly improved (P < 0.001), with no significant differences between treatment groups (P = 0.97). If our results can be confirmed in a larger clinical trial, nefazodone ought to be considered over fluoxetine given its secondary beneficial effects regarding the reduction of extrapyramidal symptoms in depressed PD patients.