Long-term safety, tolerability and efficacy of apomorphine sublingual film in patients with Parkinson's disease complicated by OFF episodes: a phase 3, open-label study.

BACKGROUND: Apomorphine sublingual film (SL-APO) is an on-demand treatment for OFF episodes in patients with Parkinson's disease (PD). OBJECTIVE: To assess the long-term (≥ 3 years) safety/tolerability and efficacy of SL-APO. METHODS: Study CTH-301 ( http://www. CLINICALTRIALS: gov NCT02542696; registered 2015-09-03) was a phase 3, multicentre, open-label study of SL-APO in PD patients with motor fluctuations, comprised of a dose-titration and long-term safety phase. All participants received SL-APO. The primary endpoint was safety/tolerability (treatment-emergent adverse events [TEAEs]) during the long-term safety phase. Efficacy assessments included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination), assessed at weeks 24, 36 and 48 during the first year of the long-term safety phase. RESULTS: 496 patients were included and 120 (24.2%) completed the long-term safety phase. Mean duration of SL-APO exposure was 294.3 days. TEAEs related to study drug were experienced by 65.3% of patients (most common: nausea [6.0%], stomatitis [1.8%], lip swelling [1.8%], dizziness [1.6%], oral mucosal erythema [1.6%], mouth ulceration [1.6%]). TEAEs leading to study drug withdrawal were experienced by 34.0% of patients (most common: nausea [5.4%], lip swelling [4.5%], mouth ulceration [2.6%], stomatitis [2.3%]). A clinically meaningful reduction in MDS-UPDRS part III score was observed as soon as 15 min following administration of SL-APO, with peak effects observed approximately 30 min post-dose and sustained up to 90 min post-dose; results were consistent over 48 weeks. CONCLUSIONS: SL-APO was generally well tolerated and efficacious over the long term as an on-demand treatment for OFF episodes in patients with PD.

Phylogeography, genetic diversity, and intraspecific genetic structure of the black-horned capuchin (Sapajus nigritus).

Recent molecular studies have clarified the overarching taxonomy of capuchin monkeys, but intraspecific genetic diversity remains unexplored for most capuchin species. One example is Sapajus nigritus, the southernmost capuchin monkey, found in Brazil and Argentina; its phenotypic diversity has been recognized as two geographic subspecies, but the intraspecific genetic structure of this taxon is poorly known. Here, we sampled across most of this species' geographic distribution, producing a newly sequenced data set for genetic analyses that included 78 individuals from 14 populations. We investigated the intraspecific diversity, genetic structure, and evolutionary history using three mitochondrial markers. Our results indicated that S. nigritus populations exhibited high levels of genetic structure. We found strong support for two monophyletic clades within this species with a deep phylogenetic split, and clear separation from other related taxa. Vicariance events seem to have played a prevalent role in shaping S. nigritus genetic differentiation. The Paraíba do Sul River may have driven the deep divergence between southern and northern clades, whereas the Tietê River may have had a weaker, more recent effect on the divergence of populations within the southern clade.

Apomorphine Sublingual Film Compared with Subcutaneous Apomorphine for OFF Episodes in Parkinson's Disease: An Open-Label, Randomized, Crossover Study.

BACKGROUND: Apomorphine sublingual film (SL-APO) and subcutaneous apomorphine (SC-APO) have been used for the treatment of OFF episodes in Parkinson's disease (PD). No study has prospectively compared efficacy and safety of these formulations. OBJECTIVE: To compare SL-APO with SC-APO for treatment of OFF episodes in PD. METHODS: An open-label, randomized, crossover study assessed SL-APO versus SC-APO in patients with PD and OFF episodes (N = 113). Doses were optimized in randomly assigned order. SL-APO dose initiation (10 mg) occurred in clinic; further dose optimization (15-30 mg; 5-mg increments) occurred primarily at home. SC-APO dosing (2-6 mg; 1-mg increments) occurred entirely in clinic. After a 3-7-day washout, patients were randomized 1 : 1 to 4 weeks of treatment with their optimized dose of SL-APO or SC-APO, followed by washout and 4 weeks of crossover treatment. RESULTS: Propensity score matching applied on 159 patients (STN-DBS n = 75, MED n = 84) resulted in 40 patients in each treatment group. At 36-month follow-up, STN-DBS led to significantly better PDSS and PDQ-8 change scores, which were significantly correlated. We observed no significant effects for HADS and no significant correlations between change scores in PDSS, HADS, and LEDD. CONCLUSIONS: We report Class IIb evidence of beneficial effects of STN-DBS on quality of sleep at 36-month follow-up, which were associated with QoL improvement independent of depression and dopaminergic medication. Our study highlights the importance of sleep for assessments of DBS outcomes. RESULTS: No difference was observed between SL-APO and SC-APO for change from predose to 90 minutes postdose in Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III score at week 4 (primary endpoint), assessed by a blinded rater (-13.6 vs. -13.8, respectively; p = NS). Overall, 72.2% of patients preferred SL-APO compared with SC-APO/no preference (p = 0.0002) per the Treatment Preference Questionnaire (secondary endpoint). Patients reported greater satisfaction with SL-APO compared with SC-APO, per mean scores of convenience (73.7 vs. 53.5) and global satisfaction (63.9 vs. 57.6) on the Treatment Satisfaction Questionnaire for Medication (other endpoint). The safety profiles of both treatments were generally comparable and were well-tolerated. CONCLUSIONS: Patients reported overall preference for and greater satisfaction with SL-APO over SC-APO.

Feasibility of home dose optimization of apomorphine sublingual film in Parkinson's disease patients with OFF episodes: results from the dose-optimization phase of an open-label, randomized crossover study.

Background: Dose optimization of sublingual apomorphine (SL-APO), a dopamine agonist for the treatment of OFF episodes in patients with Parkinson's disease (PD), has been performed under clinical supervision in clinical trials. SL-APO may be a candidate for home dosing optimization which would be less burdensome for patients. Objectives: To evaluate the feasibility and safety of home optimization of SL-APO in patients with PD and OFF episodes. Design: A multicenter, randomized, crossover study comparing SL-APO with subcutaneous apomorphine was conducted, comprising an open-label dose-optimization phase and a treatment phase. This non-comparative analysis focuses on the outcomes of the dose-optimization phase with SL-APO only. Methods: Patients with PD and OFF episodes received SL-APO at an initial dose of 10 mg in the clinic (open-label). Further optimization could continue at home in 5 mg increments during subsequent OFF episodes (maximum dose of 30 mg). Optimization and tolerability were assessed daily by patient-reported feedback via telephone. Patients reporting a FULL ON returned to the clinic for a dose-confirmation visit (DCV). In patients with inadequate response as determined during the DCV, the dose could be further optimized at home. Results: Home optimization was continued by 81.4% (83/102) of patients. Of these, 80.7% identified an effective, tolerable dose. Mean time between initial clinic visit and DCV 1 was 6.8 days, and the final optimized dose of SL-APO was 30 mg (mode). In total, 62.7% of patients reported ⩾1 adverse event; the most common included nausea (31.4%), dizziness (9.8%), somnolence (8.8%), dyskinesia (7.8%), and fatigue (5.9%). The safety profile in this study in which most patients performed home dose optimization was consistent with the study utilizing clinic-based optimization. Conclusion: After the first clinic dose, home dose optimization of SL-APO appears feasible in patients with PD and OFF episodes, with most patients identifying their optimal SL-APO dose at home. Trial registration: This study is registered with EudraCT (2016-003456-7): Clinical Trials register - Search for eudract_number:2016-003456-70.

Lack of serological and molecular evidences of Zika virus circulation in non-human primates in three states from Brazil.

BACKGROUND: Zika virus (ZIKV) was discovered in 1947 with the virus isolation from Rhesus monkey (Macaca mulatta) in Uganda forest, Africa. Old World Primates are involved in a sylvatic cycle of maintenance of this arbovirus, however a limited knowledge about the role of New World primates in ZIKV transmission cycles has been established. OBJECTIVE: This work aimed to investigate the presence of enzootic circulation of ZIKV in New World Primates from three Brazilian states: São Paulo, Paraíba, and Paraná. METHODS: We analyzed 100 non-human primate samples collected in 2018 and 2020 from free-ranging and captive environments from São Paulo (six municipalities belonging to Sorocaba region), Paraíba (João Pessoa municipality), and Paraná (Foz do Iguaçu municipality) using reverse transcriptase quantitative polymerase reaction (RT-qPCR) assays, indirect enzyme-linked immunosorbent assay (ELISA), and plaque reduction neutralization test (PRNT). FINDINGS: All samples (n = 141) tested negative for the presence of ZIKV genome from tissue and blood samples. In addition, all sera (n = 58) from Foz do Iguaçu' non-human primates (NHPs) were negative in serological assays. MAIN CONCLUSION: No evidence of ZIKV circulation (molecular and serological) was found in neotropical primates. In addition, the absence of antibodies against ZIKV suggests the absence of previous viral exposure of NHPs from Foz do Iguaçu-PR.

A pilot study about assisted reproduction in harpy eagles (Harpia harpyja) in the course of species conservation including collection, storage, and analysis of semen.

Currently, 52% of all raptor species demonstrate a decreasing population tendency, and the American harpy eagle (Harpia harpyja) has been categorized as "near threatened" by the IUCN. Habitat loss, persecution, and subsequent reduction of genetic diversity are regarded as major threats to the world's strongest eagle. Captive breeding and reintroduction into protected habitats are approaches of species conservation projects, but captive propagation is difficult due to low ex-situ numbers and scarce successful breeding pairs. The aim of the present study was to collect, analyze, and store semen from harpy eagles and to use aliquots for artificial insemination to increase the number of offspring and to include more individuals into the ex-situ gene pool. First, semen collection and semen availability were assessed in four males during the course of 1 year in European zoos. Second, these experiences were transferred to ex-situ breeding programs in Brazilian zoos to attempt semen collection in 13 male eagles. Semen collection was successful in 51.7% of the attempts and in 8/13 males (individual success rates 20-100%) using electro-stimulation. Most commonly, whey-like to milky, whitish semen samples were collected, regularly containing urate impurities (67.7%). The median semen volume was 106 µl and the median sperm concentration 5,000 sperm/µl (750-22,500 sperm/µl). Mean values for pH were 6.7, for sperm motility 27.7 ± 22.6%, for progressive motility 2.9 ± 5.6%, and for sperm viability 46.6 ± 16.3%. Using semen extenders, a sperm motility of 8% was maintained for 27 h in the refrigerator. Artificial insemination was performed in one female, but the success of fertilization could not be assessed due to egg destruction. In this study, methods for assisted reproduction were refined for use in harpy eagles, and the first semen samples were evaluated as a start to establish species-specific orientation values.

Lack of serological and molecular evidences of Zika virus circulation in non-human primates in three states from Brazil

BACKGROUND Zika virus (ZIKV) was discovered in 1947 with the virus isolation from Rhesus monkey (Macaca mulatta) in Uganda forest, Africa. Old World Primates are involved in a sylvatic cycle of maintenance of this arbovirus, however a limited knowledge about the role of New World primates in ZIKV transmission cycles has been established. OBJECTIVE This work aimed to investigate the presence of enzootic circulation of ZIKV in New World Primates from three Brazilian states: São Paulo, Paraíba, and Paraná. METHODS We analyzed 100 non-human primate samples collected in 2018 and 2020 from free-ranging and captive environments from São Paulo (six municipalities belonging to Sorocaba region), Paraíba (João Pessoa municipality), and Paraná (Foz do Iguaçu municipality) using reverse transcriptase quantitative polymerase reaction (RT-qPCR) assays, indirect enzyme-linked immunosorbent assay (ELISA), and plaque reduction neutralization test (PRNT). FINDINGS All samples (n = 141) tested negative for the presence of ZIKV genome from tissue and blood samples. In addition, all sera (n = 58) from Foz do Iguaçu' non-human primates (NHPs) were negative in serological assays. MAIN CONCLUSION No evidence of ZIKV circulation (molecular and serological) was found in neotropical primates. In addition, the absence of antibodies against ZIKV suggests the absence of previous viral exposure of NHPs from Foz do Iguaçu-PR.

Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study.

BACKGROUND: In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with fingolimod. METHODS: Patients randomly assigned to receive 0.5 mg or 1.25 mg daily oral fingolimod in the core study continued with the same treatment in our extension; patients who originally received 30 µg weekly intramuscular interferon beta-1a were randomly reassigned (1:1) to receive either 0.5 mg or 1.25 mg fingolimod. The initial randomisation and dose of fingolimod assigned for the extension remained masked to the patients and investigators. As in the core study, re-randomisation was done centrally in blocks of six and stratified according to site. Our efficacy endpoints were annualised relapse rate (ARR), disability progression, and MRI outcomes. Our within-group analyses were based on the intention-to-treat and safety populations that entered our extension study. Our between-group analyses were based on the intention-to-treat and safety populations from the core study. This study is registered with ClinicalTrials.gov, number NCT00340834. FINDINGS: 1027 patients entered our extension and received the study drug, and 882 completed 24 months of treatment. Patients receiving continuous fingolimod showed persistent benefits in ARR (0.5 mg fingolimod [n=356], 0.12 [95% CI 0.08-0.17] in months 0-12 vs 0.11 [0.08-0.16] in months 13-24; 1.25 mg fingolimod [n=330], 0.15 [0.10-0.21] vs 0.11 [0.08-0.16]; however, in patients who initially received interferon beta-1a, ARR was lower after switching to fingolimod compared with the previous 12 months (interferon beta-1a to 0.5 mg fingolimod [n=167], 0.31 [95% CI 0.22-0.43] in months 0-12 vs 0.22 [0.15-0.31], in months 13-24 p=0.049; interferon beta-1a to 1.25 mg fingolimod [n=174], 0.29 [0.20-0.40] vs 0.18 [0.12-0.27], p=0.024). After switching to fingolimod, numbers of new or newly enlarging T2 and gadolinium (Gd)-enhancing T1 lesions were significantly reduced compared with the previous 12 months of interferon beta-1a therapy (p<0.0001 for T2 lesions at both doses; p=0.002 for T1 at 0.5 mg; p=0.011 for T1 at 1.25 mg), and the pattern of adverse events shifted towards that typical for fingolimod. Over 24 months, in continuous fingolimod groups compared with the group that switched from interferon beta-1a to fingolimod, we recorded lower ARRs (0.18 [95% CI 0.14-0.22] for 0.5 mg; 0.20 [0.16-0.25] for 1.25 mg; 0.33 [0.27-0.39] for the switch group; p<0.0001 for both comparisons), fewer new or newly enlarged T2 lesions (p=0.035 for 0.5 mg, p=0.068 for 1.25 mg), and fewer patients with Gd-enhancing T1 lesions (p=0.001 for 0.5 mg fingolimod vs switch group; p=0.002 for 1.25 mg fingolimod vs switch group). There was no benefit on disability progression. INTERPRETATION: Switching from interferon beta-1a to fingolimod led to enhanced efficacy with no unexpected safety concerns. Compared with patients switched from interferon beta-1a to fingolimod, continuous treatment with fingolimod for 2 years provides a sustained treatment effect with improved clinical and MRI outcomes. FUNDING: Novartis Pharma AG.

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

BACKGROUND: Fingolimod (FTY720), a sphingosine-1-phosphate-receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis. METHODS: In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months. RESULTS: A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the primary results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels. CONCLUSIONS: This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.)

Treatment of Parkinson's disease : what's on the horizon?

Few neurological diseases have received as much attention and investment in research as Parkinson's disease. Although great strides have been made in the development of agents to treat this neurodegenerative disease, none yet address the underlying problem associated with it, the progressive loss of dopaminergic neurons. Current therapeutic strategies for Parkinson's disease focus primarily on reducing the severity of its symptoms using dopaminergic medications. Although providing substantial benefit, these agents are burdened by adverse effects and long-term complications. This review highlights new and emerging therapies for Parkinson's disease, categorised as symptomatic, neuroprotective and neurorestorative, although at times, this distinction is not easily made. Novel symptomatic treatments target nondopaminergic areas in the hope of avoiding the motor complications seen with dopaminergic therapies. Two emerging treatment approaches under investigation are adenosine A(2A) receptor antagonists (such as istradefylline [KW-6002]) and glutamate AMPA receptor antagonists (such as talampanel [LY-300164]). In 2003, the results from two studies using istradefylline in patients with Parkinson's disease were published, with both showing a positive benefit of the study drug when used as adjunctive therapy to levodopa. In non-human primate models of Parkinson's disease, talampanel has been found to have antiparkinsonian effects when administered as high-dose monotherapy and antidyskinetic effects on levodopa-induced dyskinesias. NS-2330, another drug currently undergoing clinical trials, is a triple monoamine reuptake inhibitor that has therapeutic potential in both Parkinson's and Alzheimer's disease. A phase II proof-of-concept study is currently underway in early Parkinson's disease. However, a recently published study in advanced Parkinson's disease showed no therapeutic benefit of NS-2330 in this patient population. Even more exciting are agents that have a neuroprotective or neurorestorative role. These therapies aim to prevent disease progression by targeting the mechanisms involved in the pathogenesis of Parkinson's disease. Several lines of investigation for neuroprotective therapies have been taken, including the antioxidant coenzyme Q10 (ubidecarenone) and anti-apoptotic agents such as CEP-1347. Studies in patients with Parkinson's disease with coenzyme Q10 have suggested that it slows down functional decline. The PRECEPT study is currently in progress to assess the neuroprotective role of CEP-1347 in the early phase of the disease. Gene therapy is another exciting arena and includes both potentially neuroprotective and neurorestorative agents. Novel methods include subthalamic glutamic acid decarboxylase gene therapy and the use of glial cell line-derived neurotrophic factor (GDNF). Eleven of 12 patients have been enrolled in the first FDA-approved phase I subthalamic glutamic acid decarboxylase gene therapy trial for Parkinson's disease, with currently no evidence of adverse events. GDNF delivered intracerebroventricularly was studied in a small population of patients with Parkinson's disease, but unfortunately did not reveal positive results. Other methods of administering GDNF include direct delivery via infusions into the basal ganglia and the use of viral vectors; thus far, these approaches have shown promising results. This is an exciting and rewarding time for research into Parkinson's disease. With so many therapies currently under investigation, the time is ripe for the beginning of a new phase of treatment strategies.