Background. There is increasing interest in methods to more rapidly and cost-efficiently investigate drugs that are approved for clinical use in the treatment of another condition. Exenatide is a type 2 diabetes treatment that has been shown to have neuroprotective/neurorestorative properties in preclinical models of neurodegeneration.Methods. As a proof of concept, using a single-blind trial design, we evaluated the progress of 45 patients with moderate Parkinson's disease (PD), randomly assigned to receive subcutaneous exenatide injection for 12 months or to act as controls. Their PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), together with several nonmotor tests, at baseline, 6 months, and 12 months and after a further 2-month washout period (14 months).Results. Exenatide was well tolerated, although weight loss was common and l-dopa dose failures occurred in a single patient. Single-blinded rating of the exenatide group suggested clinically relevant improvements in PD across motor and cognitive measures compared with the control group. Exenatide-treated patients had a mean improvement at 12 months on the MDS-UPDRS of 2.7 points, compared with mean decline of 2.2 points in control patients (P = 0.037).Conclusion. These results demonstrate a potential cost-efficient approach through which preliminary clinical data of possible biological effects are obtainable, prior to undertaking the major investment required for double-blind trials of a potential disease-modifying drug in PD.Trial registration. Clinicaltrials.gov NCT01174810.Funding. Cure Parkinson's Trust.

The presentation and outcome of 50 patients with neonatal Ebstein's anomaly seen from 1961 to 1990 were reviewed. The majority (88%) presented in the 1st 3 days of life; cyanosis (80%) was the most common presenting feature. Associated defects, present in 27 infants (54%), included pulmonary stenosis in 11 and atresia in 7. Nine patients (18%) died in the neonatal period; there were 15 late deaths (due to hemodynamic deterioration in 9, sudden death in 5 and a noncardiac cause in 1) at a mean age of 4.5 years (range 4 months to 19 years). Actuarial survival at 10 years was 61%. A new echocardiographic grade (1 to 4 in order of increasing severity of the defect) was devised with use of the ratio of the area of the right atrium and atrialized right ventricle to the area of the functional right ventricle and left heart chambers. Cardiac death occurred in 0 of 4 infants with grade 1, 1 (10%) of 10 with grade 2, 4 (44%) of 9 with grade 3 and 5 (100%) of 5 with grade 4. In a multivariate analysis of clinical and investigational features at presentation, echocardiographic grade of severity was the best independent predictor of death. Neonates with Ebstein's anomaly have a high early mortality rate and those surviving the 1st month of life remain at high risk of late hemodynamic deterioration or sudden death. Echocardiographic grading of severity of the defect permits prognostic stratification.

Abstract. Background:Data from an open label randomised controlled trial have suggested possible advantages on both motor and non-motor measures in patients with Parkinson's disease following 12 months exposure to exenatide. Objective: Continued follow up of these same patients was performed to investigate whether these possible advantages persisted in the prolonged absence of this medication. Methods: All participants from an open label, randomised controlled trial of exenatide as a treatment for Parkinson's disease, were invited for a further follow up assessment at the UCL Institute of Neurology. This visit included all 20 individuals who had previously completed twelve months exposure to exenatide 10ug bd and the 24 individuals who had acted as randomised controls. Motor severity of PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the MDS-UPDRS, together with several non-motor tests. This assessment was thus 24 months after their original baseline visit, i.e. 12 months after cessation of exenatide. Results: Compared to the control group of patients, patients previously exposed to exenatide had an advantage of 5.6 points (95% CI, 2.2-9.0; p = 0.002) using blinded video rating of the MDS-UPDRS part 3 motor subscale. There was also a difference of 5.3 points; (95% CI, 9.3-1.4; p = 0.006) between the 2 groups on the Mattis Dementia Rating scale.

Background: The majority of current pharmacological treatments for Parkinson's disease (PD) were approved for clinical use in the second half of the last century and they only provide symptomatic relief. Derivatives of these therapies continue to be explored in clinical trials, together with potentially disease modifying therapies that can slow, stop or reverse the condition. Objective: To provide an overview of the pharmacological therapies-both symptomatic and disease modifying-currently being clinically evaluated for PD, with the goal of creating greater awareness and opportunities for collaboration amongst commercial and academic researchers as well as between the research and patient communities. Methods: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov database and performed a breakdown analysis of studies that were active as of January 21, 2020. Results: We identified 145 registered and ongoing clinical trials for therapeutics targeting PD, of which 51 were Phase 1 (35% of the total number of trials), 66 were Phase 2 (46%), and 28 were Phase 3 (19%). There were 57 trials (39%) focused on long-term disease modifying therapies, with the remaining 88 trials (61%) focused on therapies for symptomatic relief. A total of 50 (34%) trials were testing repurposed therapies. Conclusion: There is a broad pipeline of both symptomatic and disease modifying therapies currently being tested in clinical trials for PD.

Clinical experience of 50 patients with the CHARGE association is reviewed and problems with management of children born with multiple system involvement is highlighted. It was found that the outlook for survival was poor if more than one of the following three features was present: cyanotic cardiac lesions, bilateral posterior choanal atresia, or tracheo-oesophageal fistula. Mortality was largely due not to the structural heart defects or choanal abnormalities, but reflected underlying pharyngeal and laryngeal incoordination, which resulted in aspiration of secretions. Outcome is likely to be improved if collaboration between specialist surgical teams allows necessary procedures to be performed using the minimum number of anaesthetics. Examination of both the short and long term management of these children has stressed the importance of a multidisciplinary approach to their care.