Solid-Phase Synthesis of Substrate-Based Dipeptides and Heterocyclic Pseudo-dipeptides as Potential NO Synthase Inhibitors.

More than 160 arginine analogues modified on the C-terminus via either an amide bond or a heterocyclic moiety (1,2,4-oxadiazole, 1,3,4-oxadiazole and 1,2,4-triazole) were prepared as potential inhibitors of NO synthases (NOS). A methodology involving formation of a thiocitrulline intermediate linked through its side-chain on a solid support followed by modification of its carboxylate group was developed. Finally, the side-chain thiourea group was either let unchanged, S-alkylated (Me, Et) or guanidinylated (Me, Et) to yield respectively after TFA treatment the corresponding thiocitrulline, S-Me/Et-isothiocitrulline and N-Me/Et-arginine substrate analogues. They all were tested against three recombinant NOS isoforms. Several compounds containing a S-Et- or a S-Me-Itc moiety and mainly belonging to both the dipeptide-like and 1,2,4-oxadiazole series were shown to inhibit nNOS and iNOS with IC50 in the 1-50 µM range. Spectral studies confirmed that these new compounds interacted at the heme active site. The more active compounds were found to inhibit intra-cellular iNOS expressed in RAW264.7 and INS-1 cells with similar efficiency than the reference compounds L-NIL and SEIT.

A new tool to adapt the treatment of Parkinson's disease patients in nursing homes.

Parkinson's disease (PD) is a common condition in nursing home (NH) residents. The primary treatment for Parkinson's disease is levodopa therapy to relieve motor symptoms and maximize physical function. Non-motor symptoms are highly prevalent in NH residents with Parkinson's disease and dramatically decrease quality of life. Choices in drug treatment need to take into account the complex interactions between aging, comorbidity and non-motor symptoms. Optimal management requires expertise and cooperative effort from prescribing neurologists and nursing home health professionals. The objective is to evaluate the pertinence of the CHEF, a new tool to screen daily life clinical data helpful for the management of neurologist consultants. NH nurses were asked to briefly report falls and gait problems, hallucinations, sleep disorders and motor fluctuations. Analysis of the results obtained in 26 patients showed that CHEF was perceived as a helpful complement to existing ressources. The use of this tool has the potential to enhance the quality of NH care of Parkinsonian patients.

Effects of Sensitive Electrical Stimulation-Based Somatosensory Cueing in Parkinson's Disease Gait and Freezing of Gait Assessment.

This study aims to investigate the effect of a somatosensory cueing on gait disorders in subjects with Parkinson's disease (PD). After having performed stepping in place and timed up and go assessing tasks, 13 participants with PD were equipped with an electrical stimulator and an inertial measurement unit (IMU) located under the lateral malleolus on the sagittal plane. Electrodes were positioned under the arch of the foot and electrical stimulation (ES) parameters (five 500 µs/phase charge-balanced biphasic pulses delivered at 200 Hz, repeated four times at 10 Hz) adjusted to deliver a sensitive signal. Online IMU signal was processed in order to trigger ES at heel off detection. Starting from a quiet standing posture, subjects were asked to walk at their preferred speed on a path including 5 m straight line, u-turn, and walk around tasks. Three situations were considered: no stimulation baseline precondition (C0), ES condition (C1), and no stimulation baseline post-condition (C0bis), for eliminating a learning effect possibility. In ES condition (C1) the time to execute the different tasks was globally decreased in all the subjects (n = 13). Participants' results were then grouped regarding whether they experienced freezing of gait (FOG) or not during C0 no stimulation baseline precondition. In "freezer" subjects (n = 9), the time to complete the entire path was reduced by 19%. FOG episodes occurrence was decreased by 12% compared to baseline conditions. This preliminary work showed a positive global effect on gait and FOG in PD by a somatosensory cueing based on sensitive electrical stimulation.

Effects of Sensitive Electrical Stimulation Based Cueing in Parkinson's Disease: A Preliminary Study.

This study aims to investigate the effect of a sensitive cueing on Freezing of Gait (FOG) and gait disorders in subjects suffering from Parkinson's disease (PD). 13 participants with Parkinson's disease were equipped with an electrical stimulator and a foot mounted inertial measurement unit (IMU). An IMU based algorithm triggered in real time an electrical stimulus applied on the arch of foot at heel off detection. Starting from standing, subjects were asked to walk at their preferred speed on a path comprising 5m straight, u-turn and walk around tasks. Cueing globally decreased the time to achieve the different tasks in all the subjects. In "freezer" subjects, the time to complete the entire path was reduced by 19%. FOG events occurrence was lowered by 12% compared to baseline before and after cueing. This preliminary work showed a positive global effect of an electrical stimulation based cueing on gait and FOG in PD.