Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo. Implications This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of Δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.

Background: This is the first report of the pharmacodynamic (PD) effects of the selective, potent and brain-penetrant P2X7 receptor (P2X7R) antagonist JNJ-54175446. Activation of the P2X7R, an adenosine triphosphate-gated ion channel, leads to the production of pro-inflammatory cytokines, which have been linked to neuroinflammation and play a role in the pathogenesis of mood disorders. Previous clinical studies with JNJ-54175446 demonstrated peripheral target engagement of JNJ-54175446 by assessing ex vivo lipopolysaccharide (LPS)-stimulated cytokine production. Blood–brain barrier penetration and a clear dose–receptor occupancy relationship was demonstrated using positron emission tomography. Aims: The objectives of this double-blind, placebo-controlled, translational study were to assess the safety and tolerability of administering multiple doses of JNJ-54175446 and to explore its PD effects using a dexamphetamine challenge. Methods: Subjects ( N = 64) were randomised to either JNJ-54175446 (50–450 mg; n = 48) or placebo ( n = 16) and underwent a baseline oral 20 mg dexamphetamine challenge followed by 11 consecutive days q.d. dosing with JNJ-54175446/placebo and a randomised crossover dexamphetamine/placebo challenge. Results: At all doses tested, JNJ-54175446 was well tolerated and suppressed the ex vivo LPS-induced release of cytokines. At doses ⩾100 mg, JNJ-54175446 attenuated dexamphetamine-induced increases in locomotion and enhanced the mood-elevating effects of dexamphetamine, suggesting that a dose that is approximately twice as high is needed to obtain a central PD response compared to the dose needed for maximum peripheral occupancy. Conclusion: Overall, the observed pharmacological profile of JNJ-54175446 in the dexamphetamine challenge paradigm is compatible with a potential mood-modulating effect.

Summary Aim To examine whether the velocity of saccadic eye movements in internuclear ophthalmoparesis ( INO ) improves with fampridine treatment in patients with multiple sclerosis ( MS ). Methods Randomized, double‐blind, placebo‐controlled, cross‐over trial with fampridine in patients with MS and INO . Horizontal saccades were recorded at baseline and at multiple time points post‐dose. Main outcome measures were the change of peak velocity versional dysconjugacy index ( PV ‐ VDI ) and first‐pass amplitude VDI ( FPA ‐ VDI ). Both parameters were compared between fampridine and placebo using a mixed model analysis of variance taking patients as their own control. Pharmacokinetics was determined by serial blood sampling. Results Thirteen patients had a bilateral and 10 had a unilateral INO . One patient had an INO of abduction (posterior INO of Lutz) and was excluded. Fampridine significantly reduced both PV ‐ VDI (−17.4%, 95% CI : −22.4%, −12.1%; P < 0.0001) and FPA ‐ VDI (−12.5%, 95% CI : −18.9%, −5.5%; P < 0.01). Pharmacokinetics demonstrated that testing coincided with the average t max at 2.08 hours ( SD 45 minutes). The main adverse event reported after administration of fampridine was dizziness (61%). Conclusion Fampridine improves saccadic eye movements due to INO in MS . Treatment response to fampridine may gauge patient selection for inclusion to remyelination strategies in MS using saccadic eye movements as primary outcome measure.

2B3-201 is considered safe, with no clinically relevant changes in central nervous system safety parameters and no serious adverse events. In addition, 2B3-201 shows a long plasma half-life and prolonged immunosuppressive effects.

Background and aims Multiple sclerosis (MS) is the is one of most common immunemediated neurodegenerative disease. The initial stage of MS implies the presence of autoreactive T and B cells not only to CNS, but also to other tissues. The presence of antiphospholipid antibodies is frequent in MS (2-88%). Influence of aPL, aCL, LA on course and prognosis of MS is still unclear. Methods 100 patients, RRMS/SPMS; EDSS≤6,0; remission; absence of another autoimmune disease except APS; clinical exam; EDSS; relapse rate (RR); lab levels of antiphospholipid (aPL), anticardiolipine (aCL), LA. Results 1st group-MSaCL-aPL-(16 males, 63 females); 2nd group-MSaCL+aPL+ (3 males, 15 females); 3rd group-MS + primary APS (3 females). No differences in duration of disease (3.8 years), strong differences in EDSS rate-2.2 vs 3.5 vs 4.0. Appearance of livedo and thrombosis in all groups, but statistically more frequent in 2nd and 3rd-15.2%, 55.5%, 66.6%, thrombosis-5.0%, 16,6% and 33,3%. Higher prevalence of motor (19.9%, 31.4%, 34.2%) and bladder dysfunction (5.9%, 2.9%, 15.7%) in 2nd and 3rd. RR was significantly higher in 2nd (0.82vs1.41vs1.17), and EDSS progression was significantly higher in 2nd and 3rd (0.53vs0.81vs0.95). Conclusion Presence of aCL and aPL, as well as presence of APS as comorbidity aggravates the course of the MS. Also there is a higher risk of thrombosis during the methylprednisolone therapy in MSaCL +aPL+ group.