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This study evaluated the effects of acute doses of zopiclone (7.5 mg), triazolam (0.25 mg) and placebo on memory and psychomotor performance of 12 normal volunteers. The subjects received both drugs in a repeated measure, double-blind Latin square design. The tests (CFF, CRT, DSST, memory assessments) were performed before and 2 and 6 hr after treatment. Zopiclone and triazolam induced an anterograde amnesia affecting short-term and long-term memory which lasted less than 6 hr. No retrograde amnesia was observed. Two hr after drug intake of both hypnotics psychomotor performances were significantly altered compared with placebo. The subjects also felt more drowsy, dizzy, clumsy and tired, and less alert and energetic 2 hr after zopiclone and triazolam compared to placebo. There was no difference between the effects of the two hypnotics at the doses studied.

A randomised double blind controlled trial of 'epidural blood-patch' as treatment for post-dural puncture headache is presented. The method was successful in 11 out of 12 cases on its first application, the twelfth patient being relieved by a second procedure. None of six patients reported benefit from a 'sham' procedure. The rationale for the use of the technique is discussed.

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Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor neuron loss and currently no effective disease-modifying treatment is available. A pathological feature of this disease is neuroinflammation, a mechanism which involves both CNS-resident and peripheral immune system cells. Regulatory T-cells are immune-suppressive agents known to be dramatically and progressively decreased in patients with ALS. Low-dose interleukin-2 promotes regulatory T-cell expansion and was proposed as an immune-modulatory strategy for this disease. A randomized placebo-controlled pilot phase-II clinical trial called Immuno-Modulation in Amyotrophic Lateral Sclerosis (IMODALS) was carried out to test safety and activity of low-dose interleukin-2 in 36 amyotrophic lateral sclerosis patients (NCT02059759). Participants were randomized to 1MIU, 2MIU-low-dose interleukin-2 or placebo and underwent one injection daily for five days every twenty-eight days for three cycles. In this report, we describe the results of microarray gene expression profiling of trial participants' leukocyte population. We identified a dose-dependent increase in regulatory T-cell markers at the end of the treatment period. Longitudinal analysis revealed an alteration and inhibition of inflammatory pathways occurring promptly at the end of the first treatment cycle. These responses are less pronounced following the end of the third treatment cycle, although an activation of immune-regulatory pathways, involving regulatory T-cells and T helper 2 cells, was evident only after the last cycle. This indicates a cumulative effect of repeated low-dose interleukin-2 administration on regulatory T-cells. Our analysis suggested the existence of inter-individual variation amongst trial participants and we therefore classified patients into low, moderate and high-Treg-responders. NanoString profiling revealed substantial baseline differences between participant immunological transcript expression profiles with the least responsive patients showing a more inflammatory-prone phenotype at the beginning of the trial. Finally, we identified two genes in which pre-treatment expression levels correlated with the magnitude of drug responsiveness. Therefore, we proposed a two-biomarker based regression model able to predict patient Treg-response to low-dose interleukin-2. These findings and the application of this methodology could be particularly relevant for future precision medicine approaches to treat amyotrophic lateral sclerosis.

Seven healthy volunteers received a single oral dose of triazolam 0.25 mg after 7 days on troleandomycin 2 g/day p.o. or placebo in a double-blind cross-over study. Plasma triazolam and psychometric and memory tests (including Critical Flicker Fusion threshold, Choice Reaction Time, Digit Symbol Substitution and Self-Rating Scales) were assessed at regular intervals after the final treatment. Troleandomycin was found to prolong the psychomotor impairment and amnesia produced by triazolam. There was a significant enhancement of the AUC, the peak concentration and the delay to tmax of triazolam after 7 days treatment with troleandomycin compared to placebo. Thus, there is a pharmacokinetic interaction, and the combination of triazolam and troleandomycin should be avoided or the dose of triazolam should be adjusted. The most likely mechanism is a diminished hepatic first-pass effect, and a decrease in the apparent oral clearance of triazolam.

The effects of single doses of levomepromazine (3,6 and 12mg) on psychomotor skills and memory tasks, as well as haemodynamic and pupil diameter parameters, were assessed in 12 normal volunteers. Each subject was given three of the four treatments, at a weekly interval in a double-blind crossover randomized balanced incomplete-block design.The three doses and a placebo were monitored using a battery of tests including critical flicker fusion (CFF), choice reaction time (CRT), subjective ratings and memory tasks before, 3 and 6 hours after drug intake. Supine standing blood pressure and pupil diameter were recorded at the same times.Compared to placebo, levomepromazine impaired both subjective and objective vigilance measures in a dose-related manner, with 3mg affecting only some subjective ratings, while 12mg impaired most objective and subjective vigilance evaluations with a moderate effect on memory tasks (i.e. anterograde amnesia). Pupil diameter was reduced by the three doses. In conclusion, levomepromazine at low doses induced a sedative effect the intensity and duration of which are compatible with its use as an hypnotic.