Study Objectives To assess the efficacy and safety of FT218, a novel once-nightly formulation of sodium oxybate (ON-SXB), in patients with narcolepsy in the phase 3 REST-ON trial. Methods Narcolepsy patients aged ≥16 years were randomized 1:1 to uptitration of ON-SXB (4.5, 6, 7.5, and 9 g) or placebo. Three coprimary endpoints were change from baseline in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression-Improvement rating, and weekly cataplexy attacks at 9, 7.5, and 6 g. Secondary endpoints included change from baseline on the Epworth Sleepiness Scale. Safety included adverse drug reactions and clinical laboratory assessments. Results In total, 222 patients were randomized; 212 received ≥1 dose of ON-SXB (n=107) or placebo (n=105). For the 3 coprimary endpoints and Epworth Sleepiness Scale, all 3 doses of ON-SXB demonstrated clinically meaningful, statistically significant improvement vs placebo (all P<0.001). For ON-SXB 9 g vs placebo, increase in mean sleep latency was 10.8 vs 4.7 min (LSMD [95% CI], 6.13 [3.52–8.75]), 72.0% vs 31.6% were rated much/very much improved on Clinical Global Impression-Improvement (OR [95% CI], 5.56 [2.76–11.23]), change in mean weekly number of cataplexy attacks was –11.5 vs –4.9 (LSMD [95% CI], –6.65 [–9.32 to –3.98]), and change in Epworth Sleepiness Scale was –6.5 and –2.7 (LSMD [95% CI], –6.52 [–5.47 to –2.26]). Common adverse reactions included nausea, vomiting, headache, dizziness, and enuresis. Conclusions ON-SXB significantly improved narcolepsy symptoms; its safety profile was consistent with SXB. ON-SXB conferred efficacy with a clearly beneficial single nighttime dose.

This was not an industry supported study. The authors have indicated no financial conflicts of interest.hypothesized damage to the serotonergic modulation, the use of fluoxetine could have restored the balance of the REM modulators by maximizing the serotonergic input over the SLD.

Mycobacterium bovis bacillus Calmette‐Guérin (BCG) priming and subunit vaccine boosting strategies are urgently needed to improve the protective efficacy of BCG in adult population. However, the schedule of subunit vaccine boosting is not well investigated, especially the optimal immune responses and vaccine immunization schedules are still not clear. We have constructed a novel subunit vaccine candidate consisting of fusion protein Ag85B‐Mpt64 (190‐198)‐Mtb8.4 (AMM) in a complex adjuvant composed of dimo‐thylidioctyl ammonium bromide (DDA) and BCG polysaccharide nucleic acid (BCG‐PSN). In this study, we compared the effect of different boosting schedules of the subunit vaccine in the prime‐boost strategies. C57BL/6 mice were primed with BCG first and then boosted with the AMM vaccine once at 10th week, twice at 8th, 10th week, or thrice at 6th, 8th, 10th week, respectively. The immune responses were evaluated at the 14th and 20th weeks, respectively. Twelve weeks after the last immunization, the mice were challenged with virulent Mycobacterium tuberculosis strain H37Rv, and the protective effect was evaluated. The results showed that BCG priming and the AMM vaccine boosting twice induced the strongest antigen‐specific IFN‐γ and IL‐2 production, down‐regulated CD4+ CD25+ FoxP3+ regulatory T cells (Tregs) and had the best protective effect among all groups, while boosting thrice induced the strongest IL‐4 production and did not improve BCG‐primed protection significantly. Boosting BCG with the AMM vaccine twice instead of once or thrice induced strong Th1‐type immunity and down‐regulated Tregs significantly, which correlated with the best protection against M. tuberculosis infection in mice.

No abstract

We describe a probable new adverse effect of the anti-hypertensive drug losartan in a patient with Parkinson's disease.The patient is a 65-year-old man with hypertension and Parkinson's disease that started at 60 years of age. He noticed rest tremors of his left hand 5 years ago, slowness of walking and stiffness of his left sided limbs 3 years ago. Similar symptoms were noticed in the right-sided limbs 2 years back. He noticed tendency to fall backwards for the last 2 years especially while turning around. He was started on a combination of levodopa and carbidopa by his general physician 3 years back and found significant improvement in his walking speed, tremors, and stiffness of his limbs. Tendency to fall did not improve significantly. For the last 1 year, he noticed that the effect of L-dopa has been lasting for shorter duration than before, but he did not report any involuntary movements with L-dopa intake or any unpredictable fluctuations in his motor functions. His clinical features fulfilled the National Institute of Neurological Disorders and Stroke criteria for the diagnosis of Probable Parkinson's disease.He had been stable on L-dopa/carbidopa (100/25 mg) twice a day and ramipril 5 mg/day. Three months ago, his family physician changed ramipril to losartan 25 mg/day and later increased it to 50-mg/day for better control of hypertension. The patient gradually worsened since then with several falls, freezing episodes, severe bradykinesia requiring constant support of his spouse for activities of daily living. His UPDRS motor score was 50 at the time of admission. We stopped losartan and continued L-dopa in the same doses. After 48 hours, patient made remarkable improvement in bradykinesia, rigidity, and tremors. He was walking independently and had only occasional brief freezing episodes. His UPDRS motor score improved to 39.To establish the causal relationship of losartan to the parkinsonism symptoms, we re-challenged the patient with losartan 25 mg/day. After 48 hours, patient deteriorated again with severe bradykinesia and frequent freezing episodes. His UP-DRS motor score worsened to 50 again. We discontinued losartan again. Twenty four hours later, patient was ambulating independently, with mild bradykinesia and occasional brief freezing. His UPDRS motor score improved to 41. Patient's blood pressure was later controlled with ramipril 10-mg/day.Losartan is an angiotensin receptor blocker. There is experimental evidence to suggest that Angiotensin facilitates nigrostriatal dopaminergic release by acting on Angiotensin receptor type 1. 1-3 Losartan blocks these receptors and inhibits dopami-nergic release. Angiotensin converting enzyme inhibitors like ramipril, on the contrary, may facilitate dopaminergic release. 4 The half-life of losartan is very short, about 2 hours. This may explain the rapid improvement that was seen in this patient after discontinuation of losartan.To our knowledge, this is the first report of parkinsonism worsened by losartan. Applying Naranjo's algorithm, the present adverse...