Rilonacept in the treatment of acute gouty arthritis: a randomized,controlled clinical trial using indomethacin as the active comparator

Introduction

In phase-3 clinical trials, the interleukin (IL-1) blocker, rilonacept (IL-1 Trap), demonstrated efficacy for gout flare prevention during initiation of urate-lowering therapy. This trial evaluated rilonacept added to a standard-of-care, indomethacin, for treatment of acute gout flares.

Methods

Adults, aged 18-70 years, with gout presenting within 48 hours of flare onset and having at least moderate pain as well as swelling and tenderness in the index joint were randomized to subcutaneous (SC) rilonacept 320 mg at baseline plus oral indomethacin 50 mg TID for 3 days followed by 25 mg TID for up to 9 days (n = 74); SC placebo at baseline plus oral indomethacin as above (n = 76); or SC rilonacept 320 mg at baseline plus oral placebo (n = 75). The primary efficacy endpoint was change in pain in the index joint (patient-reported using a Likert scale (0 = none; 4 = extreme)) from baseline to the average of values at 24, 48 and 72 hours (composite time point) for rilonacept plus indomethacin versus indomethacin alone. Comparison of rilonacept monotherapy with indomethacin monotherapy was dependent on demonstration of significance for the primary endpoint. Safety evaluation included clinical laboratory and adverse event (AE) assessments.

Results

Patient characteristics were comparable among the groups; the population was predominantly male (94.1%), white (75.7%), with mean ± SD age of 50.3 ± 10.6 years. All treatment groups reported within-group pain reductions from baseline (P < 0.0001). Although primary endpoint pain reduction was greater with rilonacept plus indomethacin (-1.55 ± 0.92) relative to indomethacin alone (-1.40 ± 0.96), the difference was not statistically significant (P = 0.33), so formal comparison between monotherapy groups was not performed. Pain reduction over the 72-hour period with rilonacept alone (-0.69 ± 0.97) was less than that in the other groups, but pain reduction was similar among groups at 72 hours. Treatment with rilonacept was well-tolerated with no reported serious AEs related to rilonacept. Across all groups, the most frequent AEs were headache and dizziness.

Conclusions

Although generally well-tolerated, rilonacept in combination with indomethacin and rilonacept alone did not provide additional pain relief over 72 hours relative to indomethacin alone in patients with acute gout flare.

Trial registration

ClinicalTrials.gov registration number {"type":"clinical-trial","attrs":{"text":"NCT00855920","term_id":"NCT00855920"}}NCT00855920.     

Wide-aperture plasma-electrode pockels cell

The results of experimental investigations of wide-aperture (100 × 100 mm) plasma-electrode Pockels are presented. Time characteristics, contrast, transmission factor, and optical uniformity of the cell are measured. It has been found that the half-wave effective voltage of the cell is 10 kV, the duration of the transmission window can vary from 250 to 550 ns, its leading and trailing edges are 40–50 and 70–100 ns in duration, respectively, and the time of the cell plasma electrode formation is 40 ± 5 ns.     

Reproductive strategies of Arctic charr Salvelinus alpinus (L.) forms in Kiryalta lakes,Transbaikalia, Russia

Lake Abaya and Lake Chamo are the two largest Ethiopian Rift Valley lakes; they are located close to each other, but have a strikingly different water transparency. We explain key differences in the structure and the functioning of the food web with variation in limnological variables and major pelagic food web compartments within and across both lakes. Data from a detailed comparative investigation of physical and chemical variables and zooplankton community characteristics during the wet and dry season from two consecutive years revealed major differences in key limnological variables between Lake Abaya and Lake Chamo. The most pronounced differences were related to water transparency and the amount of suspended solids in the water column. Lake Abaya is much more turbid, has lower phyto- and zooplankton biomass, and has considerably lower primary production than Lake Chamo. Based on our results, we infer that the profound differences in food web structure between both lakes probably result from differences in sediment load. Finally, our results indicate that conservation programs should focus on reducing sediment inflow from the catchments into the lakes.

     

Peculiarities of brain mechanisms of compensation of oxygen-dependent energy deficit,organization of emotions and cognitive activity at delayed consequences of perinatal lesion of CNS of the hypoxic-ischemic genesis in the 3–6-year-old children with delay of psychic development

There are summarized results of studies on peculiarities of the compensatory-adaptive mechanisms of brain circulation and respiration at oxygen-dependent energy deficit in the 3–6-yearold children with delayed consequences of perinatal CNS lesion of hypoxic-ischemic genesis and delay of psychic development (DPD), with use of the systemic-integrative psychophysiological approach and of parameters of superslow information-controlled systems of the brain and of organism. In the examined contingent of children, differences have been revealed in development of emotional sphere and the higher psychic functions, depending on the character of disorganization of regulatory CNS functions and of the type of the formed compensatory-adaptive mechanisms of autoregulation of cerebral circulation and of the system of outer respiration.     

COPI–TRAPPII activates Rab18 and regulates its lipid droplet association

The transport protein particle (TRAPP) was initially identified as a vesicle tethering factor in yeast and as a guanine nucleotide exchange factor (GEF) for Ypt1/Rab1. In mammals, structures and functions of various TRAPP complexes are beginning to be understood. We found that mammalian TRAPPII was a GEF for both Rab18 and Rab1. Inactivation of TRAPPII‐specific subunits by various methods including siRNA depletion and CRISPR–Cas9‐mediated deletion reduced lipolysis and resulted in aberrantly large lipid droplets. Recruitment of Rab18 onto lipid droplet (LD) surface was defective in TRAPPII‐deleted cells, but the localization of Rab1 on Golgi was not affected. COPI regulates LD homeostasis. We found that the previously documented interaction between TRAPPII and COPI was also required for the recruitment of Rab18 to the LD. We hypothesize that the interaction between COPI and TRAPPII helps bring TRAPPII onto LD surface, and TRAPPII, in turn, activates Rab18 and recruits it on the LD surface to facilitate its functions in LD homeostasis.     

High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model

There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimer's disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ₄₂, AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD‐like model mice on high‐AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ₄₂ and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ₄₂ and regulates its transport across the blood–brain barrier, suggesting a mediating pathway. Because exposure to AGEs can be diminished, these insights provide an important simple noninvasive potential therapeutic strategy for alleviating a major lifestyle‐linked disease epidemic.