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Background and aims Preclinical data suggest that the chemokine receptor 2 (CCR2) is involved in the pathophysiology of neuropathic pain through modulation of neuronal excitability, synaptic transmission and activation of spinal cord microglia. CCR2-antagonists have shown to be effective in preclinical models of neuropathic pain. The aim of this study was to evaluate the analgesic efficacy, safety and tolerability of a novel CCR2-antagonist, AZD2423, in patients with painful diabetic neuropathy (PDN). Methods This was a double-blind, randomized, parallel-group, multi-center study in patients with symmetric distal sensory polyneuropathy due to type 1 or 2 diabetes and duration of neuropathic pain between 3 months and 5 years. Concomitant treatment with neuropathic pain medications (e.g. anticonvulsants, tricyclic antidepressants, serotonin-noradrenaline uptake inhibitors, opioids, topical lidocaine or capsaicin) was not allowed. 134 patients with PDN were equally randomized to 28 days oral administration of 20 mg AZD2423,150 mg AZD2423, or placebo. The primary efficacy variable was the change of average pain score from 5-days baseline to the last 5 days of treatment, measured with numerical rating scale (NRS, 0-10). The secondary efficacy measures included NRS worst pain scores, patient global impression of change, pain interference on sleep and activity, and neuropathic pain symptom inventory (NPSI). Results The change of NRS average pain score was not significantly different between treatment groups (AZD2423 20mg: -1.50; AZD2423 150 mg: -1.35; placebo: -1.61). The NPSI total score and three out of five subscores (evoked pain, pressing/deep pain and paresthesia/dysesthesia) tended to be reduced more by AZD2423 150 mg than by placebo. No other secondary efficacy variables differed between treatment groups. The frequency and type of adverse events for AZD2423 were similar to placebo. The achieved plasma levels of AZD2423 in the two dose groups were in line with predictions from pharmacokinetic data previously obtained in healthy volunteers. Dose-dependent increase of plasma levels of the ligand of CCR2 (CCL2; chemokine ligand 2) and decrease of the mean levels of monocytes (-27% by AZD2423 150 mg) suggested that the administrated doses of AZD2423 interacted with the CCR2 target. Conclusion The CCR2-antagonist AZD2423 showed no analgesic efficacy in PDN based on NRS average pain scores and global and functional pain outcome measures. The NPSI data suggested possible effects on certain sensory components of pain. There were no major safety or tolerability concerns. Implications Treatment with a CCR2-antagonist does not have a clinically important analgesic effect in an overall PDN population.

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Temperate estuaries are inherently variable and productive ecosystems that provide nursery habitat, migration pathways, and forage areas for diadromous, estuarine, and marine fish. We used multifrequency scientific echo sounders (SIMRAD EK60 split‐beam, 38 and 120 kHz) to describe the distribution of pelagic fish in the Penobscot River estuary, Maine, in 2012 and 2013. Differences in responses between frequencies were used to distinguish fish from other biota. Acoustic area backscatter from echo integration (sA [m2/nautical mile2], a common measure proportional to fish density) and target strength (TS; dB re 1 m2, an acoustic measure of fish size) distributions varied with season and salinity. Overall, the sA and TS distributions were similar in both years, with detectable spatial and temporal patterns. The highest value of sA occurred in July of both years, when dense schools of fish were detected in higher‐salinity areas of the lower estuary. The middle estuary had high sA values in April both years, particularly in the vicinity of the seawater–freshwater interface. The mixing area in the middle estuary stratum appears to be important fish habitat; we found fish in this area throughout the year. Fish of variable TS were using this mixing zone throughout the survey period. In full freshwater, upstream from the salinity mixing area, sA was generally low. The majority (~77%) of discrete fish detected had TS values less than −42 dB. The TS distributions varied seasonally, with the highest TS measurements occurring more frequently in April and May and the lowest ones occurring most frequently in July and August. This study demonstrates the efficacy of using a mobile hydroacoustic survey to assess pelagic fish distribution in a complex estuary and may provide a template for long‐term monitoring in dynamic estuarine ecosystems. Received November 3, 2016; accepted March 15, 2017 Published online June 20, 2017