Failure to achieve improvement in DAS28 within the first 12 weeks of therapy was predictive of a low probability of achieving LDA at Year 1. Moreover, the accuracy of the prediction was found to be strongly dependent on the magnitude and timing of the lack of the response. (Clinical Trial Registration Nos. NCT00152386 and NCT00175877).
The present study was designed to investigate the role of adenosine in the hypoxic depression of synaptic transmission in rat hippocampus. An in vivo model of hypoxic synaptic depression was developed in which the common carotid artery was occluded on one side in the urethane-anesthetized rat. Inspired oxygen levels were controlled through a tracheal cannula. Rats were placed in a stereotaxic apparatus for stimulation and recording of bilateral hippocampal field excitatory postsynaptic potentials. The percent inspired oxygen could be reduced to levels that produced a reversible and repeatable depression of evoked synaptic transmission restricted to the hippocampus ipsilateral to the occlusion. Further reduction in the level of inspired oxygen depressed synaptic transmission recorded from both hippocampi. The adenosine nonselective antagonist caffeine and the A(1) selective antagonist 8-cyclopentyltheophylline prevented the initial depression in synaptic transmission. We conclude that the initial depression of synaptic transmission observed in the rat hippocampus in vivo is due to endogenous adenosine acting at neuronal adenosine A(1) receptors.
ObjectiveThe aim of the Patient/Physician Reported Efficacy Determination In Clinical Practice Trial (PREDICT; ClinicalTrials identifier NCT01255761) was to compare the patient‐reported Routine Assessment of Patient Index Data 3 (RAPID‐3) instrument with the investigator‐based Clinical Disease Activity Index (CDAI) for assessing certolizumab pegol (CZP) treatment response in rheumatoid arthritis patients at 12 weeks and to predict the treatment response at week 52 using the data from week 12 (coprimary end points).MethodsPatients received 400 mg of CZP at weeks 0, 2, and 4 (loading dose), followed by 200 mg every 2 weeks thereafter. Patients were randomized 1:1 to assessment with the RAPID‐3 or the CDAI. Responder classification was performed at week 12; treatment response was defined as a score of ≤6 or a 20% improvement over baseline on the RAPID‐3 or a score of ≤10 or a 20% improvement over baseline on the CDAI. Long‐term treatment success was defined as a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28‐ESR) of ≤3.2 at week 52. Comparisons were made for the coprimary end points using noninferiority methods. Patients with improvement of <1 on the CDAI score or with no improvement on the RAPID‐3 score at week 12 or patients with high levels of disease activity (CDAI score >22 or RAPID‐3 score >12) at 2 consecutive visits were withdrawn from the study.ResultsPatients had longstanding disease (mean 8.9 years) and high levels of disease activity (mean scores of 6.3 on the DAS28‐ESR, 16.1 on the RAPID‐3, and 40.2 on the CDAI). Previous anti–tumor necrosis factor therapy had failed in 55.5% of them. At week 12, a total of 64.7% (by RAPID‐3) and 76.4% (by CDAI) of the patients were classified as responders (difference of −11.9% [95% confidence interval −18.4%, −5.3%]). At week 52, a total of 31.5% (by RAPID‐3) and 32.3% (by CDAI) of the responders achieved a low level of disease activity on the DAS28‐ESR (difference of −1.3% [95% confidence interval −9.3%, 6.6%]).ConclusionThe CDAI classified more patients as CZP responders at week 12 than did the RAPID‐3. Although these outcome measures were not statistically comparable, the positive predictive value for low disease activity at week 52 was similar. As these tools cover differing domains of therapy response, further evaluation for clinical disease activity assessments and treatment decisions is needed.
ObjectiveEvaluate open-label sarilumab monotherapy in patients with rheumatoid arthritis switching from adalimumab monotherapy in MONARCH (NCT02332590); assess long-term safety and efficacy in patients continuing sarilumab during open-label extension (OLE).MethodsDuring the 48-week OLE, patients received sarilumab 200 mg subcutaneously once every 2 weeks. Safety (March 2017 cut-off) and efficacy, including patient-reported outcomes, were evaluated.ResultsIn the double-blind phase, patients receiving sarilumab or adalimumab monotherapy showed meaningful improvements in disease activity; sarilumab was superior to adalimumab for improving signs, symptoms and physical function. Overall, 320/369 patients completing the 24-week double-blind phase entered OLE (155 switched from adalimumab; 165 continued sarilumab). Sarilumab safety profile was consistent with previous reports. Treatment-emergent adverse events were similar between groups; no unexpected safety signals emerged in the first 10 weeks postswitch. Among switch patients, improvement in disease activity was evident at OLE week 12: 47.1%/34.8% had changes ≥1.2 in Disease Activity Score (28 joints) (DAS28)-erythrocyte sedimentation rate/DAS28-C-reactive protein. In switch patients achieving low disease activity (LDA: Clinical Disease Activity Index (CDAI) ≤10; Simplified Disease Activity Index (SDAI) ≤11) by OLE week 24, 70.7%/69.5% sustained CDAI/SDAI LDA at both OLE weeks 36 and 48. Proportions of switch patients achieving CDAI ≤2.8 and SDAI ≤3.3 by OLE week 24 increased through OLE week 48. Improvements postswitch approached continuation-group values, including scores ≥normative values.ConclusionsDuring this OLE, there were no unexpected safety issues in patients switching from adalimumab to sarilumab monotherapy, and disease activity improved in many patients. Patients continuing sarilumab reported safety consistent with prolonged use and had sustained benefit.
The relationship between step reductions in inspired oxygen and the amplitude of evoked field excitatory postsynaptic potentials (fEPSPs) recorded from hippocampal CA1 neurons was examined in anaesthetized rats with a unilateral common carotid artery occlusion. The amplitudes of fEPSPs recorded from the hippocampus ipsilateral to the occlusion were significantly more depressed with hypoxia than were the fEPSPs recorded from the contralateral hippocampus. The adenosine A1‐selective antagonist, 8‐cyclopentyl‐1,3‐dimethylxanthine (8‐CPT), blunted the hypoxic depression of the fEPSP. Tissue partial pressure of oxygen (Ptiss,O2) was measured in the ipsilateral and contralateral hippocampus using glass Clark‐style microelectrodes. Ptiss,O2 fell to similar levels as a function of inspired oxygen in the ipsilateral and contralateral hippocampus, and in the ipsilateral hippocampus after administration of 8‐CPT. Hippocampal blood flow (HBF) was measured using laser Doppler flowmetry. A decline in HBF was associated with systemic hypoxia in both hippocampi. HBF, as a function of inspired oxygen, fell significantly more in the ipsilateral than in the contralateral hippocampus. We conclude that endogenous adenosine acting at the neuronal A1 receptor plays a major role in the depression of synaptic transmission during hypoxic ischaemia. The greater susceptibility of the fEPSP in the ipsilateral hippocampus to systemic hypoxia cannot be explained entirely by differences in Ptiss,O2 or HBF between the two hemispheres.
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