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.
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