Differential interaction of competitive NMDA and AMPA antagonists with selective dopamine D-1 and D-2 agonists in a rat model of Parkinson's disease.

peer reviewedStimulation of the dopamine (DA) D-2 and D-1 receptors results in behavioural activation (i.e., induction of contralateral rotations) in 6-hydroxydopamine (6-OHDA) substantia nigra lesioned rats. Competitive N-methyl-D-aspartate (NMDA) antagonists as well as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists potentiate the stimulatory responses to threshold doses of L-DOPA or the mixed dopamine D-1/D-2 agonist apomorphine in this model, indicating the potential of such combinations for the management of Parkinson's disease. Neuroanatomic and electrophysiologic data indicate a differential distribution of DA D-1 and DA D-2 receptors within motor loops of the basal ganglia. DA D-1 receptors are preferentially located on GABAergic neurones projecting to the substantia nigra compacta (SNc) and to the substantia nigra reticulata (SNr), whereas DA D-2 receptors are preferentially located on neurones that innervate the external pallidum. NMDA receptors are present in high densities within the striatum, whereas AMPA receptors are enriched in the entopeduncular nucleus/internal pallidum and the SNr. To further characterise the functional interaction between DA and glutamate receptors, we tested the competitive NMDA antagonist 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f] quinoxaline (NBQX) following systemic administration in combination with the DA D-2 selective agonist quinpirole or the DAD-1 selective agonist A 68 930 (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman) in rats with chronic 6-OHDA lesions of the SNc. CPP potentiated quinpirole-induced rotations and did not affect those induced by the D-1 agonist A 68930. By contrast, NBQX had no effect on quinpirole-induced rotations, whereas synergism was seen with A 68930. These results suggest that rotations induced by combined treatment with glutamate antagonists and DA agonists are mediated by different pathways within the basal ganglia, depending on which subtype of receptor is involved. AMPA antagonists could act preferentially by activating the direct motor pathway, whereas NMDA antagonists could modulate the indirect loop

Etanercept is Effective and Halts Radiographic Progression in Rheumatoid Arthritis and Psoriatic Arthritis: Final Results from a German Non-interventional Study (PRERA)

Abstract Introduction Etanercept (ETN) has been shown to slow radiographic progression of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in clinical trials. This real-world, non-interventional study assessed radiographic progression in patients with RA or PsA treated with ETN for ≤ 36 months in outpatient care in Germany (NCT01623752). Methods Patients with RA or PsA attended ≤ 10 visits across two study phases (phase 1: seven visits, baseline to month 18; phase 2: three visits until month 36). Radiographs were taken at baseline (Rx1), months 12–18 (Rx2), and/or months 30–36 (Rx3). Historic radiographs (Rx0) taken 12–48 months pre-baseline were also evaluated (if available). The primary endpoint was the change in modified total Sharp score (mTSS). The erosion score (ES) and joint space narrowing score (JSN) were also evaluated. Results Overall, 1821 patients were enrolled (RA: n = 1378; PsA: n = 440). In patients with Rx1 and Rx2 (RA: n = 511; PsA: n = 167), the mean mTSS remained stable for both disease groups, and the annualized median change in mTSS was 0. In patients with Rx0, Rx1, and Rx2 (RA: n = 180; PsA: n = 47), annualized radiographic progression in mTSS, ES, and JSN was larger in the pre-ETN treatment phase than during ETN treatment in both disease groups. The percentage of patients with radiographic non-progression was higher during ETN treatment versus pre-ETN. Improvement in clinical disease activity and patient-reported outcomes was also observed. Conclusions This was the first real-world, non-interventional study to report systematically collected radiographic data in a large cohort of patients with RA or PsA under treatment with a biologic. In patients with available radiographic data, mean radiographic progression was lower and the proportion of patients without progression was greater during ETN treatment than in the pre-ETN period

Effectiveness of Etanercept in Rheumatoid Arthritis: Real-World Data from the German Non-interventional Study ADEQUATE with Focus on Treat-to-Target and Patient-Reported Outcomes

Abstract Background For rheumatoid arthritis (RA), the treat-to-target concept suggests attaining remission or at least low disease activity (LDA) after 12 weeks. Objectives This German, prospective, multicenter, non-interventional study aimed to determine the proportion of patients with RA who achieved their treat-to-target aim after 12 and 24 weeks of etanercept (ETN) treatment in a real-life setting, as opposed to patients achieving their therapeutic target at a later timepoint (week 36 or 52). Methods A total of 824 adults with a confirmed diagnosis of RA without prior ETN treatment were included. Remission and LDA were defined as DAS28 < 2.6 and DAS28 ≤ 3.2, respectively. Results The proportion of patients achieving remission was 24% at week 12 and 31% at week 24. The proportion of patients achieving LDA was 39% at week 12 and 45% at week 24. The proportion of patients achieving remission or LDA further increased beyond week 24 up to week 52. Improvement in pain and reduction in concomitant glucocorticoid treatment were observed. Improvements in patient-reported outcomes were also seen in patients who did not reach remission or LDA. No new safety signals were detected. Conclusions A considerable proportion of patients with RA attained the target of remission or LDA after 12 weeks of ETN treatment. Even beyond that timepoint, the proportion of patients achieving treatment targets continued to increase up to week 52. Trial Registration ClinicalTrials.gov Identifier: NCT02486302