ACTH and corticosterone responses to minor stress (saline injection).

<p><b>A.</b> Saline injection significantly increased ACTH secretion in IA-treated rats (* P<0.05 compared with stress control rats; <b>&</b> P<0.05 compared with non-stress IA-treated rats). <b>B.</b> The basal level of corticosterone was increased in IA treated rats than control rats (<b>&</b> P<0.05 compared with non-stress control rats; * P<0.05 stress rats compared with non-stress rats) (see text for details). Data represent the mean ± SEM of 8 rats per group. (* =  Significantly different from control group) <b>C.</b> Representative Photographs (Magnification: 10x) of CRF change in paraventricular nucleus (PVN) and central nucleus of the amgdyla (CeA). <b>D.</b> Change of CRF staining Density in PVN and CeA area. Data represent the mean ± SEM of 3 sections per rat, 4 rats per group. (* =  Significantly different from control group).</p

The effect of neonatal IA treatment on psychological behavior of adult rats.

<p><b>A... </b><b><i>Sucrose consumption test</i></b>. The percentage of animals with sucrose consumption ≥75% was significantly lower in IA-treated rats as compared with control rats (*P<0.05) (see text for details). <b>B... </b><b><i>Forced swimming test</i></b>. Immobility was significantly increased (P<0.001) and the climbing and swimming were significantly reduced (P<0.001 and P<0.05) in IA-treated rats compared with control rats (see text for details). Data represent the mean ± SEM of 20 rats per group. <b>C... </b><b><i>Elevated plus maze test</i></b>. <b>i.</b> The total distance traveled (cm) in the 5-minute test time was not different between the IA-treated and control groups. <b>ii.</b> The percentage distance traveled in open arm was significantly reduced in IA-treated rats.</p

Effects of intragastric RTX and antalarmin.

<p><b>A: Gastric afferent activity after intragastric RTX as compared to vehicle treatement. </b><b>A.i:</b> There is a significant (p<0.05 using ANOVA) decline in basal splanchnic nerve activity after RTX but not in vehicle treated group. <b>A.ii:</b> There is a significant (p<0.05 using ANOVA) decline in the evoked response to gastric distention, GD, at 80 mmHg of pressure) 30 minutes after RTX but no change in the vehicle treated group (n =  4 each). (*  =  Significantly different than Pre-treatment baseline using Bunnet multiple comparison test). <b>B: Effects of gastric sensory ablation on depression-like behavior.</b> No differences were seen in the results of the forced swimming test in IA-treated animals that underwent intragastric RTX treatment as compared with animals that received vehicle only. <b>C. Effects of the CRF1 antagonist antalarmin on depression-like behavior.</b> Antalarmin resulted in a significant reduced in immobility and an increase in the climbing and swimming in IA-treated rats compared with vehicle treated IA-treated rats.</p

The effect of neonatal IA treatment on psychological behavior of adult rats (continued).

<p><b>A.. </b><b><i>Open field test</i></b>. <b>i.</b> The total distance traveled (cm) in the 30-minute test time. <b>ii.</b> The percentage time spent in center. There was a significant decrease in the time that IA-treated rats spent in the center as well as the total distance traveled. Data represent the mean ± SEM of 20 rats per group. <b>B.. </b><b><i>Light dark box test</i></b>. <b>i.</b> The percent of time spent in the light box was significantly shorter in the IA-treated rats as compared with control rats. <b>ii.</b> The number of light-dark box transitions was not significantly different between the two groups (n = 10 per group). (* =  Significantly different from control group).</p

Two-dimensional hierarchical cluster analysis (HCA) of significant genes induced by bezafibrate, fenofibrate and WY-14,643

<p><b>Copyright information:</b></p><p>Taken from "Differential gene expression in mouse primary hepatocytes exposed to the peroxisome proliferator-activated receptor α agonists"</p><p>BMC Bioinformatics 2006;7(Suppl 2):S18-S18.</p><p>Published online 26 Sep 2006</p><p>PMCID:PMC1683558.</p><p></p

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

Background Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. Methods PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. Findings Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Interpretation Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function.</p