Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction.

Renin-angiotensin system inhibitors are recommended for treating hypertension with chronic kidney disease. The addition of a mineralocorticoid receptor blocker may be one option to achieve target blood pressure. We investigated the efficacy and safety of esaxerenone, a mineralocorticoid receptor blocker, in Japanese hypertensive patients with moderate kidney dysfunction. Two multicenter, open-label, nonrandomized dose escalation studies were conducted to investigate esaxerenone monotherapy and add-on therapy to renin-angiotensin system inhibitor treatment. Esaxerenone therapy was initiated at 1.25 mg/day and titrated to 2.5 and then 5 mg/day for a treatment duration of 12 weeks. Primary endpoints were changes from baseline in sitting systolic and diastolic blood pressure. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also assessed. Thirty-three patients received monotherapy, and 58 received add-on therapy; the mean baseline estimated glomerular filtration rates were 51.9 and 50.9 mL/min/1.73 m2, respectively. The esaxerenone dosage was increased to ≥2.5 mg/day in 100% (n = 33) and 93.1% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. Reductions in sitting blood pressure from baseline to the end of treatment were similar (monotherapy: -18.5/-8.8 mmHg; add-on therapy: -17.8/-8.1 mmHg; both P < 0.001). The antihypertensive effects of esaxerenone were consistent across patient subgroups. A serum K+ level ≥5.5 mEq/L was observed in seven patients (12.1%) receiving add-on therapy but in none receiving monotherapy. All increases in serum K+ levels were transient, and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment owing to kidney function decline. Esaxerenone was effective and well tolerated in hypertensive patients with moderate kidney dysfunction.

Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism.

Mineralocorticoid receptor (MR) blockers are very beneficial for patients with hypertension and primary aldosteronism (PA). We investigated the efficacy and safety of a newly available nonsteroidal MR blocker, esaxerenone, in Japanese patients with hypertension and PA. A multicenter, open-label study was conducted in Japan between October 2016 and July 2017. Patients with hypertension and PA received 12 weeks of treatment with esaxerenone, initiated at 2.5 mg/day and escalated to 5 mg/day during week 2 or 4 of treatment, based on individual response. The only other permitted antihypertensive therapies were stable dosages of a Ca2+ channel blocker or α-blocker. The primary efficacy outcome was a change in sitting systolic and diastolic blood pressure (SBP/DBP) from baseline to the end of treatment. Forty-four patients were included; dose escalation to 5 mg/day was implemented for 41 of these patients. Significant decreases in SBP and DBP were observed (point estimates [95% confidence interval] -17.7 [-20.6, -14.7] and -9.5 [-11.7, -7.3] mmHg, respectively; both p < 0.0001 at the end of treatment). Significant BP reductions were evident from week 2 and continued through to week 8; BP remained stable until week 12. The antihypertensive effect of esaxerenone on SBP was significantly greater in females and in patients receiving monotherapy. The major drug-related adverse events were serum K+ increase and estimated glomerular filtration rate decrease (both 4.5%, n = 2); no gynecomastia or breast pain was observed. We conclude that esaxerenone is a potent MR blocker with favorable efficacy and safety profiles in patients with hypertension and PA.

Effect of white wheat bread containing sugar beet fiber on serum lipids and hepatic mRNA in rats fed on a cholesterol-free diet.

We examined the effects of white wheat bread powder (BP) and white wheat bread powder containing sugar beet fiber (BBP) on serum cholesterol. The total cholesterol (-11%, -16%), HDL-cholesterol (-12%, -11%), non-HDL-cholesterol (-9%, -18%) and triacylglycerol (-44%, -58%) concentrations in the BP and BBP groups, respectively, were significantly different from those in the control group. The fecal excretion of neutral sterols in the BP and BBP groups and of acidic sterols in the BBP group was significantly higher than that in the control group. The hepatic cholesterol 7alpha-hydroxylase (CYP7A1) mRNA level in the BP and BBP groups was significantly higher than that in the control group. The cecal total short-chain fatty acid concentrations in the BBP group were significantly higher than those in the control group. These results indicate that the observed changes in serum lipid levels in the BP and BBP groups were due to the increased fecal lipid and CYP7A1 mRNA levels.

Amylomyces rouxii strain CBS 438.76 affects cholesterol metabolism in cholesterol-fed rats.

We examined the effects of Amylomyces rouxii, which is a mold found in some fermented foods in Indonesia, on serum cholesterol and hepatic LDL receptor mRNA in rats. Rats were fed a 0.5% cholesterol-enriched diet with (A. rouxii group) or without (control group) 30 g/kg A. rouxii for 4 wk. There were no significant differences in the body weight, food intake or liver weight among the groups. However, the weight of the cecum in the A. rouxii-fed group was significantly higher than that in the control group. The cecal pH in the A. rouxii-fed group was significantly lower than that in the control group. Cecal acetic acid, propionic acid and total SCFA concentrations in the A. rouxii-fed group were significantly higher than those in the control group. The serum total cholesterol and VLDL+intermediate density lipoprotein (IDL)+LDL-cholesterol concentrations in the control group were significantly higher than those in the A. rouxii-fed group at the end of the 4-wk feeding period. There were no significant differences in the HDL-cholesterol or triglyceride concentrations between the groups. The hepatic LDL receptor and cholesterol 7alpha-hydroxylase mRNA levels in the A. rouxii-fed group were significantly higher than those in the control group. The results of this study demonstrate that feeding of A. rouxii lowers the serum total cholesterol level by enhancement of the cecal SCFA concentration and the hepatic LDL receptor mRNA.

Exopeptidase degradation for the analysis of phosphorylation site in a mono-phosphorylated peptide with matrix-assisted laser desorption/ionization mass spectrometry.

The utility of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) coupled with a peptide ladder sequencing method employing exopeptidase degradation for the analysis of phosphorylation site in a mono-phosphorylated peptide is investigated. MALDI-TOFMS analysis of time-dependent exopeptidase digestion using carboxypeptidase W and aminopeptidase M of the mono-phosphorylated 33-48 fragment isolated from a beta-casein tryptic digestion mixture allowed for the sequencing analysis from both the C-terminus and N-terminus. Negative ion detection MALDI-TOFMS made it possible to clearly measure the peptide ladder of mono-phosphorylated peptide by the strong negative charge localized at the phosphoric acid group. Since exopeptidase activity was suppressed by the existence of a phosphorylated amino acid residue, the termination exopeptidase degradation therefore suggested the existence of a phosphorylated amino acid residue at that site. This peptide ladder sequencing method using exopeptidases was effective for the identification of the site of a phosphorylated amino acid residue by a simple MALDI-TOFMS analysis in the negative ion detection mode.