Oral SSTR5 Antagonist SCO-240 for Growth Hormone Stimulation: A Phase I Single-Dose Study in Healthy Individuals.

Somatostatin inhibits endocrine and exocrine secretion in various tissues by acting on five somatostatin receptor subtypes (SSTR1-5). The clinical effects of SSTR5 antagonism remain unknown. Herein, we evaluated the effects of SCO-240, an oral SSTR5 antagonist, in healthy individuals. This randomized, single-center, double-blind, placebo-controlled, phase I study included healthy Japanese and White individuals. The effects of ascending single oral doses of SCO-240 were evaluated in healthy individuals. The main outcome measures were safety, tolerability, pharmacokinetics, and pharmacodynamics (gallbladder contractions and levels of serum insulin and plasma glucagon-like peptide-1 (GLP-1)). The levels of pituitary hormones were evaluated in our exploratory analysis. The results indicated that SCO-240 was safe and well-tolerated at all tested doses. Oral SCO-240 was readily absorbed, with its systemic exposure increasing in a dose-dependent manner. The median time to maximum concentration and mean terminal half-life of SCO-240 were 3-4 and 10.2-12.6 hours, respectively, in the ascending dose section. No clinically meaningful changes in SCO-240 pharmacokinetic profiles were observed between fed and fasted or between Japanese and White individuals. No increase in gallbladder contractions or levels of insulin and GLP-1 were detected. SCO-240 induced robust growth hormone (GH) secretion without altering the levels of other pituitary hormones. In conclusion, the study is the first to demonstrate that SSTR5 antagonism stimulates GH secretion in humans. SCO-240 was safe and well-tolerated and exhibited once-daily oral dosing potential. The robust effects of SCO-240 on GH secretion suggest that it may be a treatment option for GH-related disorders.

An Exploratory Randomized Trial of SCO-792, an Enteropeptidase Inhibitor, in Patients With Type 2 Diabetes and Albuminuria.

Introduction: Elevated plasma amino acid levels overload kidney function by increasing glomerular filtration rate (GFR). Inhibiting gut amino acid intake may have therapeutic benefits for patients with kidney dysfunction. For a prospective phase 2a trial, we carried out an exploratory evaluation of the safety and efficacy of SCO-792, an enteropeptidase inhibitor that blocks gut amino acid intake, in patients with type 2 diabetes mellitus (T2DM) and albuminuria. Methods: Seventy-two patients with T2DM, a urine albumin-to-creatinine ratio (UACR) of 200-5000 mg/g, and an estimated GFR >30 ml/min per 1.73 m2 were included. Patients were randomly assigned (1:2:2) to the following groups and received treatment for 12 weeks: placebo (n = 15), SCO-792 500 mg once daily (SCO-792 QD; n = 29), or SCO-792 500 mg 3 times daily (SCO-792 3 times a day (TID); n = 28) by following a double-blind approach. We evaluated UACR changes from the baseline along with safety as the primary end points and other parameters as secondary or exploratory end points. Results: SCO-792 was safe and well tolerated up to 1500 mg/day for 12 weeks. UACR changes from baseline were -14% (P = 0.4407), -27% (P = 0.0271), and -28% (P = 0.0211) in placebo, SCO-792 QD, and SCO-792 TID, respectively, whereas UACR changes in SCO-792 groups were not statistically significant compared with placebo. The hemoglobin A1c (HbA1c) levels from baseline, an exploratory end point, decreased in the SCO-792 TID group. Conclusion: SCO-792 was safe and well tolerated for 12 weeks and may be associated with decreased UACR in patients with T2DM and albuminuria. Further clinical studies are essential to confirm our findings.

SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans.

SCO-267 is a full agonist of the free fatty acid receptor 1 (GPR40), which regulates the secretion of islet and gut hormones. In this phase 1 study, we aimed to evaluate the clinical profile of single and multiple once-daily oral administration of SCO-267 in healthy adults and patients with diabetes. Plasma SCO-267 concentration was seen to increase in a dose-dependent manner after administration, and its plasma exposure was maintained for 24 h. Repeated dose did not alter the pharmacokinetic profile of SCO-267 in healthy adults. SCO-267 was generally safe and well tolerated at all evaluated single and multiple doses. Single and repeated doses of SCO-267 stimulated the secretion of insulin, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and peptide YY in healthy adults. Furthermore, a single dose of SCO-267 stimulated the secretion of these hormones, decreased fasting hyperglycemia, and improved glycemic control during an oral glucose tolerance test in patients with diabetes, without inducing hypoglycemia. This study is the first to demonstrate the clinical effects of a GPR40 full agonist. SCO-267 is safe and well tolerated and exhibits once-daily oral dosing potential. Its robust therapeutic effects on hormonal secretion and glycemic control make SCO-267 an attractive drug candidate for the treatment of diabetes.

Efficacy and Safety of Imarikiren in Patients with Type 2 Diabetes and Microalbuminuria: A Randomized, Controlled Trial.

BACKGROUND AND OBJECTIVES: Imarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing. RESULTS: Changes in the urine albumin-to-creatinine ratio from baseline to the end of treatment were 16% (placebo), -16% (imarikiren 5 mg), -27% (imarikiren 20 mg), -38% (imarikiren 40 mg), -39% (imarikiren 80 mg), and -31% (candesartan cilexetil 8 mg). Urine albumin-to-creatinine ratio reductions from baseline were statistically significant in all imarikiren groups versus placebo (P<0.001 each) as well as for candesartan cilexetil 8 mg versus placebo (P<0.001). Remission rates (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased ≥30% from baseline) were higher in all imarikiren groups versus the placebo group. Incidence of adverse events was higher in the imarikiren 80-mg group (52%) versus placebo (42%) and candesartan cilexetil (43%) groups. Incidence of adverse events for the other imarikiren groups ranged from 33% to 42%. Adverse events were mild or moderate in severity. All imarikiren doses were well tolerated. CONCLUSIONS: Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria.

Pharmacokinetics and Safety After a Single Dose of Imarikiren in Subjects with Renal or Hepatic Impairment.

BACKGROUND AND OBJECTIVE: Imarikiren hydrochloride (TAK-272; SCO-272) is a novel direct renin inhibitor. The objective of this study was to determine the effects of renal impairment (RI) or hepatic impairment (HI) on the pharmacokinetics and safety of imarikiren. METHODS: This phase I, open-label, parallel-group comparative study evaluated the pharmacokinetics and safety of a single 40 mg oral dose of imarikiren in RI [mild, moderate, severe, or end-stage renal disease (ESRD), and on hemodialysis] or HI (mild or moderate) subjects compared with subjects with normal renal or hepatic function. RESULTS: Following administration of a single 40 mg oral imarikiren dose, the geometric mean imarikiren area under the plasma concentration-time curve from time zero to infinity (AUC∞) and maximum observed plasma concentration (Cmax) in subjects with mild, moderate, and severe RI (including non-hemodialysis and ESRD), and hemodialysis subjects compared with normal renal function subjects were approximately 0.5-, 1.2-, 2.7-, and 1.8-fold, respectively, for AUC∞; and approximately 0.6-, 0.8-, 2.1-, and 1.4-fold, respectively, for Cmax. The mean fraction of excretion of imarikiren in dialysate was ~ 3% during the 4 h dialysis period. The geometric mean imarikiren AUC∞ and Cmax in mild and moderate HI subjects compared with normal hepatic function subjects were approximately 1.0- and 1.4-fold, respectively, for AUC∞, and approximately 0.9- and 1.3-fold, respectively, for Cmax. No deaths or serious adverse events were observed; all adverse events were mild or moderate in intensity. CONCLUSIONS: RI and HI are associated with limited changes in imarikiren pharmacokinetics. Imarikiren was safe and well-tolerated, regardless of the severity of RI or HI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02367872.

Pharmacokinetics, Pharmacodynamics and Safety of a Single Dose of Imarikiren, a Novel Renin Inhibitor, in Healthy Male Subjects.

Imarikiren hydrochloride (TAK-272/SCO-272) is a novel direct renin inhibitor with potential indications for cardiovascular and renal diseases. This phase I study evaluated the pharmacokinetics, pharmacodynamics and safety of a single oral administration of imarikiren in healthy Japanese male subjects. The Dose-Ascending part (double-blind, placebo-controlled, parallel-group design; n = 60) comprised six steps from 5 to 200 mg (n = 8 for imarikiren and n = 2 for placebo per step). The Food Effect part (n = 12) was an open-label, 2 × 2 crossover design with a dose of 50 mg to evaluate the effect of food on the pharmacokinetics and safety of imarikiren. There was a generally linear relationship between dose and area under the plasma concentration-time curve (0 to infinity) or maximum plasma concentration of imarikiren. Food had no clinically significant effect on the exposure of imarikiren. Inhibition of plasma renin activity was rapid and lasted up to 24 hr at all doses. Plasma active renin concentration increased, reaching a maximum at approximately 6 hr, in a nearly dose-dependent manner. Across both study parts, the number of subjects with treatment-emergent adverse events ranged from 0 to 3 per group with no dependency on dose. All treatment-emergent adverse events except two were mild in intensity; there were no serious adverse events or deaths. Single oral administration of imarikiren from 5 to 200 mg was safe and well tolerated. These findings suggest that further clinical development of a once-daily imarikiren regimen is warranted.

A Randomized, Single-Center, Double-Blind, Placebo-Controlled Multiple-Dose Phase 1 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Imarikiren in Healthy Adult Nonelderly and Elderly Male Subjects.

Imarikiren hydrochloride (TAK-272/ SCO-272) is a novel direct renin inhibitor. This randomized, double-blind, phase I study evaluated the safety and pharmacokinetics/pharmacodynamics of multiple oral administrations of imarikiren in healthy nonelderly (aged 20-45 years) and elderly (aged 65-85 years) Japanese male subjects. Subjects were randomized within 1 of 3 cohorts to receive imarikiren or placebo: Cohort 1 (imarikiren 80 mg; nonelderly), Cohort 2 (imarikiren 160 mg; nonelderly), or Cohort 3 (imarikiren 80 mg; elderly). Imarikiren or placebo was administered orally, once daily, for 7 days. Accumulation of imarikiren did not occur during the 7-day treatment period. Area under the plasma-concentration time curve and maximum plasma concentration of imarikiren were higher in elderly than in nonelderly subjects (52% and 39% higher, respectively). Inhibition of plasma renin activity was observed for 7 days and was maintained for at least 71 hours after the last imarikiren administration at the 80-mg (nonelderly and elderly) and 160-mg (nonelderly) doses. Plasma active renin concentration increased in nonelderly and elderly subjects; peak concentrations were higher on day 7 than on day 1. Increase from baseline in plasma active renin concentration was smaller in elderly than in nonelderly subjects during the 7-day treatment period and until 71 hours after last imarikiren administration. Treatment-emergent adverse events were reported in 33.3% (elderly) and 22.2% (nonelderly) of imarikiren subjects. Multiple oral administrations of imarikiren for 7 days were safe and well tolerated with no drug accumulation and strong and sustained suppression of plasma renin activity.

Increases of microRNA let-7e in peripheral blood mononuclear cells in Hashimoto's disease.

MicroRNA (miRNA) is a family of non-coding RNAs that have important roles in various vital functions. It has been reported that let-7e, a miRNA, may be involved in the regulation of interleukin (IL)-10 production. The purpose of this study was to evaluate the role of let-7e as a regulator of IL-10 production in the pathological processes of autoimmune thyroid diseases (AITDs). We evaluated the association between let-7e expression and intracellular expression of IL-10 in the peripheral blood mononuclear cells (PBMCs) collected from 11 healthy volunteers. Then we investigated the expression levels of let-7e in the PBMCs of 50 patients with Graves' disease (GD), 42 patients with Hashimoto's disease (HD) and 28 healthy controls. We found negative correlations between the expression level of let-7e and IL-10 messengerRNA (mRNA) and between the expression level of let-7e and proportion of IL-10(+) cells in stimulated PBMCs from healthy volunteers (r = -0.44, p = 0.0267 and r = -0.49, p = 0.0166, respectively). The expression levels of let-7e were significantly increased in HD patients compared with those in GD patients and healthy volunteers (p = 0.0003 and p = 0.0011, respectively). let-7e may be associated with the pathogenesis of HD through the regulation of intracellular IL-10 expression.

Effect of TAK-085 on Low-density Lipoprotein Particle Size in Patients with Hypertriglyceridemia: A Double-blind Randomized Clinical Study.

BACKGROUND: Low-density lipoproteins (LDLs) comprise a heterogeneous group of particles with various size and density. A shift to larger LDL particle size is mainly the result of a decrease in small dense LDL (sd-LDL) levels and an increase in large buoyant LDL (lb-LDL) levels. METHODS: In a randomized, double-blind study of TAK-085 (containing docosahexaenoic and eicosapentaenoic acid-ethyl esters [EPA-E]) and an EPA-E product in Japanese patients with hypertriglyceridemia, exploratory evaluations of the effects of the LDL particle size were performed on the basis of LDL-cholesterol/apolipoprotein B ratios and LDL subfractions, which were analyzed with a polyacrylamide gel electrophoresis system. RESULTS: Patients were randomized to 12-week treatment with TAK-085 4 g/day (N = 210), TAK-085 2 g/day (N = 205), or EPA-E 1.8 g/day (N = 195). Treatment with TAK-085 4 g/day, TAK-085 2 g/day, and EPA-E 1.8 g/day caused an increase in the LDL cholesterol/apolipoprotein B ratios (3.99%, 3.35%, and 0.66%, respectively), the mean diameter of LDL particles (1.12%, 0.84%, and 0.67%, respectively), and the level of lb-LDL at the end of the study (16.37%, 9.51%, and 7.31%, respectively). The increases in the LDL cholesterol/apolipoprotein B ratios and the mean diameter of LDL particles from baseline to the end of the study were greater with TAK-085 4 g/day than EPA-E 1.8 g/day. TAK-085 4 g/day and TAK-085 2 g/day caused a decrease in the sd-LDL levels (-16.21% and -6.96%, respectively). CONCLUSION: TAK-085 produced a favorable shift in the LDL particle size in Japanese patients with hypertriglyceridemia. JAPIC Clinical Trials Information: Japic CTI-090937.

Evaluation of the efficacy and tolerability of fixed-dose combination therapy of azilsartan and amlodipine besylate in Japanese patients with grade I to II essential hypertension.

BACKGROUND: Guidelines for the management of hypertension recommend using drugs with different mechanisms of action in antihypertensive regimens that include simple single-pill fixed-dose combination (FDC) products. OBJECTIVE: The objective of this study was to compare the efficacy and tolerability of the FDC of azilsartan (AZI) and amlodipine besylate (AML) with those of AZI monotherapy and AML monotherapy in Japanese patients with grade 1 to 2 essential hypertension. METHODS: This was a multicenter, randomized, double-blind, parallel-group study. After receiving placebo during a 4-week run-in period in a single-blind manner, patients were randomized to receive 1 of the following 5 treatments for 8 weeks: FDC containing AZI 20 mg and AML 5 mg (AZI/AML 20/5 mg), FDC containing AZI 20 mg and AML 2.5 mg (AZI/AML 20/2.5 mg), AZI 20 mg, AML 5 mg, or AML 2.5 mg once daily in a fasting or fed state. The primary end point was the change from baseline (week 0) in the seated trough diastolic blood pressure at week 8 (last observation carried forward [LOCF]), and the secondary end point was the change from baseline in the seated trough systolic blood pressure at week 8 (LOCF). Tolerability was assessed based on adverse events, vital signs, and physical examination findings. RESULTS: Of the 800 patients who provided informed consent, 603 were randomized to receive AZI/AML 20/5 mg (150 patients), AZI/AML 20/2.5 mg (151 patients), AZI 20 mg (151 patients), AML 5 mg (75 patients), or AML 2.5 mg (76 patients). The mean baseline systolic/diastolic blood pressure was 160.7/100.3 mm Hg. The mean change from baseline in seated blood pressure at week 8 (LOCF) was -35.3/-22.3 mm Hg in the AZI/AML 20/5 mg group and -31.4/-19.2 mm Hg in the AZI/AML 20/2.5 mg group, indicating a reduction significantly greater than that in corresponding monotherapy groups (-21.5/-13.9 mm Hg in the AZI 20 mg group, -26.4/-15.5 mm Hg in the AML 5 mg group, and -19.3/-11.6 mm Hg in the AML 2.5 mg group; p < 0.0001 for all contrast tests). No remarkable difference was found in the incidences of adverse events, vital signs, and physical examination findings among the treatment groups. CONCLUSION: This study found that the FDC of AZI/AML 20/5 mg and 20/2.5 mg exhibited greater antihypertensive effects compared with each monotherapy. The FDC of AZI/AML had a similar safety profile to that of each monotherapy and was tolerable to Japanese patients with grade 1 to 2 essential hypertension. JAPAN PHARMACEUTICAL INFORMATION CENTER REGISTRATION: Japic CTI-111606.

Preparation and photocatalytic activity of robust titania monoliths for water remediation.

TiO(2) monoliths were prepared, characterized, and evaluated for photocatalytic performance. The TiO(2) monoliths were found to have an interconnected void lattice and a bimodal porous structure with macropores and mesopores after calcination at 500-700 °C. Monoliths calcined at 500 °C had high specific surface area (93.1 m(2)/g) and porosity (68%), which were maintained after calcination at 700-1100 °C (51-46%). The calcined monoliths had relatively high Vickers hardness (∼104) despite their porous structure. Monoliths calcined at 500 and 700 °C exhibited high performance for methylene blue decolorization because of their high specific surface area.