The Efficacy and Tolerability of Irbesartan/Amlodipine Combination Therapy in Patients With Essential Hypertension Whose Blood Pressure Were not Controlled by Irbesartan Monotherapy.

PURPOSE: This study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy. METHODS: Two multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography. FINDINGS: In I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were -14.78 (12.35) mmHg, -21.47 (12.78) mmHg, and -8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were -13.30 (12.47) mmHg and -7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study. IMPLICATIONS: The combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).

Effects of Teneligliptin on HbA1c levels, Continuous Glucose Monitoring-Derived Time in Range and Glycemic Variability in Elderly Patients with T2DM (TEDDY Study).

BACKGROUND: To evaluate the effects of teneligliptin on glycosylated hemoglobin (HbA1c) levels, continuous glucose monitoring (CGM)-derived time in range, and glycemic variability in elderly type 2 diabetes mellitus patients. METHODS: This randomized, double-blinded, placebo-controlled study was conducted in eight centers in Korea (clinical trial registration number: NCT03508323). Sixty-five participants aged ≥65 years, who were treatment-naïve or had been treated with stable doses of metformin, were randomized at a 1:1 ratio to receive 20 mg of teneligliptin (n=35) or placebo (n=30) for 12 weeks. The main endpoints were the changes in HbA1c levels from baseline to week 12, CGM metrics-derived time in range, and glycemic variability. RESULTS: After 12 weeks, a significant reduction (by 0.84%) in HbA1c levels was observed in the teneligliptin group compared to that in the placebo group (by 0.08%), with a between-group least squares mean difference of -0.76% (95% confidence interval [CI], -1.08 to -0.44). The coefficient of variation, standard deviation, and mean amplitude of glycemic excursion significantly decreased in participants treated with teneligliptin as compared to those in the placebo group. Teneligliptin treatment significantly decreased the time spent above 180 or 250 mg/dL, respectively, without increasing the time spent below 70 mg/dL. The mean percentage of time for which glucose levels remained in the 70 to 180 mg/dL time in range (TIR70-180) at week 12 was 82.0%±16.0% in the teneligliptin group, and placebo-adjusted change in TIR70-180 from baseline was 13.3% (95% CI, 6.0 to 20.6). CONCLUSION: Teneligliptin effectively reduced HbA1c levels, time spent above the target range, and glycemic variability, without increasing hypoglycemia in our study population.

Comparison of the Efficacy and Safety of Ketoprofen Plaster and Diclofenac Plaster for Osteoarthritis-Related Knee Pain: A Multicenter, Randomized, Active-Controlled, Open-Label, Parallel-Group, Phase III Clinical Trial.

PURPOSE: To compare the efficacy and safety of ketoprofen plasters and diclofenac plasters after 3 weeks of administration in patients with osteoarthritis-related knee pain. METHODS: This multicenter, randomized, active-controlled, open-label, parallel-group, noninferiority phase III study randomized 236 adults with osteoarthritis-related knee pain for 3 weeks with ketoprofen plaster 30 mg twice daily (n = 118) or diclofenac plaster 15 mg once daily (n = 118). The primary efficacy end point was the mean change from baseline to week 3 in the mean knee pain intensity score during walking, as measured by a 100-mm visual analog scale with a predefined noninferiority margin of 10.0 mm. Secondary end points included changes in knee pain intensity score during walking (weeks 1 and 2) and at rest (weeks 1, 2, and 3), Knee Injury and Osteoarthritis Outcome Score, Patient Global Impression of Improvement scale assessments, and frequency of rescue medication use after 2 and 3 weeks of treatment. FINDINGS: A total of 223 patients (115 in the ketoprofen group and 108 in the diclofenac group) were included in the per-protocol analysis. After 3 weeks of treatment, the least squares mean change from baseline in knee pain intensity scores during walking was -35.9 (95% CI, -39.7 to -32.2) in the ketoprofen group and -31.7 (95% CI, -35.5 to -27.9) in the diclofenac group, with noninferiority found (least squares mean difference, -4.2; 95% CI, -9.6 to 1.1). Ketoprofen significantly (P < 0.05) reduced the pain intensity score at rest after 2 and 3 weeks of treatment compared with diclofenac. No statistically significant difference was found between the groups in terms of changes in pain intensity score during walking at weeks 1, 2, and 3. The mean Patient Global Impression of Improvement score was statistically significant (P < 0.001) in favor of ketoprofen after 2 and 3 weeks of treatment. In addition, the Knee Injury and Osteoarthritis Outcome Score improved in both groups, and no statistically significant difference was found between the groups in terms of frequency of rescue medication use. The overall adverse event profile of the groups was similar, and no difference was found in skin reaction rates between the 2 groups. IMPLICATIONS: Ketoprofen plasters can be effectively and safely administered to patients with osteoarthritis-related knee pain.

Safety, tolerability and pharmacokinetics and pharmacodynamics of HL2351, a novel hybrid fc-fused interleukin-1 receptor antagonist, in healthy subjects: A first-in-human study.

AIMS: We performed a first-in-human study with HL2351, a novel hybrid Fc-fused interleukin (IL)-1 receptor antagonist, to evaluate its tolerability, pharmacokinetics and pharmacodynamics (PD) after a single subcutaneous (SC) administration in healthy subjects. METHODS: A randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted. Eligible subjects randomly received a single SC administration of HL2351 (1, 2, 4, 8 and 12 mg/kg) or placebo in a ratio of 8:2. Subjects in the active-controlled group received a single SC administration of anakinra at 100 mg. Serial blood samples were collected for pharmacokinetics and PD analyses. An ex-vivo activation test was performed to evaluate the PD using peripheral blood mononuclear cells treated with IL-1ß. Anti-HL2351 antibodies were determined at baseline and 29 days postdose. Tolerability was assessed throughout the study. RESULTS: HL2351 was eliminated more slowly than anakinra (terminal half-life: 27.21-45.28 vs 3.97 h). Serum concentrations of HL2351 were increased dose-proportionally. The mean apparent clearance of HL2351 were 0.6, 0.66, 0.75, 0.51, 0.65 L/h at 1, 2, 4, 8 and 12 mg/kg, respectively. The percent inhibition of IL-6 expression varied widely (range: 0-92.1%), showing no clear trend or discernible difference between HL2351, anakinra and placebo. HL2351 was well tolerated after a single SC administration. CONCLUSION: HL2351 was well tolerated and showed linear pharmacokinetic characteristics after a single SC administration at doses up to 12 mg/kg in healthy subjects. HL2351 remained in the body 7-11 times longer than anakinra. HL2351 can be developed as a potential therapeutic alternative to anakinra.

Effect of Continuous Multi-Walled Carbon Nanotubes on Thermal and Mechanical Properties of Flexible Composite Film.

To investigate the effect of continuous multi-walled carbon nanotubes (MWCNTs) on the thermal and mechanical properties of composites, we propose a fabrication method for a buckypaper-filled flexible composite film prepared by a two-step process involving buckypaper fabrication using vacuum filtration of MWCNTs, and composite film fabrication using the dipping method. The thermal conductivity and tensile strength of the composite film filled with the buckypaper exhibited improved results, respectively 76% and 275% greater than those of the individual MWCNT-filled composite film. It was confirmed that forming continuous MWCNT fillers is an important factor which determines the physical characteristics of the composite film. In light of the study findings, composite films using buckypaper as a filler and polydimethylsiloxane (PDMS) as a flexible matrix have sufficient potential to be applied as a heat-dissipating material, and as a flexible film with high thermal conductivity and excellent mechanical properties.

Multiple mutations of the critical amino acid residues for the sweetness of the sweet-tasting protein, brazzein.

We have previously identified critical residues important for sweetness of the sweet protein brazzein by site-directed mutagenesis (Yoon, Kong, Jo, & Kong, 2011). In order to elucidate the interaction mechanisms of brazzein with the sweet taste receptor, we made multiple mutations of three residues (His31 in loop 30-33, Glu36 in ß-strand III, and Glu41 in loop 40-43). We found that all double mutations (H31R/E36D, H31R/E41A and E36D/E41A) made the molecules sweeter than des-pE1M-brazzein and three single mutants. Moreover, the triple mutation (H31R/E36D/E41A) made the molecule significantly sweeter than three double mutants. These results strongly support the hypothesis that brazzein binds to the multisite surface of the sweet taste receptor. Our findings also suggest that mutations reducing the overall negative charge and/or increasing the positive charge favour sweet-tasting protein potency.