Search

Abstract: TAK-385 (relugolix) is a novel, non-peptide, orally active gonadotropin-releasing hormone (GnRH) antagonist, which builds on previous work with non-peptide GnRH antagonist TAK-013. TAK-385 possesses higher affinity and more potent antagonistic activity for human and monkey GnRH receptors compared with TAK-013. Both TAK-385 and TAK-013 have low affinity for the rat GnRH receptor, making them difficult to evaluate in rodent models. Here we report the human GnRH receptor knock-in mouse as a humanized model to investigate pharmacological properties of these compounds on gonadal function. Twice-daily oral administration of TAK-013 (10mg/kg) for 4 weeks decreased the weights of testes and ventral prostate in male knock-in mice but not in male wild-type mice, demonstrating the validity of this model to evaluate antagonists for the human GnRH receptor. The same dose of TAK-385 also reduced the prostate weight to castrate levels in male knock-in mice. In female knock-in mice, twice-daily oral administration of TAK-385 (100mg/kg) induced constant diestrous phases within the first week, decreased the uterus weight to ovariectomized levels and downregulated GnRH receptor mRNA in the pituitary after 4 weeks. Gonadal function of TAK-385-treated knock-in mice began to recover after 5 days and almost completely recovered within 14 days after drug withdrawal in both sexes. Our findings demonstrate that TAK-385 acts as an antagonist for human GnRH receptor in vivo and daily oral administration potently, continuously and reversibly suppresses the hypothalamic–pituitary–gonadal axis. TAK-385 may provide useful therapeutic interventions in hormone-dependent diseases including endometriosis, uterine fibroids and prostate cancer. [Copyright &y& Elsevier]

Abstract: We previously reported the bioavailability enhancement of lipophilic Coenzyme Q10 (CoQ10) by complexing with γ- Cyclodextrin (γCD). Here, we report on its mechanism. Hydrophobic CoQ10 generally agglutinates but the dissociated CoQ10 from γCD was captured by bile acid to form nanometer molecular micelle without aggregation and therefore both solubility and bioavailability could be enhanced. Furthermore, we succeeded in the expansion of this finding to personal care field by the use of Dipotassium glycyrrhizate (GZK2) instead of bile acid. The skin absorptions of actives could be significantly enhanced by the combination of cosme-ceutical-γCD complexes with GZK2. [Copyright &y& Elsevier]

Abstract: The objective of this study was to determine the effect of molecular encapsulation of coenzyme Q10 (CoQ10) by complexation with γ-cyclodextrin (γ-CD) (CoQ10-γ-CD) compared with a mixture of CoQ10 with microcrystalline cellulose (CoQ10-MCC) on absorption and bioavailability of CoQ10 in supplement form in healthy adults. Twenty-two volunteers received a single dose of a 150-mg capsule containing 30 mg CoQ10 under fasting conditions in an open-label, crossover design with a 2-week washout period. Blood was collected before dosing and after dosing periodically over 48 hours. Plasma levels of CoQ10 were determined by high-performance liquid chromatography using an electrochemical detector and an online reduction system. After 6 and 8 hours of dosing there was a significant increase in mean CoQ10 plasma levels of subjects after a single oral administration of the CoQ10-γ-CD capsule compared with those with the CoQ10-MCC capsule. In addition, the mean plasma levels at 24 and 48 hours tended to be higher after CoQ10-γ-CD administration in comparison with CoQ10-MCC administration. The area under the plasma CoQ10 concentration curve and the maximum plasma concentration (C max) values as well as their corresponding log-transformed values, log area under the plasma CoQ10 concentration curve, and log C max for the CoQ10-γ-CD formulation were significantly higher than those for the CoQ10-MCC formulation. These results indicate that the oral absorption and bioavailability of CoQ10 in healthy adult volunteers could be significantly enhanced by complexation with γ-CD, suggesting the potential use of γ-CD as formulation aid for orally administered CoQ10. [Copyright &y& Elsevier]

α2,8-Linked polysialic acid (polySia) is a structurally unique anti-adhesive glycotope that covalently modifies N-linked glycans on neural cell adhesion molecules (N-CAMs). These sugar chains play a key role in modulating cell-cell interactions, principally during embryonic development, neural plasticity, and tumor metastasis. The degree of polymerization (DP) of polySia chains on N-CAM is postulated to be of critical importance in regulating N-CAM function. There are limitations, however, in the conventional methods to accurately determine the DP of polySia on N-CAM, the most serious being partial acid hydrolysis of internal α2,8-ketosidic linkages that occur during fluorescent derivatization, a step necessary to enhance chromatographic detection. To circumvent this problem, we have developed a facile method that combines the use of Endo-β-galactosidase to first release linear polySia chains from N-CAM, with high resolution high pressure liquid chromatography profiling. This strategy avoids acid hydrolysis prior to chromatographic profiling and thus provides an accurate determination of the DP and distribution of polySia on N-CAM. The potential of this new method was evaluated using a nonpolysialylated construct of N-CAM that was polysialylated in vitro using a soluble construct of ST8Sia II or ST8Sia IV. Whereas most of the oligosialic acid/polySia chains consisted of DPs ∼50–60 or less, a subpopulation of chains with DPs ∼150 to ∼180 and extending to DP ∼400 were detected. The DP of this subpopulation is considerably greater than reported previously for N-CAM. Endo-β-galactosidase can also release poly-Sia chains from polysialylated membranes expressed in the neuroblastoma cell line, Neuro2A, and native N-CAM from embryonic chick brains. [ABSTRACT FROM AUTHOR]

This paper presents the design methodology and performance testing of an additively manufactured resistojet operating on hydrogen as propellant. Additive manufacturing allows to produce complex monolithic resistors, resulting in reliable high efficiency thrusters. The concept, to be used in combination with advanced cryogenic storage technologies, is proposed for short time and high specific impulse orbit transfers. The simplified two-dimensional thermal design approach adopted is discussed, and its application to the engineering of the resistor is shown for both Inconel 718 and tungsten. The paper reports the performance testing of the proof-of-concept version of the thruster, manufactured in Inconel 718. Experiments on hydrogen show near ideal performance, demonstrating a peak thermal efficiency of 96%. The thruster proves the validity of the design methodology proposed, and the feasibility of the approach to develop monolithic additively manufactured hydrogen resistojets as main propulsion units. • Developed a simple modeling approach for concentric resistojets. • Successfully 3D printed a thin wall cylindrical multi-layer heater. • Demonstrated the first 3D printed hydrogen resistojet. • Achieved near ideal thermal efficiency in the thruster. [ABSTRACT FROM AUTHOR]

Nano-infiltration and transient eutectic phase (NITE) SiC matrix composites are designed for application in aerospace propulsion systems, particularly in fasteners and thrusters. A variety of carbon fibers with different properties have been selected as reinforcements for SiC matrix composites. Carbon fibers are known to be stable at high temperatures; however, the effects of high applied pressure at high temperatures on the fiber microstructure evolution and mechanical properties are not well-known. As a scoping study for fabricating NITE C/SiC composites, the behaviors of various carbon fibers in SiC composites. Pitch-based fibers, namely, GRANOX XN-05 and YS-90A, and a polyacrylonitrile-based fiber, namely, TORAYCA T-300B, were selected for matrix reinforcement. The 3-point bending test results indicated pseudo-ductile behaviors in the cases of YS-90A and T-300B fiber reinforcements. Fracture resistance evaluation based on the single-notch bending test indicated that the YS-90A fiber reinforced composite afforded the highest fracture resistance among the three C/SiC composites. The microstructure evolution on YS-90A and T-300B fibers was limited to near the fiber surface. Therefore, YS-90A and T-300B carbon fibers are potential candidates for reinforcement in NITE C/SiC composites. [ABSTRACT FROM AUTHOR]

Liquid propellants are commonly used in rocket engines due to their high energy density. In this study, we focused on the use of liquid ethanol and liquid nitrous oxide as propellants in a cylindrical rotating detonation engine (RDE) for practical applications, and examined the effects of various conditions on the bipropellant RDE performance. We varied the vapor quality of nitrous oxide in a mixture of liquid and gaseous nitrous oxide due to the flash boiling. In addition, we varied the liquid ethanol temperature, the injector stiffness, and momentum angle of the propellant. We then analyzed the effects of these changes on the propagation mode of the RDE under atmospheric pressure conditions. The results showed that a rotating detonation wave was observed under the combination of high vapor quality of nitrous oxide, high injector stiffness, high liquid ethanol temperature, and high momentum angle. The propagation velocity was obtained as 73∼83 % of the Chapman-Jouguet velocity. Long-duration combustion tests were also conducted, and the internal combustion structure was confirmed from the erosion of the carbon-carbon (C/C) composite material. The detonation wave was considered to propagate near the bottom of the RDE with liquid propellants from the erosion heights of the C/C composite. The erosion height was confirmed to be consistent with the fill height calculated using the sound speed of the nitrous oxide. In addition, characteristic exhaust velocity efficiencies of more than 85 % were achieved in all combustion tests. [ABSTRACT FROM AUTHOR]

Abstract: Kisspeptin/metastin, a hypothalamic peptide, plays a pivotal role in controlling gonadotropin-releasing hormone (GnRH) neurons, and we have shown that continuous subcutaneous administration of kisspeptin analogues suppresses plasma testosterone in male rats. This study examined pharmacologic profiles of investigational kisspeptin analogues, TAK-448 and TAK-683, in male rats. Both analogues showed high receptor-binding affinity and potent and full agonistic activity for rat KISS1R, which were comparable to natural peptide Kp-10. A daily subcutaneous injection of TAK-448 and TAK-683 (0.008–8μmol/kg) for consecutive 7 days initially induced an increase in plasma luteinizing hormone and testosterone levels; however, after day 7, plasma hormone levels and genital organ weights were reduced. Continuous subcutaneous administrations of TAK-448 (≥10pmol/h, ca. 0.7nmol/kg/day) and TAK-683 (≥30pmol/h, ca. 2.1nmol/kg/day) induced a transient increase in plasma testosterone, followed by abrupt reduction of plasma testosterone to castrate levels within 3–7 days. This profound testosterone-lowering effect was sustained throughout 4-week dosing periods. At those dose levels, the weights of the prostate and seminal vesicles were reduced to castrate levels. These suppressive effects of kisspeptin analogues were more rapid and profound than those induced by the GnRH agonist analogue leuprolide treatment. In addition, TAK-683 reduced plasma prostate specific antigen (PSA) in the JDCaP androgen-dependent prostate cancer rat model. Thus, chronic administration of kisspeptin analogues may hold promise as a novel therapeutic approach for suppressing reproductive functions and hormone-related diseases such as prostate cancer. Further studies are warranted to elucidate clinical significance of TAK-448 and TAK-683. [Copyright &y& Elsevier]