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Jimin Lee,1 Yoojin Noh,1 Sooyoung Shin,1 Hong-Seok Lim,2 Rae Woong Park,3 Soo Kyung Bae,4 Euichaul Oh,4 Grace Juyun Kim,5 Ju Han Kim,5 Sukhyang Lee1 1Division of Clinical Pharmacy, College of Pharmacy, Ajou University, Suwon, South Korea; 2Department of Cardiology, School of Medicine, Ajou University, Suwon, South Korea; 3Department of Biomedical Informatics, School of Medicine, Ajou University, Suwon, South Korea; 4Division of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea; 5Division of Biomedical Informatics, College of Medicine, Seoul National University, Seoul, South Korea Abstract: Statin therapy is beneficial in reducing cardiovascular events and mortalities in patients with atherosclerotic cardiovascular diseases. Yet, there have been concerns of increased risk of diabetes with statin use. This study was aimed to evaluate the association between statins and new onset diabetes mellitus (NODM) in patients with ischemic heart disease (IHD) utilizing the Korean Health Insurance Review and Assessment Service claims database. Among adult patients with preexisting IHD, new statin users and matched nonstatin users were identified on a 1:1 ratio using proportionate stratified random sampling by sex and age. They were subsequently propensity score matched further with age and comorbidities to reduce the selection bias. Overall incidence rates, cumulative rates and hazard ratios (HRs) between statin use and occurrence of NODM were estimated. The subgroup analyses were performed according to sex, age groups, and the individual agents and intensities of statins. A total of 156,360 patients (94,370 in the statin users and 61,990 in the nonstatin users) were included in the analysis. The incidence rates of NODM were 7.8% and 4.8% in the statin users and nonstatin users, respectively. The risk of NODM was higher among statin users (crude HR 2.01, 95% confidence interval [CI] 1.93–2.10; adjusted HR 1.84, 95% CI 1.63–2.09). Pravastatin had the lowest risk (adjusted HR 1.54, 95% CI 1.32–1.81) while those who were exposed to more than one statin were at the highest risk of NODM (adjusted HR 2.17, 95% CI 1.93–2.37). It has been concluded that all statins are associated with the risk of NODM in patients with IHD, and it is believed that our study would contribute to a better understanding of statin and NODM association by analyzing statin use in the real-world setting. Periodic screening and monitoring for diabetes are warranted during prolonged statin therapy in patients with IHD. Keywords: Atorvastatin, Fluvastatin, Lovastatin, Rosuvastatin, Pitavastatin, Pravastatin, Simvastatin, Ischemic heart disease, IHD, new onset diabetes mellitus, NODM

Jee Sun Min,1 Doyun Kim,1 Jung Bae Park,1 Hyunjin Heo,1 Soo Hyeon Bae,2 Jae Hong Seo,1 Euichaul Oh,1 Soo Kyung Bae1 1Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, 2Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, South Korea Background: Evaluating the potential risk of metabolic drug–drug interactions (DDIs) is clinically important. Objective: To develop a physiologically based pharmacokinetic (PBPK) model for sarpogrelate hydrochloride and its active metabolite, (R,S)-1-{2-[2-(3-methoxyphenyl)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol (M-1), in order to predict DDIs between sarpogrelate and the clinically relevant cytochrome P450 (CYP) 2D6 substrates, metoprolol, desipramine, dextromethorphan, imipramine, and tolterodine. Methods: The PBPK model was developed, incorporating the physicochemical and pharmacokinetic properties of sarpogrelate hydrochloride, and M-1 based on the findings from in vitro and in vivo studies. Subsequently, the model was verified by comparing the predicted concentration-time profiles and pharmacokinetic parameters of sarpogrelate and M-1 to the observed clinical data. Finally, the verified model was used to simulate clinical DDIs between sarpogrelate hydrochloride and sensitive CYP2D6 substrates. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministering sarpogrelate hydrochloride and metoprolol. Results: The developed PBPK model accurately predicted sarpogrelate and M-1 plasma concentration profiles after single or multiple doses of sarpogrelate hydrochloride. The simulated ratios of area under the curve and maximum plasma concentration of metoprolol in the presence of sarpogrelate hydrochloride to baseline were in good agreement with the observed ratios. The predicted fold-increases in the area under the curve ratios of metoprolol, desipramine, imipramine, dextromethorphan, and tolterodine following single and multiple sarpogrelate hydrochloride oral doses were within the range of ≥1.25, but

Jae Hong Seo, Jung Bae Park, Woong-Kee Choi, Sunhwa Park, Yun Jin Sung, Euichaul Oh, Soo Kyung Bae College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea Objective: Cilostazol is a Biopharmaceutical Classification System class II drug with low solubility and high permeability, so its oral absorption is variable and incomplete. The aim of this study was to prepare two sulfonate salts of cilostazol to increase the dissolution and hence the oral bioavailability of cilostazol.Methods: Cilostazol mesylate and cilostazol besylate were synthesized from cilostazol by acid addition reaction with methane sulfonic acid and benzene sulfonic acid, respectively. The salt preparations were characterized by nuclear magnetic resonance spectroscopy. The water contents, hygroscopicity, stress stability, and photostability of the two cilostazol salts were also determined. The dissolution profiles in various pH conditions and pharmacokinetic studies in rats were compared with those of cilostazol-free base.Results: The two cilostazol salts exhibited good physicochemical properties, such as nonhygroscopicity, stress stability, and photostability, which make it suitable for the preparation of pharmaceutical formulations. Both cilostazol mesylate and cilostazol besylate showed significantly improved dissolution rate and extent of drug release in the pH range 1.2–6.8 compared to the cilostazol-free base. In addition, after oral administration to rats, cilostazol mesylate and cilostazol besylate showed increases in Cmax and AUCt of approximately 3.65- and 2.87-fold and 3.88- and 2.94-fold, respectively, compared to cilostazol-free base.Conclusion: This study showed that two novel salts of cilostazol, such as cilostazol mesylate and cilostazol besylate, could be used to enhance its oral absorption. The findings warrant further preclinical and clinical studies on cilostazol mesylate and cilostazol besylate at doses lower than the usually recommended dosage, so that it can be established as an alternative to the marketed cilostazol tablet. Keywords: BCS class II, cilostazol, besylate, mesylate, acid addition reaction, dissolution

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that perioperative neurocognitive disorders be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Theoretically probing the physics underlying the photoluminescence of phosphors and predicting their thermal quenching properties are significant issues in the field of phosphor research. The electronic ground states of a series of Eu(II)-doped alkali-earth sulfide phosphors, i.e., MS:Eu2+ (M = Mg, Ca, Sr, Ba), have been analyzed using density functional theory calculations to characterize and analyze their photoluminescence properties in terms of quantum efficiency and its thermal decay tendency. Anderson's impurity model to MS:Eu2+ enables devising a physical picture of how the electronic ground states | ψ Eu − 5 d ⟩ representing the Eu(II)-5d orbitals are mixed with those of the conduction bands (CBs) of host materials. The focus is on quantitatively deducing the electron delocalization nature of | ψ Eu − 5 d ⟩ over |CB〉, especially ∑ k | ψ k M − d k ⟩ , which represents the bands formed by the d orbitals of M atoms. The ratio of the probability amplitudes of | ψ Eu − 5 d ⟩ and ∑ k | ψ k M − d k ⟩ , i.e., C Eu − 5 d / C M − d , proves to be correlated with the electron localization nature of | ψ Eu − 5 d ⟩ , thereby suggesting that this ratio can be an effective parameter for evaluating the thermal quenching tendency of photoluminescence without more precise information on the electronic excited states. Energetically small gaps and large spatial overlaps between | ψ Eu − 5 d ⟩ and |CB〉 delocalize electrons in a hybridized state, which gives these electrons the tendency to dissipate without luminescence. The results explain the rankings of the quantum yield and its temperature dependence in the MS:Eu2+ (M = Ca, Sr, Ba) systems, which follow the Dorenbos thermal quenching model, while MgS:Eu2+ does not have the same mechanistic origin. [ABSTRACT FROM AUTHOR]

Ecosystem structure and function are increasingly threatened by changing climate, with profound effects observed globally in recent decades. Based on standardized visual censuses of reef biodiversity, we describe 27 years of community-level change for fishes, mobile macroinvertebrates and macroalgae in the Tasmanian ocean-warming hotspot. Significant ecological change was observed across 94 reef sites (5–10 m depth range) spanning four coastal regions between three periods (1992–95, 2006–07, 2017–19), which occurred against a background of pronounced sea temperature rise (+0.80°C on average). Overall, fish biomass increased, macroinvertebrate species richness and abundance decreased and macroalgal cover decreased, particularly during the most recent decade. While reef communities were relatively stable and warming was slight between the 1990s and mid-2000s (+0.12°C mean temperature rise), increased abundances of warm affinity fishes and invertebrates accompanied warming during the most recent decade (+0.68°C rise). However, significant rises in the community temperature index (CTI) were only found for fishes, invertebrates and macroalgae in some regions. Coastal warming was associated with increased fish biomass of non-targeted species in fished zones but had little effect on reef communities within marine reserves. Higher abundances of larger fishes and lobsters inside reserves appeared to negate impacts of 'thermophilization'. [ABSTRACT FROM AUTHOR]

Peptides show biological activity, and are more easily digested than complex proteins. In the present work, we evaluated the effects of soy hydrolysate on skeletal muscle. Soy protein isolate (SPI) was hydrolysed using 2% Alcalase (SPHA) and Flavourzyme (SPHF) at pH 8 for 3 h at 60°C, and at pH 7 for 3 h at 55°C, respectively. Antioxidant properties (total phenolic content and DPPH activity) and inhibition of muscle loss (myogenin, myosin heavy chain [MyHC], creatine kinase, and myostatin) by the SPI hydrolysates in C2C12 cells were compared with those of SPI. Alcalase produced more hydrolysed soy oligopeptides than Flavourzyme. Enzymatic hydrolysis increased the levels of essential amino acids, particularly in SPHF (2,466.85 mg/L) as compared to SPI (56.08 mg/L). The total phenolic contents of hydrolysates increased from 12.02 mg GAE/g in SPI to 22.87 and 18.67 mg GAE/g in SPHA and SPHF, respectively. The IC50 value of DPPH activity decreased four times after hydrolysis (SPI: 124.38, SPHA: 32.18, and SPHF: 30.21 mg/mL). SPHA and SPHF treatments increased the expression levels of both MyHC1 and MyHC3, as well as creatine kinase activity. A significant increase in MyHC3 expression was observed in SPHF at 10 µg/mL. Soy hydrolysates (SPHA: 93.5% and SPHF: 61.0%) induced a greater decrease in the expression of myostatin, a muscle reduction marker, than SPI (30.4%). In conclusion, soy hydrolysates may inhibit muscle loss, showing particularly better effects when Alcalase is used for hydrolysis. [ABSTRACT FROM AUTHOR]

The acousto-optic modulation over a broad near-infrared (NIR) spectrum with high speed, excellent integrability, and relatively simple scheme is crucial for the application of next-generation opto-electronic and photonic devices. This study aims to experimentally demonstrate ultrafast acousto-optic phenomena in the broad NIR spectral range of 0.77–1.1 eV (1130–1610 nm). Hundreds of GHz of light modulation are revealed in an all-optical configuration by combining ultrafast optical spectroscopy and light–sound conversion in 10–20 nm-thick bismuth selenide (Bi2Se3) van der Waals thin films. The modified optical transition energy and the line shape in the NIR band indicate phonon–photon interactions, resulting in a modulation of optical characteristics by the photoexcited interlayer vibrations in Bi2Se3. This all-optical, ultrafast acousto-optic modulation approach may open avenues for next-generation nanophotonic applications, including optical communications and processing, due to the synergistic combination of large-area capability, high photo-responsivity, and frequency tunability in the NIR spectral range.

Kinetics of oxygen reduction reaction on supported Pt and several Pt alloy electrocatalysts (PtCo/C and PtFe/C) are investigated in terms of the effect of alloying on the initiation and extent of surface oxide formation. The results are discussed in the context of a PEM fuel cell operating in the low to medium temperature range (70-120 degree C) and humidity variation (100 to10 percent).