π-Conjugated Polymer with Pendant Side Chains as a Dopant-Free Hole Transport Material for High-Performance Perovskite Solar Cells.

Dopant-free polymeric hole transport materials (HTMs) have attracted considerable attention in perovskite solar cells (PSCs) due to their high carrier mobilities and excellent hydrophobicity. They are considered promising candidates for HTMs to replace commercial Spiro-OMeTAD to achieve long-term stability and high efficiency in PSCs. In this study, we developed BDT-TA-BTASi, a conjugated donor-π-acceptor polymeric HTM. The donor benzo[1,2-b:4,5-b']dithiophene (BDT) and acceptor benzotriazole (BTA) incorporated pendant siloxane, and alkyl side chains led to high hole mobility and solubility. In addition, BDT-TA-BTASi can effectively passivate the perovskite layer and markedly decrease the trap density. Based on these advantages, dopant-free BDT-TA-BTASi-based PSCs achieved an efficiency of over 21.5%. Furthermore, dopant-free BDT-TA-BTASi-based devices not only exhibited good stability in N2 (retaining 92% of the initial efficiency after 1000 h) but also showed good stability at high-temperature (60 °C) and -humidity conditions (80 ± 10%) (retaining 92 and 82% of the initial efficiency after 400 h). These results demonstrate that BDT-TA-BTASi is a promising HTM, and the study provides guidance on dopant-free polymeric HTMs to achieve high-performance PSCs.

Multifunctional Narrow Band Gap Terpolymer-Enabled High-Performance Dopant-Free Perovskite and Additive-Free Organic Solar Cells with Long-Term Stability.

The optoelectronic devices endowing multifunctionality while utilizing a single low-cost material have always been challenging. For this purpose, we adopted a random ternary copolymerization strategy for designing two terpolymers, namely TP-0.8-EG and TP-0.8-TEG comprising a benzothiadiazole (BT)-benzo[1,2-b:4,5-b']dithiophene-diketopyrrolo[3,4-c]pyrrole (A1-π-D-π-A2) backbone. The figure of merits of the narrow band gap TP-0.8-EG terpolymer include deepened frontier energy levels, high hole mobility, better film formability, enriched multifunctionality, and passivation capability. Accordingly, the suitable electronic properties of TP-0.8-EG revealed that it can function as a dopant-free hole-transporting material in perovskite solar cells (PSCs) as well as the third component in organic solar cells (OSCs). Remarkably, TP-0.8-EG outperforms by exhibiting a higher power conversion efficiency (PCE) of 20.9% over TP-0.8-TEG (PCE of 18.3%) and BT-UF (PCE of 14.6%) in dopant-free PSCs. Interestingly, TP-0.8-EG fabricated along with PM6:Y7 displayed a high PCE of 16.52% in ternary OSCs. Also, TP-0.8-EG established good device storage stabilities (85 and 83% of their initial PCEs for 1200 and 500 h) in dopant-free PSC as well as OSC devices. Notably, the devices with TP-0.8-EG showed excellent thermal and moisture stabilities. To the best of our knowledge, A1-π-D-π-A2 terpolymer performing both in PSCs and OSCs with decent efficiencies and good device stabilities is a rare scenario.

Finely Tuned Molecular Packing Realized by a New Rhodanine-Based Acceptor Enabling Excellent Additive-Free Small- and Large-Area Organic Photovoltaic Devices Approaching 19 and 12.20% Efficiencies.

A new nonfullerene acceptor (NFA), BTA-ERh, was synthesized and integrated into a PM6:Y7:PC71BM ternary system to regulate the blend film morphology for enhanced device performance. Due to BTA-ERh's good miscibility with host active blend films, an optimized film morphology was obtained with appropriate phase separation and fine-tuning of film crystallinity, which ultimately resulted in efficient exciton dissociation, charge transport, lower recombination loss, and decreased trap-state density. The resulting additive-free quaternary devices achieved a remarkable efficiency of 18.90%, with a high voltage, fill factor, and current density of 0.87 V, 76.32%, and 28.60 mA cm-2, respectively. By adding less of a new small molecule with high crystallinity, the favorable nanomorphology shape of blend films containing NFAs might be adjusted. Consequently, this strategy can enhance photovoltaic device performance for cutting-edge NFA-based organic solar cells (OSCs). In contrast, the additive-free OSCs exhibited good operational stability. More importantly, large-area modules with the quaternary device showed a remarkable efficiency of 12.20%, with an area as high as 55 cm2 (substrate size, 100 cm2) in an air atmosphere via D-bar coating. These results highlight the enormous research potential for a multicomponent strategy for future additive-free OSC applications.

Hexagonal Boron Nitride for Next-Generation Photonics and Electronics.

Hexagonal boron nitride (h-BN), an insulating 2D layered material, has recently attracted tremendous interest motivated by the extraordinary properties it shows across the fields of optoelectronics, quantum optics, and electronics, being exotic material platforms for various applications. At an early stage of h-BN research, it is explored as an ideal substrate and insulating layers for other 2D materials due to its atomically flat surface that is free of dangling bonds and charged impurities, and its high thermal conductivity. Recent discoveries of structural and optical properties of h-BN have expanded potential applications into emerging electronics and photonics fields. h-BN shows a very efficient deep-ultraviolet band-edge emission despite its indirect-bandgap nature, as well as stable room-temperature single-photon emission over a wide wavelength range, showing a great potential for next-generation photonics. In addition, h-BN is extensively being adopted as active media for low-energy electronics, including nonvolatile resistive switching memory, radio-frequency devices, and low-dielectric-constant materials for next-generation electronics.

Bifidobacterial carbohydrate/nucleoside metabolism enhances oxidative phosphorylation in white adipose tissue to protect against diet-induced obesity.

BACKGROUND: Comparisons of the gut microbiome of lean and obese humans have revealed that obesity is associated with the gut microbiome plus changes in numerous environmental factors, including high-fat diet (HFD). Here, we report that two species of Bifidobacterium are crucial to controlling metabolic parameters in the Korean population. RESULTS: Based on gut microbial analysis from 99 Korean individuals, we observed the abundance of Bifidobacterium longum and Bifidobacterium bifidum was markedly reduced in individuals with increased visceral adipose tissue (VAT), body mass index (BMI), blood triglyceride (TG), and fatty liver. Bacterial transcriptomic analysis revealed that carbohydrate/nucleoside metabolic processes of Bifidobacterium longum and Bifidobacterium bifidum were associated with protecting against diet-induced obesity. Oral treatment of specific commercial Bifidobacterium longum and Bifidobacterium bifidum enhanced bile acid signaling contributing to potentiate oxidative phosphorylation (OXPHOS) in adipose tissues, leading to reduction of body weight gain and improvement in hepatic steatosis and glucose homeostasis. Bifidobacterium longum or Bifidobacterium bifidum manipulated intestinal sterol biosynthetic processes to protect against diet-induced obesity in germ-free mice. CONCLUSIONS: Our findings support the notion that treatment of carbohydrate/nucleoside metabolic processes-enriched Bifidobacterium longum and Bifidobacterium bifidum would be a novel therapeutic strategy for reprograming the host metabolic homeostasis to protect against metabolic syndromes, including diet-induced obesity. Video Abstract.

Butyrate modulates mucin secretion and bacterial adherence in LoVo cells via MAPK signaling.

Short-chain fatty acids contribute to normal bowel function and prevent bacterial infections. In particular, butyrate is a promising candidate that plays an important role in regulating the functional integrity of the gastrointestinal tract by stimulating mucin secretion. We investigated whether butyrate treatment modulates mucin secretion and bacterial adherence in LoVo cells. In addition, the possible signaling pathways were also examined in connection with the upregulation of mucin secretion. The results showed that butyrate induced mucin secretion in LoVo cells, resulting in the inhibition of Escherichia coli adhesion by increasing the adherence of Lactobacillus acidophilus and Bifidobacterium longum. The gene expression analysis suggests that mitogen-activated protein kinase (MAPK) signaling pathways including Cdc42-PAK pathway appears to be involved in stimulating mucin secretion. More importantly, butyrate induced the increased actin expression and polymerization in LoVo cells, which could be attributable to the Cdc42-PAK signaling pathway, implicated in actin cytoskeleton and mucin secretion. Our results provide a molecular basis in modulating bacterial adherence and the MAPK signaling pathway for the improved homeostasis of colonic epithelial cells.

Transition metal-doped Ni-rich layered cathode materials for durable Li-ion batteries.

Doping is a well-known strategy to enhance the electrochemical energy storage performance of layered cathode materials. Many studies on various dopants have been reported; however, a general relationship between the dopants and their effect on the stability of the positive electrode upon prolonged cell cycling has yet to be established. Here, we explore the impact of the oxidation states of various dopants (i.e., Mg2+, Al3+, Ti4+, Ta5+, and Mo6+) on the electrochemical, morphological, and structural properties of a Ni-rich cathode material (i.e., Li[Ni0.91Co0.09]O2). Galvanostatic cycling measurements in pouch-type Li-ion full cells show that cathodes featuring dopants with high oxidation states significantly outperform their undoped counterparts and the dopants with low oxidation states. In particular, Li-ion pouch cells with Ta5+- and Mo6+-doped Li[Ni0.91Co0.09]O2 cathodes retain about 81.5% of their initial specific capacity after 3000 cycles at 200 mA g-1. Furthermore, physicochemical measurements and analyses suggest substantial differences in the grain geometries and crystal lattice structures of the various cathode materials, which contribute to their widely different battery performances and correlate with the oxidation states of their dopants.

Lactobacillus fermentum promotes adipose tissue oxidative phosphorylation to protect against diet-induced obesity.

The gut microbiota has pivotal roles in metabolic homeostasis and modulation of the intestinal environment. Notably, the administration of Lactobacillus spp. ameliorates diet-induced obesity in humans and mice. However, the mechanisms through which Lactobacillus spp. control host metabolic homeostasis remain unclear. Accordingly, in this study, we evaluated the physiological roles of Lactobacillus fermentum in controlling metabolic homeostasis in diet-induced obesity. Our results demonstrated that L. fermentum-potentiated oxidative phosphorylation in adipose tissue, resulting in increased energy expenditure to protect against diet-induced obesity. Indeed, oral administration of L. fermentum LM1016 markedly ameliorated glucose clearance and fatty liver in high-fat diet-fed mice. Moreover, administration of L. fermentum LM1016 markedly decreased inflammation and increased oxidative phosphorylation in gonadal white adipose tissue, as demonstrated by transcriptome analysis. Finally, metabolome analysis showed that metabolites derived from L. fermentum LM1016-attenuated adipocyte differentiation and inflammation in 3T3-L1 preadipocytes. These pronounced metabolic improvements suggested that the application of L. fermentum LM1016 could have clinical applications for the treatment of metabolic syndromes, such as diet-induced obesity.

AlGaN Deep-Ultraviolet Light-Emitting Diodes with Localized Surface Plasmon Resonance by a High-Density Array of 40 nm Al Nanoparticles.

We present a remarkable improvement in the efficiency of AlGaN deep-ultraviolet light-emitting diodes (LEDs) enabled by the coupling of localized surface plasmon resonance (LSPR) mediated by a high-density array of Al nanoparticles (NPs). The Al NPs with an average diameter of ∼40 nm were uniformly distributed near the Al0.43Ga0.57N/Al0.50Ga0.50N multiple quantum well active region for coupling 285 nm emission by block copolymer lithography. The internal quantum efficiency is enhanced by 57.7% because of the decreased radiative recombination lifetime by the LSPR. As a consequence, the AlGaN LEDs with an array of Al NPs show 33.3% enhanced electroluminescence with comparable electrical properties to those of reference LEDs without Al NPs.

Self-protective GaInN-based light-emitting diodes with VO2 nanowires.

We presented a new functional GaInN-based light-emitting diode (LED) that is capable of protecting itself from unwanted thermal damage (a so-called self-protective LED). This functionality was achieved by incorporating VO2 nanowires on the LED chip. VO2 nanowires, as metal-insulator transition materials, show a phase transition from insulating to metallic at a characteristic transition temperature. By placing a VO2 nanowire between the n- and p-contacts of an LED, a parallel circuit was formed with the existing diode. As the VO2 nanowire became metal-like at its characteristic temperature, it induced a short-circuit state in the device, protecting the LED from heat damage at elevated temperatures. Details on the self-protective LED were elucidated, from a conceptual description to experimental proof.

Amelioration of high fat diet-induced nephropathy by cilostazol and rosuvastatin.

Multiple comorbidities of metabolic disorders are associated with facilitated chronic kidney disease progression. Anti-platelet cilostazol is used for the treatment of peripheral artery disease. In this study, we investigated the potential beneficial effects of cilostazol and rosuvastatin on metabolic disorder-induced renal dysfunctions. C57BL/6 mice that received high fat diet (HFD) for 22 weeks and a low dose of streptozotocin (STZ, 40 mg/kg) developed albuminuria and had increased urinary cystatin C excretion, and cilostazol treatment (13 weeks) improved these markers. Histopathological changes, including glomerular mesangial expansion, tubular vacuolization, apoptosis, and lipid accumulation were ameliorated by cilostazol treatment. Tubulointerstitial fibrosis that was indicated by the increases in collagen and transforming growth factor-ß1 subsided by cilostazol. Renoprotective effects were also observed in rosuvastatin-treated mice, and combinatorial treatment with cilostazol and rosuvastatin demonstrated enhanced ameliorative effects in histopathological evaluations. Notably, repressed renal heme oxygenase-1 (Ho-1) level in HFD/STZ mice was restored in cilostazol group. Further, we demonstrated that cilostazol enhanced Nrf2/Ho-1 signaling in cultured proximal tubular epithelial cells. Collectively, these results suggest the potential advantageous use of cilostazol as an adjunctive therapy with statins for the amelioration of metabolic disorder-associated renal injury.

Beneficial Effects of Sarpogrelate and Rosuvastatin in High Fat Diet/Streptozotocin-Induced Nephropathy in Mice.

Chronic kidney disease (CKD) is a major complication of metabolic disorders such as diabetes mellitus, obesity, and hypertension. Comorbidity of these diseases is the factor exacerbating CKD progression. Statins are commonly used in patients with metabolic disorders to decrease the risk of cardiovascular complications. Sarpogrelate, a selective antagonist of 5-hydroxytryptamine (5-HT) 2A receptor, inhibits platelet aggregation and is used to improve peripheral circulation in diabetic patients. Here, we investigated the effects of sarpogrelate and rosuvastatin on CKD in mice that were subjected to a high fat diet (HFD) for 22 weeks and a single low dose of streptozotocin (STZ, 40 mg/kg). When mice were administrated sarpogrelate (50 mg/kg, p.o.) for 13 weeks, albuminuria and urinary cystatin C excretion were normalized and histopathological changes such as glomerular mesangial expansion, tubular damage, and accumulations in lipid droplets and collagen were significantly improved. Sarpogrelate treatment repressed the HFD/STZ-induced CD31 and vascular endothelial growth factor receptor-2 expressions, indicating the attenuation of glomerular endothelial proliferation. Additionally, sarpogrelate inhibited interstitial fibrosis by suppressing the increases in transforming growth factor-ß1 (TGF-ß1) and plasminogen activator inhibitor-1 (PAI-1). All of these functional and histological improvements were also seen in rosuvastatin (20 mg/kg) group and, notably, the combinatorial treatment with sarpogrelate and rosuvastatin showed additive beneficial effects on histopathological changes by HFD/STZ. Moreover, sarpogrelate reduced circulating levels of PAI-1 that were elevated in the HFD/STZ group. As supportive in vitro evidence, sarpogrelate incubation blocked TGF-ß1/5-HT-inducible PAI-1 expression in murine glomerular mesangial cells. Taken together, sarpogrelate and rosuvastatin may be advantageous to control the progression of CKD in patients with comorbid metabolic disorders, and particularly, the use of sarpogrelate as adjunctive therapy with statins may provide additional benefits on CKD.

Quantitative determination of cyclosporine in human whole blood by ultra-performance liquid chromatography with triple quadrupole tandem mass spectrometry.

Cyclosporine is an immunosuppressant drug used in organ transplants or for the treatment of autoimmune diseases. We developed and validated a simple, sensitive, and specific method using UPLC-MS/MS to determine cyclosporine levels in human whole blood. MS/MS detection was performed in the positive electrospray ionization mode with multiple reaction monitoring. Cyclosporine was extracted from whole-blood samples using ascomycin as an internal standard. The mass transitions m/z 1203.49 → 1185.53 and m/z 814.71 → 796.67 were used to assay the analyte and IS. This method was validated with respect to linearity, specificity, accuracy, precision, recovery, and stability. The method exhibited a linear response from 10 to 1000 ng mL(-1) with correlation coefficient values >0.99. The precision and the accuracy values were within 15%, except at the lower limit of quatification (LLOQ). Cyclosporine was stable in whole blood with no evidence of degradation. This method was successfully applied to a pharmacokinetic study of cyclosporine in healthy volunteers following oral administration.

Pharmacometabolomic approach to predict QT prolongation in guinea pigs.

Drug-induced torsades de pointes (TdP), a life-threatening arrhythmia associated with prolongation of the QT interval, has been a significant reason for withdrawal of several medicines from the market. Prolongation of the QT interval is considered as the best biomarker for predicting the torsadogenic risk of a new chemical entity. Because of the difficulty assessing the risk for TdP during drug development, we evaluated the metabolic phenotype for predicting QT prolongation induced by sparfloxacin, and elucidated the metabolic pathway related to the QT prolongation. We performed electrocardiography analysis and liquid chromatography-mass spectroscopy-based metabolic profiling of plasma samples obtained from 15 guinea pigs after administration of sparfloxacin at doses of 33.3, 100, and 300 mg/kg. Principal component analysis and partial least squares modelling were conducted to select the metabolites that substantially contributed to the prediction of QT prolongation. QTc increased significantly with increasing dose (r = 0.93). From the PLS analysis, the key metabolites that showed the highest variable importance in the projection values (>1.5) were selected, identified, and used to determine the metabolic network. In particular, cytidine-5'-diphosphate (CDP), deoxycorticosterone, L-aspartic acid and stearic acid were found to be final metabolomic phenotypes for the prediction of QT prolongation. Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs. In addition, this integrative pharmacometabolomic approach would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose.

Rapid determination of sumatriptan in human plasma by ultra performance liquid chromatography-tandem mass spectrometry and its application to clinical pharmacokinetic study.

A sensitive and simple detection method coupling ultra-performance liquid chromatography with tandem mass spectrometry was developed and validated to analyze sumatriptan levels in human plasma. The plasma sample preparations for the analysis were based on liquid-liquid extraction with ethyl acetate, evaporation, and reconstitution. MS/MS detection was performed on a triple-quadrupole tandem mass spectrometer by monitoring the protonated parent→daughter ion pairs at m/z 296→58 and m/z 388→71 for sumatriptan and terazosin (internal standard), respectively. The method was validated with respect to its specificity, linearity, sensitivity, accuracy, precision, recovery, and stability. The calibration curve was linear from 0.5 to 50 ng/mL (r>0.999). The mean extraction recovery for sumatriptan was higher than 62.3%. The method accuracy was within 97.4%, and the relative standard deviation of the intra- and inter-day precision values was within 11.7% at all quality control levels. Plasma samples that contained sumatriptan were stable under three freeze-thaw cycles, short- and long-term storage, and autosampler conditions. This method was successfully applied to a pharmacokinetic study conducted with 10 healthy volunteers. After oral administration of 50-mg sumatriptan and serial blood sampling over 12 h, the mean area under the plasma concentration-time curve from time 0 to 12 h and the maximum plasma concentration were 116.2 ng h/mL and 33.2 ng/mL, respectively.

High-throughput screening of inhibitory effects of Bo-yang-hwan-o-tang on human cytochrome P450 isoforms in vitro using UPLC/MS/MS.

Bo-yang-hwan-o-tang (BHT) is an oriental herbal medicine for treating brain disorders such as cerebral ischemia. The objective of this study was to develop an economically feasible and time-saving high-throughput screening method to monitor the potential inhibitory effects of BHT on human cytochrome P450 (CYP) enzymes in vitro. Two cocktail sets were used for incubation of human liver microsomes: Cocktail A: 6 probe substrates for CYP1A2, CYP2A6, CYP2C8, CYP2C19, CYP2D6, CYP3A4; Cocktail B: 3 for CYP2B6, CYP2C9, CYP2E1. The concentrations of the substrate metabolites were simultaneously analyzed using UPLC/MS/MS. The BHT extract had almost negligible inhibitory effects on the nine human CYP isoforms tested, with the half-maximal inhibitory concentration value ranged from 3624.99 to 45412.44 µg/ml. The results suggest that BHT extract has no inhibitory effects on CYP isoforms within the clinically recommended dosage range. We conclude that BHT might be free of drug-herb interactions when co-administered with other medicines. However, more in vivo human studies are needed to confirm these results. The high-throughput screening method can be a useful tool for drug discovery and for understanding drug interactions.

Quantile normalization approach for liquid chromatography-mass spectrometry-based metabolomic data from healthy human volunteers.

In metabolomic research, it is important to reduce systematic error in experimental conditions. To ensure that metabolomic data from different studies are comparable, it is necessary to remove unwanted systematic factors by data normalization. Several normalization methods are used for metabolomic data, but the best method has not yet been identified. In this study, to reduce variation from non-biological systematic errors, we applied 1-norm, 2-norm, and quantile normalization methods to liquid chromatography-mass spectrometry (LC-MS)-based metabolomic data from human urine samples after oral administration of cyclosporine (high- and low-dose) in healthy volunteers and compared the effectiveness of the three methods. The principal component analysis (PCA) score plot showed more obvious groupings according to the cyclosporine dose after quantile normalization than after the other two methods and prior to normalization. Quantile normalization is a simple and effective method to reduce non-biological systematic variation from human LC-MS-based metabolomic data, revealing the biological variance.

Single-dose pharmacokinetics and dose proportionality of intravenous pazufloxacin mesilate in healthy Korean volunteers.

OBJECTIVE: The aim of this study was to investigate the pharmacokinetics and dose proportionality of a single, intravenous dose of pazufloxacin mesilate, an injectable fluoroquinolone antibiotic, in healthy Korean male volunteers. METHODS: In this open-label, four-dose, parallel study, subjects were randomized to receive a single dose of pazufloxacin mesilate 300, 500, 600, and 1,000 mg (n = 6, 20, 6, and 8, respectively) administered as a 1-h intravenous infusion. Blood and urine samples were collected serially from 0 to 24 h after drug administration and analyzed using a validated HPLC method. Tolerability was assessed by monitoring clinical laboratory parameters and adverse events. RESULTS: After single-dose intravenous administration of pazufloxacin mesilate, the mean C(max) for groups treated with 300, 500, 600, and 1,000 mg doses ranged from 5.11 to 18.06 µg/mL; the mean AUC(0-t) ranged from 13.70 to 58.60 µg × h/mL. Pazufloxacin exhibits Lack of dose proportionality was concluded over the dose range of 300 - 1,000 mg, based on linear regression model and power model . At all four dosages studied, pazufloxacin mesilate was well tolerated. CONCLUSIONS: Our data suggest that all regimens of pazufloxacin administration were well tolerated. Pazufloxacin exhibits lack of dose proportionality over the dose range of 300 - 1,000 mg.

Assessment of pharmacokinetic proportionality of levofloxacin and cyclosporine over a 100-fold dose range in healthy human volunteers.

OBJECTIVE: Levofloxacin and cyclosporine show different pharmacokinetic properties, but are known to be dose proportional within the therapeutic range. The authors evaluated the pharmacokinetic proportionality of levofloxacin and cyclosporine over a 100-fold dose range in healthy human volunteers, by liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: Two independent, randomized, crossover studies were performed. For levofloxacin, eight volunteers were randomly assigned in a 1:1 ratio to receive a low dose (7.5 mg) orally or intravenously, followed by a 1-week washout period and administration via the alternate route. After another 1-week washout period, a therapeutic dose (750 mg) was administered to all eight subjects. For cyclosporine, another eight volunteers received a low dose (2 mg) or a therapeutic dose (200 mg) orally with a 1-week washout period. Drug concentrations were determined by LC-MS/MS. RESULTS: For levofloxacin, the mean values for dose-normalized C(max) and AUC(last) with the two doses were as follows: therapeutic dose, 15.2 ± 4.6 ng/ml/mg and 103.6 ± 15.5 ng·h/ml/mg, respectively; low dose, 17.1 ± 6.5 ng/ml/mg and 72.6 ± 8.7 ng·h/ml/mg, respectively. For cyclosporine, the mean values for dose-normalized C(max) and AUC(last) were as follows: therapeutic dose, 4.9 ± 1.5 ng/ml/mg and 15.4 ± 4.9 ng·h/ml/mg, respectively; low dose, 1.6 ± 0.6 ng/ml/mg and 9.3 ± 7.3 ng·h/ml/mg, respectively. CONCLUSION: In this study levofloxacin, which is completely absorbed and primarily eliminated renally without modification, showed better pharmacokinetic proportionality than cyclosporine, which is poorly absorbed and extensively metabolized.

A phase I study to characterize the multiple-dose pharmacokinetics, pharmacodynamics and safety of new enteric-coated triflusal formulations in healthy male volunteers.

OBJECTIVES: An enteric-coated formulation of triflusal (triflusal EC), an antiplatelet agent, was developed to reduce the high incidence of gastrointestinal adverse events (AEs). The aim of this study is to compare the pharmacokinetics, pharmacodynamics and safety of triflusal EC with triflusal in healthy Korean male subjects to determine bioequivalence and non-inferiority for the purposes of marketing approval. METHODS: A randomized, open-label, two-period, crossover study was conducted in 38 subjects. Either triflusal EC or triflusal was administered orally as a single 900 mg loading dose (day 1) followed by eight 600 mg/day maintenance doses on days 2 - 9, with a 13-day washout period. The plasma concentrations of 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), the predominant active metabolite of triflusal, were assessed after administration of the loading dose, using HPLC/MS/MS. The platelet aggregation response to arachidonic acid was determined using turbidimetric aggregometry. RESULTS: The 90% CIs, for the geometric mean ratios of the log-transformed AUC(τ) and C(max) of HTB were seen to be within the predetermined range of 0.8 - 1.25. Triflusal EC was also shown to be non-inferior in its anti-aggregatory effect. No serious AEs were reported during this study. CONCLUSIONS: The pharmacokinetic and pharmacodynamic profiles of the two triflusal formulations met the requirements for bioequivalence and non-inferiority, respectively. Both formulations were well tolerated.