OBJECTIVE: Fingolimod is a sphingosine-1-phosphate receptor modulator that prevents lymphocytes egress from lymphoid organs. It has been used as a disease-modifying drug for human multiple sclerosis and has shown better therapeutic effects than other conventional therapies. Therefore, this study was performed to obtain preclinical data of fingolimod in dogs.
METHODS: Nine laboratory Beagle dogs were used and randomized into three groups for pharmacokinetics (PK) and pharmacodynamics (PD). The dogs were administered once with a low-dose (0.01 mg/kg, n=3), medium-dose (0.05 mg/kg, n=3), and high-dose (0.1 mg/kg, n=3) of fingolimod, orally. Samples were collected serially at predetermined time points, and whole blood fingolimod concentrations were measured using high-performance liquid chromatography-mass spectrometry. Differential counts of leukocytes over time were determined to identify immune cells\' response to fingolimod.
RESULTS: Regarding PK, the concentration of fingolimod in the blood increased in a dose-dependent manner, but it was not proportional. Regarding PD, the number of lymphocytes significantly decreased compared to baseline in all dose groups (low-dose, p=0.0002; medium-dose, p<0.0001; high-dose, p=0.0012). Eosinophils were significantly reduced in low- (p=0.0006) and medium- (p=0.0006) doses, and neutrophils were also significantly reduced in medium-(p=0.0345) and high- (p=0.0016) doses.
CONCLUSIONS: This study provides the basis for future clinical applications of fingolimod in dogs with immune-mediated diseases, such as meningoencephalitis of unknown etiology.

Passive exposure to the aerosols of electronic cigarettes (e-cigarettes) has been little studied. We assessed this exposure in late pregnancy in a woman and her 3-year-old child, exposed through e-cigarette use by another household member.
This prospective longitudinal case study involved a family unit consisting of an e-cigarette user, a pregnant woman who delivered an infant during the study, and the couple\'s older 3-year-old son. At 31, 36, and 40 weeks of the pregnancy, we measured biomarkers (nicotine metabolites, tobacco-specific nitrosamines, propanediols, glycerol, and metals) in the urine and hair of all three participants and in the saliva of the adults, in cord blood at delivery, and in the breast milk at the postpartum period.
Samples from the e-cigarette user showed quantifiable concentrations of all analytes assessed (maximum urinary cotinine concentration, 4.9 ng/mL). Among samples taken from the mother, nicotine and its metabolites were found mainly in urine and also in saliva and hair, but not in cord blood. During the postpartum period, we found cotinine concentrations of 2.2 ng/mL in the mother\'s urine and 0.22 ng/mL in breast milk; 1,2-propanediol was generally detected in urine and saliva, but not in cord blood or breast milk. The maximum urinary cotinine concentration in the 3-year-old child was 2.6 ng/mL and propanediols also were detected in his urine. Nitrosamines were not detected in samples taken from the mother or the 3-year-old. Metals found in the refill liquid were detected at low levels in both the mother and the 3-year-old.
We detected low but not negligible concentrations of e-cigarette-related analytes (including cord blood and breast milk) in an exposed pregnant non-user and in a 3-year-old child also living in the home. Passive exposure to e-cigarette aerosols cannot be disregarded and should be assessed in larger observational studies.

BACKGROUND: The European baseline series (EBS) of contact allergens is subject to change. An allergen is considered for inclusion when routine patch testing of patients with suspected contact dermatitis results in ≥0.5% prevalence rate.
OBJECTIVE: We aimed to determine the frequency of sensitizations to 30 EBS allergens and 10 locally added allergens. Additionally, we assessed the strength and evolution of reactions to all tested allergens and co-reactivity of additional allergens.
METHODS: Patch testing with our baseline series of 40 allergens was done in 748 consecutive adults. Tests were applied to the upper back and removed by patients after 48 h. Readings were done on Day 3 (D3) and D6 or D7 (D6/7). Positive reactions fulfilled the criteria of at least one plus (+) reaction. A retrospective analysis was done.
RESULTS: Eight allergens not listed in the EBS had ≥0.5% prevalence rate (i.e., cocamidopropyl betaine, thiomersal, disperse blue mix 106/124, 2-bromo-2-nitropropane-1,3-diol, diazolidinyl urea, propylene glycol, Compositae mix II and dexamethasone-21-phosphate), and 16.6% of positive reactions would have been missed without D6/7 readings.
CONCLUSIONS: We propose further studies to evaluate whether cocamidopropyl betaine, disperse blue mix 106/124, 2-bromo-2-nitropropane-1,3-diol, diazolidinyl urea and Compositae mix II need to be added to the EBS.

The use of cisplatin is restricted by systemic toxicity and drug resistance. Supramolecular nano-drug delivery systems involving drugs as building blocks circumvent these limitations promisingly. Herein, we describe a novel supramolecular system [Pt(IV)-SSNPs] based on poly(β-cyclodextrin), which was synthesized for efficient loading of adamantly-functionalized platinum(IV) prodrug [Pt(IV)-ADA2] via the host-guest interaction between β-cyclodextrin and adamantyl. Pt(IV)-ADA2 can be converted to active cisplatin in reducing environment in cancer cells, which further reduces systemic toxicity. The introduction of the adamantane group-tethered mPEG2k endowed the Pt(IV)-SSNPs with a longer blood circulation time. In vitro assays exhibited that the Pt(IV)-SSNPs could be uptaken by CT26 cells, resulting in cell cycle arrest in the G2/M and S phases, together with apoptosis. Furthermore, the Pt(IV)-SSNPs showed effective tumor accumulation, better antitumor effect, and negligible cytotoxicity to major organs. These results indicate that supramolecular nanoparticles are a promising platform for efficient cisplatin delivery and cancer treatment.

Disturbed sleep can cause to m health problems such as cognitive impairment, depressed mood, and negative effects on cardiovascular, endocrine, and immune function. This study formulates and optimizes Eszopiclone trilaminate fast dissolving film.
Prepared Eszopiclone trilaminate fast dissolving film (Eszopiclone TFDF) was characterized by disintegration time, drug release, tensile strength (TS), percentage elongation (EB%), folding endurance, taste masking test, and in vitro dissolution test. The selected formulas were F2 (0.5% xanthan gum, 10% propylene glycol), F4 (3% sodium alginate, 10% propylene glycol) and F6 (1.5% pullulan, 10% propylene glycol) were subjected to in vivo study compared to conventional Lunesta® tablet.
The results indicated that disintegration time was in the range of 940 m. Drug release was found to be in the field of 78.51%-99.99%, while TS values and EB% differed from 11.12 to 25.74 (MPa) and 25.38%-36.43%, respectively. The folding endurance went between 200 and 300 times. All formulas exhibited acceptable uniformity content, surface pH, film thickness, and a good taste feeling.
F4 had the highest Cmax (39.741 ± 6.785-μg/l) and lower Tmax (1.063 hr) among other formulas and conventional tablets. Therefore, FDFs\' technology could increase the therapeutic effect of Eszopiclone.

A hydrazone (T1) was synthesized by reacting 8-hydroxyjulolidine-9-carboxaldehyde with 2-furoic hydrazide and then modified with Al3+ ion to form a novel hydrazone Al3+ complex (T1-Al3+) in an aqueous solution (8% propylene glycol in 10 mM HEPES pH 5.5). The T1-Al3+ complex was studied as a Cu2+ selective sensor due to its highly efficient capacibility of paramagnetic quenching. The results showed that the T1-Al3+ complexed sensor possesses remarkable sensitivity and selectivity for Cu2+ ion in 8% propylene glycol in 10 mM HEPES pH 5.5 as compared with other tested analytes. Notably, this sensor has a broad linear detection range of 10-110 µM for Cu2+ ion and a detection limit level of 0.62 µM, which is lower than the Cu2+ concentration threshold in drinking water designated by the United States Environmental Protection Agency (EPA). Additionally, it was detectable for the presence of Cu2+ ion in mineral water and tap water samples. The selectivity of T1-Al3+ complexed sensor with Cu2+ ion could be explained by the basis of computation with Gaussian software complied with the basis sets of B3LYP/6-31 G(d,p)/LANL2DZ. Furthermore, only T1 exhibited anticancer efficacy against HeLa and U251 cells with MTT assay.

Thermo-responsive behavior of ethylene oxide (EO)-propylene oxide (PO) copolymers makes them suitable for many potential applications. Reproducing the origins of the tunable properties of EO-PO copolymers using coarse-grained (CG) models such as the MARTINI force field is critically important for building a better understanding of their behavior. In the present work, we have investigated the effects of coarse-graining on the water-polymer interaction across a temperature range. We compared the performance of different all-atom force fields to find the most appropriate one for the purpose of PO block parameterization in the MARTINI platform. We parameterized a CG temperature-dependent PO model based on the reproduction of the atomistic free energy of transfer of propylene oxide trimer from octane to water over a range of temperatures (20-60 °C) and compared the atomistic bond and angle distributions. Then, we used the model to study the effects of EO/PO ratio, molecular weight, and concentration on the thermo-responsive behavior of EO-PO copolymers in water. The results show an excellent agreement with experiments in different areas. Our temperature-dependent model reproduces (1) micellar phase above critical micelle temperature (CMT) and unimer phase below CMT for different Pluronics (a class of EO-PO triblock copolymers) spanning many EO/PO ratios and molecular weights; (2) spherical-to-rodlike micellar shape transition for Pluronics with 60 wt % of PO content or more; (3) diffusion coefficients for Pluronics with high PO content (P104 Pluronic with a PO mass of 3500 g mol-1) across a broad range of temperatures; and (4) micelle core size and micelle diameter similar to experimental results. Overall, our model improves the temperature sensitivity of EO-PO copolymers of existing models significantly, particularly for copolymers that are dominated by PO agents.

We previously demonstrated that lubrication of an endotracheal tube (ETT) cuff with K-Y™ jelly strongly and significantly inhibited the increase in cuff pressure during nitrous oxide (N2O) exposure in vitro. However, in our previous study, we identified critical differences between some influential factors, such as the amount of lubricant retained on the cuff, and studied temperature differences between laboratory and clinical conditions. Therefore, it remained unclear whether this effect holds true in clinical settings.
We first sought to study how changes in the amount of K-Y™ jelly and temperature influence the inhibitory effects of the lubricant on the increase in N2O-induced cuff pressure in vitro. Furthermore, we aimed to determine whether the application of K-Y™ jelly inhibits the increase in ETT cuff pressure during general anesthesia using N2O in adult patients.
In the laboratory studies, we found that K-Y™ jelly inhibited the cuff pressure increase dose-dependently when the dose of K-Y™ jelly was varied (P = 0.02), and that such an inhibitory effect decreased with an increase in the studied temperature (P = 0.019). In the clinical study, lubrication with K-Y™ jelly slightly, but significantly, delayed the increase in ETT cuff pressure during general anesthesia with N2O (P = 0.029). However, the inhibitory effect in the clinical settings was smaller than that in vitro.
Lubrication of the ETT cuff with K-Y™ jelly may delay the increase in cuff pressure during general anaesthesia with N2O. However, the clinical significance of this effect may be limited.
UMIN Clinical Trials Registry: UMIN000031377 on March 1, 2019.

Nano-emulgel has become one of the most significant controlled release systems, which has the advantages of both gels and nano-emulsions. This work aims at the formulation of nasal nano-emulgel for resveratrol, employing carbopol 934 and poloxamer 407 as the gelling agents. The optimum nano-emulsion was determined through further characterization of the selected system. The nasal nano-emulgel was prepared and tested for the in vitro release, the release kinetics, FTIR, ex vivo permeation, nasal mucosa toxicity, and in vivo pharmacokinetic study. The optimum nano-emulsion consisted of Tween 20, Capryol 90, and Transcutol at a ratio of (54.26: 23.81: 21.93%v/v), and it exhibited transmittance of 100%, resveratrol solubility of 159.9 ± 6.4 mg/mL, globule size of 30.65 nm. The in vitro resveratrol released from nano-emulsion and nasal nano-emulgel was 96.17 ± 4.43% and 78.53 ± 4.7%, respectively. Ex vivo permeation was sustained during 12 h up to 63.95 ± 4.7%. The histopathological study demonstrated that the formula is safe and tolerable to the nasal mucosa. Cmax and AUC (0-∞) of resveratrol obtained after nasal administration of nasal nano-emulgel was 2.23 and 8.05 times, respectively. Similarly, Tmax was increased up to 3.67 ± 0.82 h. The optimized nasal nano-emulgel established intranasal safety and bioavailability enhancement so it is considered as a well-designed system to target the brain.

OBJECTIVE: This study aimed to demonstrate the efficacy and safety of a newly developed elastomeric sealant, which does not require any blood coagulation system to exert its effect, during thoracic aortic surgery.
METHODS: This is a multicenter, randomized study conducted in six hospitals in Japan. A total of 81 patients undergoing replacement surgery of a thoracic aortic aneurysm using cardiopulmonary bypass were randomized with a ratio of 2-:1 for those patients designated to receive the sealant (Group S, 54 patients) or those without the usage of the sealant (Group C, 27 patients). The primary endpoints were bleeding from each anastomosis at two time points: (1) immediately before applying protamine and (2) 15 min after applying protamine. The patients were followed for 6 months.
RESULTS: The number of anastomoses checked for bleeding was 196 in Group S and 117 in Group C. Before protamine sulfate administration, complete hemostasis was obtained in 155 anastomoses (79%) in Group S compared to 45 anastomoses (38%) in Group C (p < 0.001). Fifteen minutes after the administration of protamine sulfate infusion, bleeding stopped completely in 173 anastomoses (88%) in Group S and in 71 anastomoses (61%, p < 0.001) in Group C. Between the two groups, there were no marked differences in the patient background or in the incidence of major adverse events.
CONCLUSIONS: The sealant is effective in achieving hemostasis, even under fully heparinized conditions. The novel sealant is safe and effective in thoracic aortic surgery, one of the most demanding surgical situations for hemostasis.