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To determine the contribution of the mdr1a gene product to digoxin pharmacokinetics, we constructed a physiologically based pharmacokinetic model for digoxin in mdr1a (-/-) and mdr1a (+/+) mice. After intravenous administration, total body clearance and tissue-to-plasma concentration ratios for muscle and heart were decreased in mdr1a (-/-) mice as compared with mdr1a (+/+) mice, and in particular, the digoxin concentration in the brain was 68-fold higher than that in mdr1a (+/+) mice at 12 h. On the other hand, mdr1a gene disruption did not change the contributions of renal and bile clearances to total clearance, the plasma protein binding, or the blood-to-plasma partition coefficient. Brain concentration-time profiles in mdr1a (+/+) and mdr1a (-/-) mice showed a different pattern from those in plasma and other tissues, indicating digoxin accumulation in the brain tissue. Because there was no difference in the uptake or release of digoxin by brain tissue slices from the two types of mice, we assumed the brain tissue compartment to consist of two parts (a well-stirred part with influx and efflux clearance and an accumulative part). Simulation with this model gave excellent agreement with observation when active efflux clearance across the blood-brain barrier was assumed to be zero in mdr1a (-/-) mice. The observations in other tissues in both types of mice were also well simulated.

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Environmentally benign lead-free ferroelectric (K0.5,Na0.5)(Mn0.005,Nb0.995)O3 (KNMN) thin film capacitors with a small concentration of a BiFeO3 (BF) dopant were prepared by a cost effective chemical solution deposition method for high energy density storage device applications. 6 mol. % BF-doped KNMN thin films showed very slim hysteresis loops with high maximum and near-zero remanent polarization values due to a phase transition from the orthorhombic structure to the pseudo-cubic structure. Increasing the electric field up to 2 MV/cm, the total energy storage density (Jtotal), the effective recoverable energy density (Jeff), and the energy conversion efficiency (η) of lead-free KNMN-BF thin film capacitors were 31.0 J/cm3, 28.0 J/cm3, and 90.3%, respectively. In addition, these thin film capacitors exhibited a fast discharge time of a few μs and a high temperature stability up to 200 °C, proving their strong potential for high energy density storage and conversion applications.

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environmental variations such as isolated places, indoors, and dark surroundings. [1][2][3] The mechanical energy for wearable electronics is more reliable and environmentally independent as well as continuous energy source than the solar or the thermal energy, and it is easily convertible to the electrical energy using electromagnetic induction, [4] triboelectric effect, [5] piezoelectric principle, [6] and so forth. Among them, in particular, triboelectric and/or piezoelectric effect-driven energy devices have drawn much higher attentions for future self-powered electronic system than electromagnetic induction-utilized devices due to simple processes, excellent flexibility, high voltage, and power output as well as easy size-scaling, etc. [5][6][7][8][9][10] Since the output power which can be derived from human motion-related activities mainly depends on the operating frequencies and the degree of deformation (i.e., strain), power generators should be composed of highly flexible and durable materials having robust structures. [6,11,12] Among various flexible substrates, the paper, consisting of multiple cellulose fibers, is identified as the most eco-friendly substrate material with very low cost and excellent recyclability. [12][13][14] Furthermore, the use of paper substrates for flexible devices is potentially beneficial for the Key solutions for material selection, processing, and performance of environmentally friendly high-power generators are addressed. High voltage and high power generation of flexible devices using piezoelectric Bi 0.5 (Na 0.78 K 0.22 ) TiO 3 nanoparticle filler-polydimethylsiloxane (PDMS) elastomeric matrix for a lead-free piezoelectric composite film on a cellulose paper substrate is demonstrated. To elucidate the principle of power generation by the piezoelectric composite configuration, the dielectric and piezoelectric characteristics of the composite film are investigated and the results are compared with those of theoretical modeling. The paper-based composite generator produces a large output voltage of ≈100 V and an average current of ≈20 µA (max. ≈30 µA) through tapping stimulation, which is a record-high performance compared to previously reported flexible lead-free piezoelectric composite energy harvesters. Moreover, a triboelectric-hybridized piezoelectric composite device using a micro-patterned PDMS shows a much higher output voltage of ≈250 V and output power of ≈0.5 mW, which drives 300 light-emitting diodes. These results prove that a new class of paper-based and lead-free energy harvesting device provides a strong possibility for enlarging the functionality and the capability of high-power scavengers in flexible and wearable electronics such as sensors and medical devices.One of the best power sources for the human activity-based self-powered wearable electronic devices is the mechanical energy source because it is easily obtained from biological activities or human motions regardless of the location and the

Summary Sixty-three patients with extensive-stage small-cell lung cancer were randomized to receive either cyclophosphamide, vincristine, doxorubicin and etoposide (CODE) alone or CODE plus recombinant human granulocyte colony-stimulating factor (rhG-CSF). rhG-CSF administration in support of CODE chemotherapy resulted in increased mean total received dose intensity for all drugs (P = 0.03) with a significant improvement in survival (P= 0.004).

The photodegradation products of the anticancer drug, dacarbazine, cause adverse reactions including local venous pain when injected intravenously. In this study, we attempted to identify which of these products is responsible. We synthesized or purchased five photodegradation products of dacarbazine (dimethylamine, 5-diazoimidazole-4-carboxamide (Diazo-IC), 4-carbamoylimidazolium-5-olate, 5-carbamoyl-2-(4-carbamoylimidazol-5-ylazo)imidazolium-5-olate and 2-azahypoxanthine) and examined the pain reaction induced by their intraperitoneal administration in mice using an abdominal stretching or constriction assay. Only Diazo-IC clearly induced pain reaction in mice in a dose-dependent manner, the other products caused no pain reaction. The threshold concentration for pain reaction in mice was estimated to be about 0.1 mg mL-1. While diclofenac sodium significantly reduced acetic-acid-induced pain reaction in mice, it did not influence those induced by Diazo-IC. This result suggests that the mechanism of Diazo-IC-induced pain is different from that of acetic-acid-induced inflammatory pain. Dacarbazine itself produced marked relaxation of rat thoracic aorta strips in a concentration-dependent manner, but there was no difference between the activity of dacarbazine and its photo-exposed solution, so constriction or relaxation of blood vessels is unlikely to be a factor in the pain reaction. In conclusion, Diazo-IC generated by photodegradation of dacarbazine solution causes the side-effect of venous pain. Dacarbazine solution that has turned pink should not be used, because Diazo-IC is an intermediate in the formation of the reddish product, 5-carbamoyl-2-(4-carbamoylimidazol-5-ylazo)imidazolium-5-olate. Drip infusion preparations of dacarbazine should be shielded from light.