An acute herb-drug interaction of Magnoliae Officinalis Cortex with methotrexate via inhibiting multidrug resistance-associated protein 2.

Magnoliae Officinalis Cortex (MOC), an herbal drug, contains polyphenolic lignans mainly magnolol (MN) and honokiol (HK). Methotrexate (MTX), a critical drug for cancers and autoimmune deseases, is a substrate of multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). This study investigated the effect of coadministration of MOC on the pharmacokinetics of MTX and relevant mechanisms. Sprague-Dawley rats were orally administered MTX alone and with single dose (2.0 and 4.0 g/kg) and repeated seven doses of MOC (2.0 g/kg thrice daily for 2 days, the 7th dose given at 0.5 h before MTX). The serum concentrations of MTX were determined by a fluorescence polarization immunoassay. The results showed that a single dose of MOC at 2.0 g/kg significantly increased the AUC0-t and MRT of MTX by 352% and 308%, and a single dose at 4.0 g/kg significantly enhanced the AUC0-t and MRT by 362% and 291%, respectively. Likewise, repeated seven doses of MOC at 2.0 g/kg significantly increased the AUC0-t and MRT of MTX by 461% and 334%, respectively. Mechanism studies indicated that the function of MRP2 was significantly inhibited by MN, HK and the serum metabolites of MOC (MOCM), whereas BCRP was not inhibited by MOCM. In conclusion, coadministration of MOC markedly enhanced the systemic exposure and mean residence time of MTX through inhibiting the MRP2-mediated excretion of MTX.

Therapeutic effects of methimazole on 3,4-methylenedioxymethamphetamine-induced hyperthermia and serotonergic neurotoxicity.

3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug, however over 200 studies demonstrate that acute (e.g. hyperthermia, rhabdomyolysis) and chronic (e.g. neurotoxicity) toxicity effects of MDMA were observed in different animals. Methimazole (MMI), an inhibitor of thyroid hormone synthesis, was found to significantly reduce the HSP72 expression of heat stress induced in fibroblasts. Hence, we attempted to understand the effects of MMI on MDMA induced changes in vivo. Male SD rats were randomly divided into four groups as follows:(a) water-saline (b) water-MDMA (c) MMI-saline and (d) MMI-MDMA group. In the temperature analysis test, MMI was found to alleviate MDMA-induced hyperthermia and increase the heat loss index (HLI), revealing its peripheral vasodilation effect. PET experiment suggested that MDMA induced elevated glucose uptake by skeletal muscles, which was resolved by MMI pretreatment. IHC staining (serotonin transporter, SERT) showed the evidence of neurotoxicity caused by MDMA (serotonin fiber loss), which was alleviated by MMI. Furthermore, the animal behaviour test (forced swimming test, FST) showed higher swimming time but lower immobility time in MMI-MDMA and MMI-saline groups. Taken together, treatment of MMI shows benefits such as lowered body temperature, alleviation of neurotoxicity and excited behaviour. However, further investigations should be conducted in the future to provide in-depth evidence for its clinical use.

Neuronal dynamics in HfOx/AlOy-based homeothermic synaptic memristors with low-power and homogeneous resistive switching.

We studied the pseudo-homeothermic synaptic behaviors by integrating complimentary metal-oxide-semiconductor-compatible materials (hafnium oxide, aluminum oxide, and silicon substrate). A wide range of temperatures, from 25 °C up to 145 °C, in neuronal dynamics was achieved owing to the homeothermic properties and the possibility of spike-induced synaptic behaviors was demonstrated, both presenting critical milestones for the use of emerging memristor-type neuromorphic computing systems in the near future. Biological synaptic behaviors, such as long-term potentiation, long-term depression, and spike-timing-dependent plasticity, are developed systematically, and comprehensive neural network analysis is used for temperature changes and to conform spike-induced neuronal dynamics, providing a new research regime of neurocomputing for potentially harsh environments to overcome the self-heating issue in neuromorphic chips.

Scaling Effect on Silicon Nitride Memristor with Highly Doped Si Substrate.

A feasible approach is reported to reduce the switching current and increase the nonlinearity in a complementary metal-oxide-semiconductor (CMOS)-compatible Ti/SiNx /p+ -Si memristor by simply reducing the cell size down to sub-100 nm. Even though the switching voltages gradually increase with decreasing device size, the reset current is reduced because of the reduced current overshoot effect. The scaled devices (sub-100 nm) exhibit gradual reset switching driven by the electric field, whereas that of the large devices (≥1 µm) is driven by Joule heating. For the scaled cell (60 nm), the current levels are tunable by adjusting the reset stop voltage for multilevel cells. It is revealed that the nonlinearity in the low-resistance state is attributed to Fowler-Nordheim tunneling dominating in the high-voltage regime (≥1 V) for the scaled cells. The experimental findings demonstrate that the scaled metal-nitride-silicon memristor device paves the way to realize CMOS-compatible high-density crosspoint array applications.

Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study.

Quercetin (Que) is known to have biological benefits including an anticancer effect, but low water solubility limits its clinical application. The aim of this study was to develop a lecithin-based mixed polymeric micelle (LMPM) delivery system to improve the solubility and bioavailability of Que. The optimal Que-LMPM, composed of Que, lecithin, Pluronic(®) P123, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy[poly(ethylene glycol)-2000] in a proportion of 3:1:17.5:2.5 (w/w), was prepared by a thin-film method. The average size, polydispersion index, encapsulating efficiency, and drug loading of Que-LMPM were 61.60 ± 5.02 nm, 0.589 ± 0.198, 96.87% ± 9.04%, and 12.18% ± 1.11%, respectively. The solubility of Que in the Que-LMPM system increased to 5.81 mg/mL, compared to that of free Que in water of 0.17-7.7 µg/mL. The Que-LMPM system presented a sustained-release property in vitro. The in vitro cytotoxicity assay showed that the 50% inhibitory concentration values toward MCF-7 breast cancer cells for free Que, blank LMPMs, and Que-LMPMs were >200, >200, and 110 µM, respectively, indicating the nontoxicity of the LMPM carrier, but the LMPM formulation enhanced the cytotoxicity of Que against MCF-7 cells. A cellular uptake assay also confirmed the intake of Que-LMPM by MCF-7 cells. An in vivo pharmacokinetic study demonstrated that Que-LMPMs had higher area under the concentration-time curve and a longer half-life, leading to better bioavailability compared to a free Que injection. Due to their nanosize, core-shell structure, and solubilization potential, LMPMs were successfully developed as a drug delivery system for Que to improve its solubility and bioavailability.

Improving the Stability of Astaxanthin by Microencapsulation in Calcium Alginate Beads.

There has been considerable interest in the biological functions of astaxanthin and its potential applications in the nutraceutical, cosmetics, food, and feed industries in recent years. However, the unstable structure of astaxanthin considerably limits its application. Therefore, this study reports the encapsulation of astaxanthin in calcium alginate beads using the extrusion method to improve its stability. This study also evaluates the stability of the encapsulated astaxanthin under different storage conditions. The evaluation of astaxanthin stability under various environmental factors reveals that temperature is the most influential environmental factor in astaxanthin degradation. Stability analysis shows that, regardless of the formulation used, the content of astaxanthin encapsulated in alginate beads remains above 90% of the original amount after 21 days of storage at 25°C. These results suggest that the proposed technique is a promising way to enhance the stability of other sensitive compounds.

Physical characterization and in vivo pharmacokinetic study of self-assembling amphotericin B-loaded lecithin-based mixed polymeric micelles.

To alleviate the inherent problems of amphotericin B (AmB), such as poor water solubility and nephrotoxicity, a novel self-assembling mixed polymeric micelle delivery system based on lecithin and combined with amphiphilic polymers, Pluronic(®), Kolliphor(®), d-alpha tocopheryl polyethylene glycol succinate, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(poly(ethylene glycol)-2000 (DSPE-PEG2K) was developed. An optimal formulation (Ambicelles) composed of AmB:lecithin:DSPE-PEG2K in a 1:1:10 weight ratio was obtained. The particle size, polydispersion index, drug encapsulation efficiency, and drug loading were 187.20±10.55 nm, 0.51±0.017, 90.14%, and 7.51%, respectively, and the solubility was increased from 0.001 to 5 mg/mL. Compared with that of Fungizone(®), the bioavailability of Ambicelles administered intravenously and orally increased 2.18- and 1.50-fold, respectively. Regarding the in vitro cytotoxicity, Ambicelles had a higher cell viability than free AmB solution or Fungizone(®) did. With pretreatment of 50 µg/mL ethanolic extract of Taiwanofungus camphoratus followed by AmB to HT29 colon cancer cells, the 50% inhibitory concentration of AmB solution was 12 µg/mL, whereas that of Ambicelles was 1 µg/mL, indicating that Ambicelles exerted a greater synergistic anticancer effect.

Formulation and process optimization of multiparticulate pulsatile system delivered by osmotic pressure-activated rupturable membrane.

In this study, a multiparticulate pulsatile drug delivery system activated by a rupturable controlled-release membrane (Eudragit(®) RS) via osmotic pressure (with NaCl as the osmogent) was developed and characterized for omeprazole, omeprazole sodium, and propranolol HCl which have different water solubilities. Multiparticulates in pellet form for incorporation with or without the osmogent were manufactured by three methods and then used to coat a polymeric membrane. Results demonstrated that drug/osmogent-containing pellets manufactured by the extrusion/spheronization method with incorporation of the osmogent were optimal. The lag time (tL) to initiate pulsatile release is regulated by tL=l(2)/(6×D), which is dependent on the coating levels (l(2)) and plasticizer content (D). The pulsatile release pattern was found to be dependent on the osmotic pressure (osmogent), drug solubility, and mechanical properties of the polymeric membrane (elasticity and toughness). Omeprazole with lower water solubility could not generate sufficient osmotic pressure to create a crack in the membrane to activate pulsatile release, whereas the two other model drugs with higher solubilities could. But adsorption of omeprazole sodium on Eudragit(®) RS via charge-charge interactions led the its incomplete release. Finally, with 4% osmogent of NaCl added, a lag time in a range from 0 to 12h proportionally regulated by varying both the membrane thickness and plasticizer level initiated the complete pulsatile release of propranolol HCl. In conclusion, a multiparticulate pulsatile drug delivery system activated by a rupturable controlled-release membrane via osmotic pressure was successfully developed, and clinical applications of chronotherapy with drugs like propranolol HCl are expected.

Pharmacokinetics, bioavailability, and tissue distribution of magnolol following single and repeated dosing of magnolol to rats.

Magnolol (M) is a polyphenol antioxidant abundant in the bark of Magnolia officinalis Rehder & E. Wilson, a popular Chinese herb. To understand the pharmacokinetics and bioavailability of M, Sprague-Dawley rats were intravenously injected with a bolus of M (20 mg/kg) and orally given a single dose and seven doses of M (50 mg/kg). Blood samples were withdrawn via cardiopuncture at specific times. Organs including the liver, kidney, brain, lung, and heart were collected at 30 min after the 7th oral dose. The serum and tissue specimens were assayed by HPLC before and after hydrolysis with ß-glucuronidase and sulfatase. The results showed that after intravenous bolus, the systemic exposure of magnolol glucuronides (MG) was comparable with that of M while after oral administration, magnolol sulfates/glucuronides (M S/G) were predominant in the bloodstream. Conversely, M was predominant in the liver, kidney, brain, lung, and heart. Among the studied organs, the liver contained the highest concentrations of M and MG. In conclusion, M S/G was the major form in circulation, whereas M was predominant in the liver, kidney, brain, lung, and heart after oral administration of M; among these organs, the liver contained the highest concentrations of M and MG.