CO2-Selective Nanoporous Metal-Organic Framework Microcantilevers.

Nanoporous anodic aluminum oxide (AAO) microcantilevers are fabricated and MIL-53 (Al) metal-organic framework (MOF) layers are directly synthesized on each cantilever surface by using the aluminum oxide as the metal ion source. Exposure of the MIL53-AAO cantilevers to various concentrations of CO2, N2, CO, and Ar induces changes in their deflections and resonance frequencies. The results of the resonance frequency measurements for the different adsorbed gas molecules are almost identical when the frequency changes are normalized by the molecular weights of the gases. In contrast, the deflection measurements show that only CO2 adsorption induces substantial bending of the MIL53-AAO cantilevers. This selective deflection of the cantilevers is attributed to the strong interactions between CO2 and the hydroxyl groups in MIL-53, which induce structural changes in the MIL-53 layers. Simultaneous measurements of the resonance frequency and the deflection are performed to show that the diffusion of CO2 into the nanoporous MIL-53 layers occurs very rapidly, whereas the binding of CO2 to hydroxyl groups occurs relatively slowly, which indicates that the adsorption of CO2 onto the MIL-53 layers and the desorption of CO2 from the MIL-53 layers are reaction limited.

Electronic nose based on multipatterns of ZnO nanorods on a quartz resonator with remote electrodes.

An electrodeless monolithic multichannel quartz crystal microbalance (MQCM) sensor was developed via the direct growth of ZnO nanorod patterns of various sizes onto an electrodeless quartz crystal plate. The patterned ZnO nanorods acted as independent resonators with different frequencies upon exposure to an electric field. The added mass of ZnO nanostructures was found to significantly enhance the quality factor (QF) of the resonator in electrodeless QCM configuration. The QF increased with the length of the ZnO nanorods; ZnO nanorods 5 µm in length yielded a 7-fold higher QF compared to the QF of a quartz plate without ZnO nanorods. In addition, the ZnO nanorods offered enhanced sensitivity due to the enlarged sensing area. The developed sensor was used as an electronic nose for detection of vapor mixtures with impurities.

Quartz resonator for simultaneously measuring changes in the mass and electrical resistance of a polyaniline film.

A novel quartz resonator was developed to measure, simultaneously, changes in the mass and electrical resistance of a polyaniline film during the absorption of water vapor. Interdigitated gold electrodes were vacuum-deposited on the sensing surfaces of the quartz crystals, and polyaniline films were drop-cast on the electrodes used to measure the changes in the electrical resistance. Two symmetric semicircular gold electrodes were deposited on the bottom surface of the quartz crystal. These electrodes were used to measure the changes in the mass of absorbed water based on the changes in the resonance frequency. The simultaneous measurements of mass and electrical resistance shed light on the interactions between the water vapor and the polyaniline film. The resonator was exposed to various organic gases, including ethanol, acetone, or chloroform, and each gas was found to produce characteristic changes in the normalized electrical resistance.

Phase transitions between the rotator phases of paraffin investigated using silicon microcantilevers.

Nanogram amounts of paraffin were coated onto a silicon cantilever, and the resonance frequency and deflection of the cantilever were measured as a function of temperature. Changes in the cantilever resonance frequency were used to determine the temperatures at which phase transitions between the rotator phases of tricosane, tetracosane, and pentacosane occurred. The phase transition measured using the cantilever was found to be more apparent than that obtained using conventional methods. The thermal hysteresis in the resonance frequency of a tetracosane-coated cantilever differed from that of the tricosane- and pentacosane-coated cantilevers, which was attributed to the even-odd effect on the crystal structures of paraffin. The even-odd effect was also observed in the temperature dependent deflection measurements. Further, the overshoot at the transition R(V) → crystal in the deflection measurement was observed and attributed to the steep increase in the modulus of paraffin during the transition.

Development of docetaxel-loaded intravenous formulation, Nanoxel-PM™ using polymer-based delivery system.

Nanoxel-PM™, docetaxel-loaded methoxy-poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PDLLA) micellar formulation was prepared in an effort to develop alternative, less toxic and efficacious Tween 80-free docetaxel formulation, and its pharmacokinetics, efficacy, and toxicity were evaluated in comparison with Taxotere® in preclinical studies. The mean diameter of the Nanoxel-PM™ was 10-50 nm and the polydispersity of samples exhibited a narrow size distribution and monodisperse unimodal pattern. Pharmacokinetic study in mice, rats and beagle dogs revealed that Nanoxel-PM™ exhibited similar pharmacokinetic profiles (C(max), AUC, t(1/2), CL, V(ss)) to Taxotere, and the relative mean AUC(t) and C(max) of Nanoxel-PM™ to Taxotere® were within 80-120%. Furthermore, excretion study in rats demonstrated that there was no statistically significant difference in the amount excreted in feces or urine as an unmetabolized docetaxel between Nanoxel-PM™ and Taxotere®. Its pharmacokinetic bioequivalence resulted in comparable anti-tumor efficacy to Taxotere® in human lung cancer xenografts H-460 in nude mice as well as in lung, ovary and breast cancer cell lines. Several animal toxicity studies on Nanoxel-PM™ compared with Taxotere® were carried out. In single dose rat and dog model and repeated dose mouse model, both Nanoxel-PM™ and Taxotere® exhibited similar toxic effects on hematology and body weight gain. On the other hand, vehicle related hypersensitivity reactions and fluid retentions were not observed when Nanoxel-PM™ was administered, unlike Taxotere®, in the beagle dog study. Based on these results, it is expected that Nanoxel-PM™ can reduce side effects of hypersensitivity reactions and fluid retention while retaining antitumor efficacy in cancer patients. Currently, Nanoxel-PM™ is under evaluation for bioequivalence with Taxotere® in a multi-center, open-label, randomized, crossover study.

Microthermogravimetry of a single microcapsule using silicon microresonators.

A chlorobenzene-containing polyurethane microcapsule was placed on the free end of a silicon cantilever, and the temperature dependence of the resonance frequency was measured. As the cantilever was heated, the resonance frequency showed steplike increases at 109 and 270 degrees C that were due to the rupture of the capsule and the thermal degradation of the polyurethane shell, respectively. The frequency changes due to the rupture of a single capsule measured by the cantilever were much sharper than the transitions measured by conventional thermogravimetric analysis (TGA), which measures the average mass change of a collection of capsules characterized by a large size distribution. When two capsules were placed on the cantilever, their individual rupture temperatures could be clearly identified. In addition, the permeability of the polyurethane shell, with respect to chlorobenzene, was measured, and the rupture temperature was observed to decrease with increasing permeability.

Pharmacokinetic/pharmacodynamic modeling of the cardiovascular effects of beta blockers in humans.

Pharmacokinetic-pharmacodynamic (PK/PD) analysis is useful study in clinical pharmacology, also PK/PD modeling is major tools for PK/PD analysis. In this study, we sought to characterize the relationship between the cardiovascular effects and plasma concentrations of the beta blocker drugs carvedilol and atenolol using PK/PD modeling in healthy humans. One group received oral doses of atenolol (50 mg) and the other group received oral doses of carvedilol (25 mg). Subsequently, blood samples were taken, and the effects of the drugs on blood pressure were determined. Plasma concentrations of drugs were measured by HPLC, and PK/PD modeling performed by applied biophase model, plasma drug concentrations were linked to the observed systolic blood pressure (SBP) and diastolic blood pressure (DBP) via an effect compartment. The model parameters were estimated using the ADAPT II program. In PK/PD analysis, it was observed the time delay between plasma concentration and effect and the time delay between SBP and DBP. The two time delays were properly explained by PD parameter "Keo" in applied biophase model. As conclusion, the biophase PK/PD model described the relationship between the plasma concentrations of the drugs and the cardiovascular effects, including the time delay between systolic blood pressure and diastolic blood pressure.

Bioequivalence and pharmacokinetics of 70 mg alendronate sodium tablets by measuring alendronate in plasma.

The bioequivalence and pharmacokinetics of alendronate sodium tablets were examined by determining the plasma concentration of alendronate. Two groups, consisting of 24 healthy volunteers, each received a 70 mg reference alendronate sodium tablet and a test tablet in a 2x2 crossover study. There was a 6-day washout period between doses. The plasma alendronate concentration was monitored for 7 h after the dose, using HPLC-Fluorescence Detector (FD). The area under the plasma concentration-time curve from time 0 to the last sampling time at 7 h (AUC(0-7h) was calculated using the linear-log trapezoidal rule. The maximum plasma drug concentration (Cmax) and the time to reach Cmax (Tmax) were derived from the plasma concentration-time data. Analysis of variance was performed using logarithmically transformed AUC(0-7h) and Cmax, and untransformed Tmax. For the test medication versus the reference medication, the AUC(0-7h) were 87.63 +/- 29.27 vs. 102.44 +/- 69.96 ng x h x mL(-1) and the Cmax values were 34.29 +/- 13.77 vs. 38.47 +/- 24.39 ng x mL(-1), respectively. The 90% confidence intervals of the mean differences of the logarithmic transformed AUC(0-7h) and Cmax values were log 0.8234-log 1.1597 and log 0.8222-log 1.1409, respectively, satisfying the bioequivalence criteria guidelines of both the U.S. Food and Drug Administration and the Korea Food and Drug Administration. The other pharmacokinetic parameters for the test drug versus reference drug, respectively, were: t(1/2), 1.87 +/- 0.62 vs. 1.77 +/- 0.54 h; V/F, 2061.30 +/- 986.49 vs. 2576.45 +/- 1826.05 L; CL/F, 835.32 +/- 357.35 vs. 889.48 +/- 485.87 L x h(-1); K(el), 0.42 +/- 0.14 vs. 0.40 +/- 0.18 h(-1); Ka, 4.46 +/- 3.63 vs. 3.80 +/- 3.64 h(-1); and Tlag, 0.19 +/- 0.09 vs. 0.18 +/- 0.06 h. These results indicated that two alendronate formulations (70-mg alendronate sodium) were biologically equivalent and can be prescribed interchangeably.

High-performance liquid chromatography method for determining alendronate sodium in human plasma by detecting fluorescence: application to a pharmacokinetic study in humans.

A high-performance liquid chromatographic (HPLC) method was developed using diethylamine (DEA) solid-phase extraction (SPE), 9-fluorenylmethyl derivative (FMOC) and fluorescence detection for quantifying alendronate in human plasma. Sample preparation involved a manual protein precipitation with trichloroacetic acid, a manual coprecipitation of the bisphosphonate with calcium phosphate and derivatization with 9-fluorenylmethyl chloroformate in citrate buffer at pH 11.9. Liquid chromatography was performed on a Capcell Pak C(18) column (4.6 mm x 150 mm, 5 microm particles), using a gradient method starting with mobile phase acetonitrile/methanol-citrate/pyrophosphate buffer (32:68, v/v). The total run time was 25 min. The fluorometric detector was operated at 260 nm (excitation) and 310 nm (emission). Pamidronate was used as the internal standard. The limit of quantification was 1 ng/ml using 3 ml of plasma. The intra- and inter-day precision expressed as the relative standard deviation was less than 15%. The assay was applied to the analysis of samples from a pharmacokinetic study. Following the oral administration of 70 mg of alendronate sodium to volunteers, the maximum plasma concentration (C(max)) and elimination half-life were 40.94 +/- 19.60 ng/ml and 1.67 +/- 0.50 h, respectively. The method was demonstrated to be highly feasible and reproducible for pharmacokinetic studies including bioequivalence test of alendronate sodium in humans.

Pharmacokinetics and bioequivalence of haloperidol tablet by liquid chromatographic mass spectrometry with electrospray ionization.

The purpose of this study is to investigate the bioequivalence of two haloperidol 5 mg tablets, Myung In haloperidol (Myung In Pharm. Co., Ltd., test drug) and Peridol (Whanin Pharm. Co., Ltd., reference drug), and also to estimate the pharmacokinetic parameters of haloperidol in Korean volunteers. The bioavailability and pharmacokinetics of haloperidol tablets were examined on 24 healthy volunteers who received a single oral dose of each preparation in the fasting state in a randomized balanced 2 way crossover design. After an oral dosing, blood samples were collected for a period of 60 h. Plasma concentrations of haloperidol were determined using a liquid chromatographic electrospray mass spectrometric (LC-MS) method. The pharmacokinetic parameters were calculated with noncompartmental pharmacokinetic analysis. The geometric means of AUC0-60h and Cmax between test and reference formulations were 17.21 +/- 8.26 ng x h/mL vs 17.31 +/- 13.24 ng x h/mL and 0.87 +/- 0.74 ng/mL vs 0.85 +/- 0.62 ng/mL, respectively. The 90% confidence intervals of mean difference of logarithmic transformed AUC0-60h and Cmax were log0.9677 - log1.1201 and log0.8208-log1.1981, respectively. It shows that the bioavailability of test drug is equivalent with that of reference drug. The geometric means of other pharmacokinetic parameters (AUCinf, t1/2, Vd/F, and CL/F) between test drug and reference drug were 21.75 +/- 8.50 ng x h/mL vs 21.77 +/- 15.63 ng x h/mL, 29.87 +/- 8.25 h vs 29.60 +/- 7.56 h, 11.51 +/- 5.45 L vs 12.90 +/- 6.12 L and 0.26 +/- 0.09 L/h vs 0.31 +/- 0.17 L/h, respectively. These observations indicate that the two formulation for haloperidol was bioequivalent and, thus, may be clinically interchangeable.

Pharmacokinetic and pharmacodynamic characterization of gliclazide in healthy volunteers.

Pharmacokinetic and pharmacodynamic properties of gliclazide were studied after an oral administration of gliclazide tablets in healthy volunteers. After an overnight fasting, gliclazide tablet was orally administered to 11 volunteers. Additional 10 volunteers were used as a control group (i.e., no gliclazide administration). Blood samples were collected, and the concentration determined for gliclazide and glucose up to 24 after the administration. Standard pharmacokinetic analysis was carried out for gliclazide. Pharmacodynamic activity of the drug was expressed by increase of glucose concentration (deltaPG), by area under the increase of glucose concentration-time curve (AUC(deltaPG)) or by the difference in increase of glucose concentration (D(deltaPG)) at each time between groups with and without gliclazide administration. Pharmacokinetic analysis revealed that Cmax, Tmax, CL/F (apparent clearance), V/F (apparent volume of distribution) and half-life of gliclazide were 4.69+/-1.38 mg/L, 3.45+/-1.11 h, 1.26+/-0.35 L/h, 17.78+/-5.27 L, and 9.99+/-2.15 h, respectively. When compared with the no drug administration group, gliclazide decreased significantly the AUC(deltaPG) s at 1, 1.5, 2, 2.5, 3 and 4 h (p<0.05). The deltaPGs were positively correlated with AUC(gliclazide) at 1 and 1.5 h (p<0.05), and the correlation coefficient was maximum at 1 h (r = 0.642) and gradually decreased at 4 h after the administration. The AUC(deltaPG)s were positively correlated with AUC(gliclazide) at 1, 2, 3 and 4 h (p<0.05), and the maximum correlation coefficient was obtained at 2 h (r=0.642) after the administration. The D(deltaPG) reached the maximum at 1 h, remained constant from 1 h to 3 h, and decreased afterwards. Therefore, these observations indicated that maximum hypoglycemic effect of gliclazide was reached at approximately at 1.5 h after the administration and the effect decreased, probably because of the homeostasis mechanism, in health volunteers.