Search

We report, for the first time, the long-awaited detection of diffuse gamma rays with energies between 100 TeV and 1 PeV in the Galactic disk. Particularly, all gamma rays above 398 TeV are observed apart from known TeV gamma-ray sources and compatible with expectations from the hadronic emission scenario in which gamma rays originate from the decay of $\pi^0$'s produced through the interaction of protons with the interstellar medium in the Galaxy. This is strong evidence that cosmic rays are accelerated beyond PeV energies in our Galaxy and spread over the Galactic disk., Comment: Accepted for publication in the Physical Review Letters

HESS J1843–033 is a very high energy gamma-ray source whose origin remains unidentified. This work presents, for the first time, the energy spectrum of gamma rays beyond 100 TeV from the HESS J1843–033 region using the data recorded by the Tibet air shower array and its underground muon detector array. A gamma-ray source with an extension of 0.°34 ± 0.°12 is successfully detected above 25 TeV at (α, δ) = (281.°09 ± 0.°10, −3.°76 ± 0.°09) near HESS J1843–033 with a statistical significance of 6.2σ, and the source is named TASG J1844–038. The position of TASG J1844–038 is consistent with those of HESS J1843–033, eHWC J1842–035, and LHAASO J1843–0338. The measured gamma-ray energy spectrum in 25 TeV < E < 130 TeV is described with dN / dE = ( 9.70 ± 1.89 ) × 10 − 16 (E/40 TeV)−3.26±0.30 TeV−1 cm−2 s−1, and the spectral fit to the combined spectra of HESS J1843–033, LHAASO J1843–0338, and TASG J1844–038 implies the existence of a cutoff at 49.5 ± 9.0 TeV. Associations of TASG J1844–038 with SNR G28.6–0.1 and PSR J1844–0346 are also discussed in detail for the first time.

We report observations of gamma-ray emissions with energies in the 100 TeV energy region from the Cygnus region in our Galaxy. Two sources are significantly detected in the directions of the Cygnus OB1 and OB2 associations. Based on their positional coincidences, we associate one with a pulsar PSR J2032+4127 and the other mainly with a pulsar wind nebula PWN G75.2+0.1 with the pulsar moving away from its original birthplace situated around the centroid of the observed gamma-ray emission. This work would stimulate further studies of particle acceleration mechanisms at these gamma-ray sources., Accepted for publication in the Physical Review Letters

Cosmic rays (protons and other atomic nuclei) are believed to gain energies of petaelectronvolts (PeV) and beyond at astrophysical particle accelerators called 'PeVatrons' inside our Galaxy. Although a characteristic feature of a PeVatron is expected to be a hard gamma-ray energy spectrum that extends beyond 100 teraelectronvolts (TeV) without a cutoff, none of the currently known sources exhibits such a spectrum due to the low maximum energy of accelerated cosmic rays or insufficient detector sensitivity around 100 TeV. Here we report the observation of gamma-ray emission from the supernova remnant G106.3+2.7 above 10 TeV. This work provides flux data points up to and above 100 TeV and indicates that the very-high-energy gamma-ray emission above 10 TeV is well correlated with a molecular cloud rather than the pulsar PSR J2229+6114. Regarding the gamma-ray emission mechanism of G106.3+2.7, this morphological feature appears to favor a hadronic origin via the {\pi}0 decay caused by accelerated relativistic protons over a leptonic one via the inverse-Compton scattering by relativistic electrons. Furthermore, we point out that an X-ray flux upper limit on the synchrotron spectrum would provide important information to firmly establish the hadronic scenario as the mechanism of particle acceleration at the source., Comment: Published in Nature Astronomy

Using the Tibet-III air shower array, we search for steady TeV -rays from 18 pulsars in the Fermi Large Area Telescope pulsar catalog. Among them, we ob- serve 8 sources including the Crab instead of the expected

The observation of the extensive air showers has been carried out since 1990 by Tibet air-shower array to study the origin of the cosmic-rays. In order to investigate the chemical composition around the knee, air-shower core detector was used in two experimental phases aiming to separate light primary elements (proton and helium). In a first phase experiment made in 1996-1999, primary proton and helium spectra were measured using a hybrid detector consisted of Tibet II air-shower array, emulsion chambers, and burst detectors. The result indicated that the fraction of light elements among the all particle spectrum is less than 30%. We performed the second phase experiment in 2002-2005 to measure proton + helium together to confirm the previous result with higher statistics by improving the detection efficiency for the air-shower cores. The P + He spectrum was obtained in a good agreement with previous result by several times higher statistics. The flux of the light elements, together with the all-particle energy spectrum, indicates the dominance of nuclei heavier than helium in the energy range around the knee. We also present the outline of the next phase experiment, which is to measure the heavy elements around the knee, using low threshold air-shower core detector named YAC. (C) 2010 COSPAR. Published by Elsevier Ltd. All rights reserved.

The Tibet-III air shower array, consisting of 789 scintillation detectors, has been operating successfully at Yangbajing in Tibet since 1999. Some recent results on gamma-ray observation by the Tibet-III air shower array are introduced and its future prospects of gamma-ray observation will be discussed.

Recent results and future prospects of the Tibet air-shower experiment are reported on the all-particle energy spectrum and the chemical composition of cosmic rays around 10 15 eV energy range. The knee of the all-particle energy spectrum has been clearly observed at the energy around 4 ×10 15 eV by Tibet III air-shower array located at Yangbajing, Tibet, China (atmospheric depth 606 g/cm 2 , area 37,000 m 2 ). The energy spectrum of light components (protons and helium) measured by air-shower-core detector exhibits steeper power index than that of direct measurements below 10 14 eV, leading to decreasing fraction of the light component toward the knee. Hence, it is strongly suggested that the origin of the knee is related with the change of the chemical composition of cosmic rays. A new air-shower-core detector called `YAC' is under the preparation for explicit measurement of the heavy component.

The Tibet-III air shower array, consisting of 533 scintillation detectors, has been operating successfully at Yangbajing in Tibet, China since 1999. Using the dataset collected by this array from 1999 November through 2005 November, we obtained the energy spectrum of $\gamma$-rays from the Crab Nebula, expressed by a power law as $(dJ/dE) = (2.09\pm0.32)\times10^{-12} (E/{\rm 3 TeV})^{-2.96\pm0.14} {\rm cm}^{-2} {\rm s}^{-1} {\rm TeV}^{-1}$ in the energy range of 1.7 to 40 TeV. This result is consistent with other independent $\gamma$-ray observations by imaging air Cherenkov telescopes. In this paper, we carefully checked and tuned the performance of the Tibet-III array using data on the moon's shadow in comparison with a detailed Monte Carlo simulation. The shadow is shifted to the west of the moon's apparent position as an effect of the geomagnetic field, although the extent of this displacement depends on the primary energy positively charged cosmic rays. This finding enables us to estimate the systematic error in determining the primary energy from its shower size. This error is estimated to be less than $\pm$12% in our experiment. This energy scale estimation is the first attempt among cosmic-ray experiments at ground level. The systematic pointing error is also estimated to be smaller than $0\fdg011$. The deficit rate and position of the moon's shadow are shown to be very stable within a statistical error of $\pm$6% year by year. This guarantees the long-term stability of point-like source observation with the Tibet-III array. These systematic errors are adequately taken into account in our study of the Crab Nebula., Comment: 12 pages, 16 figures, accepted by ApJ

We report the detection of 10 new X-ray filaments using the data from the {\sl Chandra} X-ray satellite for the inner $6^{\prime}$ ($\sim 15$ parsec) around the Galactic center (GC). All these X-ray filaments are characterized by non-thermal energy spectra, and most of them have point-like features at their heads that point inward. Fitted with the simple absorbed power-law model, the measured X-ray flux from an individual filament in the 2-10 keV band is $\sim 2.8\times10^{-14}$ to $10^{-13}$ ergs cm$^{-2}$ s$^{-1}$ and the absorption-corrected X-ray luminosity is $\sim 10^{32}-10^{33}$ ergs s$^{-1}$ at a presumed distance of 8 kpc to the GC. We speculate the origin(s) of these filaments by morphologies and by comparing their X-ray images with the corresponding radio and infrared images. On the basis of combined information available, we suspect that these X-ray filaments might be pulsar wind nebulae (PWNe) associated with pulsars of age $10^3 \sim 3\times 10^5$ yr. The fact that most of the filament tails point outward may further suggest a high velocity wind blowing away form the GC.

We present an updated all-particle energy spectrum using data collected in the period from 2000 November through 2004 October by Tibet III air-shower array. The energy determination of the air showers is made by fitting the lateral density distribution of the shower particles to the modified NKG function which is optimized by simulation calculation using interaction models of QGSJET01c and SIBYLL2.1 taking into account of the detector configurations. It is shown that the model dependence in the energy determination is not significant, being less than 5% in the absolute flux value, and we obtained the cosmic ray energy spectrum in a wide range over 3 decades between 10(14) eV and 10(17) eV, in which the position of the knee is clearly seen at around 4 PeV. The spectral index is -2.68 +/- 0.02(stat.) below 1PeV, while it is -3.12 +/- 0.01(stat.) above 4 PeV. The various systematic errors are under study now.

We are planning to build a large water-Cherenkov-type muon detector array around the Tibet air shower array for Gamma-ray astronomy in the 100 TeV Region. In this paper, we describe the design of the Tibet MD array and details of the Monte Carlo simulation to demonstrate the sensitivity of the Tibet AS+MD array.

The Tibet air shower array with effective area 37,000 m 2 located at 4300m in altitude, in Tibet, China, is sensitive to celestial gamma rays with energies above a few TeV. We have a plan to add a large underground muon detector array to it in order to discriminate cosmic gamma rays from cosmic-ray hadrons and to increase its sensitivity by approximately one order of magnitude to cosmic gamma rays in the 100 TeV energy region. The overview of the plan will be briefly described.

We searched for steady 100 TeV gamma-ray point sources from −10° to +70° in declination based on six year data obtained from Nov. 1999 to Nov. 2005 by the Tibet air shower array. No new source was found and no significant excess of events could be detected from known TeV sources. We set flux upper limits above 100 TeV on several nearby objects located inside Our Galaxy. All of them are slightly higher than extrapolation from lower energies by a factor of 1 to 20. Our new project named Tibet MD will improve our sensitivity by a factor of ∼10 in this energy region. We would discover ∼10 new sources and be able to measure cutoff energy of known and unknown sources, which might lead to identification of the origin of cosmic rays.

We report on the spectral index of cosmic rays around 10 TeV energy region obtained by observation of the Compton-Getting anisotropy due to the terrestrial orbital motion around the Sun with the Tibet III air shower array during the period from 1999 to 2005. The spectral index has turned out to be 2.99 ± 0.54 , which is consistent with 2.74 by the direct energy spectrum measurement. This method is a new approach to measure the spectral index and is complementary to the conventional energy spectrum measurement.

Ulysses observed a stable strong CIR from early 1992 through 1994 during its first journey into the southern hemisphere. After the rapid latitude scan in early 1995, Ulysses observed a weaker CIR from early 1996 to mid-1997 in the northern hemisphere as it traveled back to the ecliptic at the orbit of Jupiter. These two CIRs are the observational basis of the investigation into the latitudinal structure of CIRs. The first CIR was caused by an extension of the northern coronal hole into the southern hemisphere during declining solar activity, whereas the second CIR near solar minimum activity was caused by small warps in the streamer belt. The latitudinal structure is described through the presentation of three 26-day periods during the southern CIR. The first at 24 Ss hows the full plasma interaction region including fast and slow wind streams, the compressed shocked flows with embedded stream interface and heliospheric current sheet (HCS), and the forward and reverse shocks with associated accelerated ions and electrons. The second at 40 S exhibits only the reverse shock, accelerated particles, and the 26-day modulation of cosmic rays. The third at 60 Ss hows only the accelerated particles and modulated cosmic rays. The possible mechanisms for the access of the accelerated particles and the CIR-modulated cosmic rays to high latitudes above the plasma

We model the propagation of three-dimensional, adiabatic, linear Alfven waves in the solar atmosphere and wind, taking into account relevant physical effects, including gravity stratification, thermal conduction, radiative losses, and heating (via a phenomenological term). Our magnetohydrodynamic solar wind model also accounts for the momentum deposition by a spectrum of non-WKB Alfven waves. The transmission and reflection of such waves has been previously studied by a variety of techniques, including calculations based on the computation of the ratio between the wavelength and the scale length of the Alfven speed change and based on a globally - computed transmission coefficient. In this paper we discuss both techniques and show how they are related. We also discuss the physics underlying the reflection process and the possible role wave reflection might play in the acceleration of the solar wind and the winds from other stars.

We search for steady TeV γ-rays from 18 pulsars in the Fermi-LAT pulsar catalog using the Tibet air shower array. We observe 8 sources including the Crab against expected 0.41 sources at a significance of 2σ or more among the 18 pulsars. The chance probability from Poisson statistics is estimated to be 1.4×10-8.With the Crab excluded, it is estimated to be 1.8×10-7. These low chance probabilities clearly show that the Fermi pulsars have a statistically significant correlation with TeV γ-ray excesses observed by the Tibet air shower array.

We analyze the large-scale two-dimensional sidereal anisotropy of multi-TeV cosmic rays by Tibet Air Shower Array, with the data taken from 1999 November to 2008 December. To explore temporal variations of the anisotropy, the data set is divided into nine intervals, each in a time span of about one year. The sidereal anisotropy of magnitude about 0.1% appears fairly stable from year to year over the entire observation period of nine years. This indicates that the anisotropy of TeV Galactic cosmic rays remains insensitive to solar activities since the observation period covers more than a half of the 23rd solar cycle., 18 pages, 2 figures, accepted by The Astrophysical Journal

Mapping the global heliosphere by detecting energetic neutral atoms (ENAs), IBEX derived the semi‐direct information on the structure of the large‐scale magnetic field surrounding the heliosphere. Multi‐TeV galactic cosmic rays (GCRs) also sense the global structure of the magnetic field within the whole heliosphere as well as the field surrounding the heliosphere, and can provide an additional tool to explore the global structure of these fields. We analyze, in this context, the multi‐TeV GCR intensity observed with the Tibet Air Shower (AS) experiment, which clearly shows a midscale component structure observed as the excess intensity along Gurnett’s HDP (Hydrogen Deflection Plane), as well as the global component structure. We find that the amplitude of the midscale component is only weakly dependent on GCR energy, while its angular extension along the HDP plane monotonously decreases with increasing energy. On the basis of these results, we discuss the possible origin of the midscale anisotropy.

Using the data taken from Tibet II High Density (HD) Array (1997 February-1999 September) and Tibet-III array (1999 November-2005 November), our previous northern sky survey for TeV $\gamma-$ray point sources has now been updated by a factor of 2.8 improved statistics. From $0.0^{\circ}$ to $60.0^{\circ}$ in declination (Dec) range, no new TeV $\gamma-$ray point sources with sufficiently high significance were identified while the well-known Crab Nebula and Mrk421 remain to be the brightest TeV $\gamma-$ray sources within the field of view of the Tibet air shower array. Based on the currently available data and at the 90% confidence level (C.L.), the flux upper limits for different power law index assumption are re-derived, which are approximately improved by 1.7 times as compared with our previous reported limits., Comment: This paper has been accepted by hepnp

We are planning to build a 10,000 m2 water‐Cherenkov‐type muon detector (MD) array under the Tibet air shower (AS) array. The Tibet AS+MD array will have the sensitivity to detect gamma rays in the 100 TeV region by an order of the magnitude better than any other previous existing detectors in the world. In the late fall of 2007, a prototype water Cherenkov muon detector of approximately 100 m2 was constructed under the existing Tibet AS array. The preliminary data analysis is in good agreement with our MC simulation. We are now ready for further expanding the underground water Cherenkov muon detector.

We have already reported the first result on the all-particle spectrum around the knee region based on data from 2000 November to 2001 October observed by the Tibet-III air-shower array. In this paper, we present an updated result using data set collected in the period from 2000 November through 2004 October in a wide range over 3 decades between $10^{14}$ eV and $10^{17}$ eV, in which the position of the knee is clearly seen at around 4 PeV. The spectral index is -2.68 $\pm$ 0.02(stat.) below 1PeV, while it is -3.12 $\pm$ 0.01(stat.) above 4 PeV in the case of QGSJET+HD model, and various systematic errors are under study now., Comment: 12 pages, 7 figures, accepted by Advances in space research

Tacrolimus, an immunosuppressant widely used after liver transplantation, is characterized by a large inter-individual variability in its pharmacokinetics. The aim of this study was to perform population pharmacokinetic analysis of oral tacrolimus in liver transplant recipients and clarify the potential role of CYP3A5, MDR1 and IL-10 genetic polymorphisms in the variability of population pharmacokinetic parameters.Tacrolimus blood concentration data (n = 1106) were collected from 104 full liver transplant patients and were analysed using a non-linear mixed-effects modelling program (nonmem). The CYP3A5*3, MDR1 G2677T/A and C3435T genetic polymorphisms were determined using polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. The IL-10 G-1082A variant was studied by allele-specific PCR method.The liver function in patients as indicated by the total bilirubin level (TBIL) and different CYP3A5*3 genotypes in donors (CYPD) and recipients (CYPR) were observed to influence tacrolimus pharmacokinetic parameter of apparent clearance (Cl/F). The final regression model can be expressed as Cl/F = 15.9 - 1.88 TBIL + 7.65 CYPD + 7.00 CYPR. The relative standard errors (%RSE) of the parameter estimation were lower than 30% and the residual variability of tacrolimus trough blood concentration was 2.81 ng/mL. No significant effect of MDR1 and IL-10 polymorphisms was observed on population pharmacokinetic parameter of tacrolimus within 175 days after liver transplantation.The TBIL in patients and CYP3A5*3 genetic polymorphism in both donors and recipients contribute to the inter-individual variability of oral tacrolimus apparent clearance in Chinese adult liver transplant patients.

The amplitude of the Compton-Getting (CG) anisotropy contains the power-law index of the cosmic-ray energy spectrum. Based on this relation and using the Tibet air-shower array data, we measure the cosmic-ray spectral index to be $-3.03 \pm 0.55_{stat} \pm < 0.62_{syst}$ between 6 TeV and 40 TeV, consistent with $-$2.7 from direct energy spectrum measurements. Potentially, this CG anisotropy analysis can be utilized to confirm the astrophysical origin of the ``knee'' against models for non-standard hadronic interactions in the atmosphere., accepted to ApJL

We have observed the shadowing of galactic cosmic ray flux in the direction of the moon, the so-called moon shadow, using the Tibet-III air shower array operating at Yangbajing (4300 m a.s.l.) in Tibet since 1999. Almost all cosmic rays are positively charged; for that reason, they are bent by the geomagnetic field, thereby shifting the moon shadow westward. The cosmic rays will also produce an additional shadow in the eastward direction of the moon if cosmic rays contain negatively charged particles, such as antiprotons, with some fraction. We selected 1.5 x10^{10} air shower events with energy beyond about 3 TeV from the dataset observed by the Tibet-III air shower array and detected the moon shadow at $\sim 40 \sigma$ level. The center of the moon was detected in the direction away from the apparent center of the moon by 0.23$^\circ$ to the west. Based on these data and a full Monte Carlo simulation, we searched for the existence of the shadow produced by antiprotons at the multi-TeV energy region. No evidence of the existence of antiprotons was found in this energy region. We obtained the 90% confidence level upper limit of the flux ratio of antiprotons to protons as 7% at multi-TeV energies., Comment: 13pages,4figures; Accepted for publication in Astroparticle Physics

The intensity of Galactic cosmic rays is nearly isotropic because of the influence of magnetic fields in the Milky Way. Here, we present two-dimensional high-precision anisotropy measurement for energies from a few to several hundred teraelectronvolts (TeV), using the large data sample of the Tibet Air Shower Arrays. Besides revealing finer details of the known anisotropies, a new component of Galactic cosmic ray anisotropy in sidereal time is uncovered around the Cygnus region direction. For cosmic-ray energies up to a few hundred TeV, all components of anisotropies fade away, showing a corotation of Galactic cosmic rays with the local Galactic magnetic environment. These results have broad implications for a comprehensive understanding of cosmic rays, supernovae, magnetic fields, and heliospheric and Galactic dynamic environments.

To evaluate numerically the vibration behaviour (stability and unbalance response) of rotor bearing foundation (RBF) systems such as turbomachinery which incorporate rotors running in several flexibly mounted hydrodynamic bearings, one needs input data parameters which adequately describe the bearings, the rotor, the foundation, the unbalance state and the system configuration state (the relative transverse alignment of the bearings). Adequate parameters for the last three are particularly hard to obtain for existing installations; and worldwide effort has been devoted to trying to identify these parameters, using field obtainable measurements of the instantaneous relative displacements between the rotor journals and their respective bearing housings. These measurements are then processed using Reynolds equation to determine the instantaneous bearing reaction forces acting on the rotor and foundation, which forces are then an essential ingredient of the desired parameter identification procedures [1]. The problem is in the accuracy to which one can reliably calculate these forces, even if it be assumed that Reynolds equation is otherwise a perfect model. This is felt to be particularly problematical because of the nonlinearity introduced into the RBF system by the hydrodynamic bearings.Copyright © 2005 by ASME

Polymorphism has been detected in a variety of drug-metabolizing enzymes at both phenotypic and genotypic level. Human cytochrome P450 enzymes have been studied extensively in recent years, and the majority of mutations which give rise to a defective phenotype have now been identified(for example CYP2D6, CYP2C19, etc.). There are some groups of enzymes showing definite polymorphism at the phenotypic level but the exact genetic mechanisms are not yet clear(CYP1A1, CYP1A2, etc.). There are still other groups of enzymes, showing some indication of polymorphism at either the phenotypic or genotypic level yet have not been unambiguously demonstrated (for example CYP2A6, CYP2C9, CYP2E1, CYP3A4, etc.). The molecular mechanism of all these polymorphisms and possible polymorphisms is discussed, with particular reference to the effects of this variation on drug metabolism and on the susceptibility to chemically-induced diseases.

In the present study, a specific and reliable method was developed for the determination of omeprazole and its two major metabolites, hydroxyomeprazole (OH-OPZ) and omeprazole sulfone (OPZ-SFN) in Chinese adult human liver microsome by reversed phase HPLC assay. Formation of these metabolites is linear for at least 60 min and between 0.25 and 1 mg.ml-1 of microsomal protein. The enzyme kinetic analysis of the reaction revealed that the hydroxylation Vmax and K(m) obtained with the human liver microsomal preparation were 42.9 nmol.min-1.(mg protein)-1 and 6.49 mumol.L-1, respectively. The maximum formation rates of OPZ-SFN (Vmax) was 6.63 nmol.min-1.(mg protein)-1, with a K(m) value of 11.8 mumol.L-1. A number of compounds were tested for their ability to inhibit OPZ metabolism. Our results showed that mephenytoin, diazepam and nordiazepam are competitive inhibitors and papaverine is an uncompetitive inhibitor of OPZ hydroxylation. These studies suggest that the same isozyme metabolising MP, DZ and NDZ (may be P450 2C or P450 3A) may be involved in the hydroxylation of OPZ. Moreover, the compounds tested also have some effects on the formation of OPZ-SFN in vitro with Chinese human liver microsomes.

The hydroxylation of S-mephenytoin exhibits a genetic polymorphism in humans and there are a large interethnic differences in the frequency of the poor metabolizer phenotype. A S-mephenytoin P450-hydroxylase termed P450 UK was purified and identified to be CYP 2C19 by amino-terminal amino acid analyses. The levels of P450 2C19 and the ability of the human liver samples to 4'-hydroxylate S-mephenytoin were found to be strongly correlative. Recent report showed that the principle defect in S-mephenytoin poor metabolizers is a single base pair (G--A) mutation in exon 5 of CYP 2C19 resulting in an aberrantly spliced mRNA and a non-functional P450 2C19 protein in liver of S-mephenytoin PM. Further investigations demonstrate that this major defect is responsible for about 75% of poor metabolizer phenotype in both caucasians and orientals who are homozygous for S-mephenytoin hydroxylation defect. This genetic defect (CYP 2C19) also affects metabolism of several other widely clinical used drugs.

A method was developed for the determination of the novel antihypertensive drug naftopidil in biological samples by HPLC. Metoprolol was used as the internal standard. The analytical column was a stainless steel column filled with 10 micron C18 packing. The mobile phase was a mixture of methanol-acetonitrile-water-0.2 mol.L-1 HAc-0.2 mol.L-1 NaAc (50:45:5:0.9:0.1). Detection was performed at UV 232 nm. Biological samples can be well purified after two extractions with ether. The lowest detection limit was 5 ng.ml-1. The precision and accuracy within-day and day-to-day ranged from 3.17 to 10.88%. The mean recoveries were 79.35% to 95.72%. The results showed that this method was simple, sensitive and good enough to be used in pharmacokinetic study of naftopidil.

The metabolism of omeprazole to its two major metabolites, hydroxyomeprazole (OH-OPZ) and omeprazole sulfone (OPZ-SFN) was studied in rat liver microsomes by a reversed phase HPLC assay. The formation of metabolites of OPZ depended on incubation time, substrate concentration, microsomal protein concentration, and was found to be optimal at pH 7.4. The Vmax and Km of OPZ hydroxylation in the rat liver microsomal preparation were 2033 nmol/(min.mg protein) and 46.8 mumol.L-1 respectively. The maximum rate of formation of OPZ-SFN (Vmax) was 187.9 nmol/(min.mg protein), with a Km value of 120.7 mumol.L-1 in rat liver microsome. Moreover, the effects of 7 drugs on OPZ metabolism were tested. The results showed that mephenytoin, benzodiazepines (DZ, NDZ, TMZ, FNZ, NZ) and papaverine caused inhibition of OPZ metabolism, among them papaverine was the only fairly strong inhibitor.

A method was developed for the determination of oxiracetam concentration in serum and urine by HPLC. Acyclovir was used as an internal standard. The analytical column was a stainless-steel column (30 mm x 4.6 mm ID) filled with 10 microns Bondapak NH2. A mixture of acetonitrile and water (80: 20) as mobile phase was used at a flow rate of 1 ml.min-1. Detection was performed at 210 nm. The retention times were 6.3 min for oxiracetam and 8.1 min for the internal standard. The lower detection limits were 1 microgram.ml-1 for serum and 20 micrograms.ml-1 for urine. The precision and accuracy within-day and day-to-day for both serum and urine samples ranged from 5.0 to 10.7%. The mean recoveries were 99.7 +/- 5.9% and 99.0 +/- 5.6% for human serum and urine, respectively. The results showed that the method is simple, rapid, sensitive, reliable and good enough to be used in studying the clinical pharmacokinetics of oxiracetam.

A gas chromatographic method equipped with nitrogen-phosphorus detector was developed for the determination of the S- and R-enantiomers of the anticonvulsant, mephenytoin (MP) in human urine. Dichloromethane (4 ml) was added to 1 ml urine, the mixture was shaken and centrifuged. The organic phase was transferred to another tube and blown to dryness under nitrogen on water bath (37 degrees C). The residue was dissolved in 10 microliters ethylacetate and 1-2 microliters was injected into the GC. Our results showed that direct enantiomeric separation of mephenytoin was obtained by using a chiral capillary column, the retention times for S- and R-mephenytoin were 25.5 and 26.2 min respectively, with a detection limit less than 50 ng/ml of mephenytoin. Similar linear and reproducible standard curves were obtained over the concentration range of 53.2 to 2128.0 ng/ml (for S-MP, r = 0.9914 +/- 0.0070, n = 6; and for R-MP, r = 0.9939 +/- 0.0070, n = 6), and the mean recoveries of S- and R-MP were 95.4% and 95.8% respectively. The within-day relative standard deviations were less than 8.8% for both S- and R-MP, and that of between-days were less than 14.3%. There was a good reproducibility of the urine S/R mephenytoin determined in China and in Sweden by using similar method in 107 Chinese volunteers after a single oral dose of 100 mg racemic mephenytoin (r = 0.9091, P0.001).

The metabolic ratio of debrisoquine hydroxylation (MR) determined as the ratio of debrisoquine over 4-OH-debrisoquine in 8 h urine after a single oral dose of DB (10 mg) in unrelated Chinese Zang and Wei volunteers was studied by using gas chromatography. The MR of 132 healthy Chinese Zang subjects ranged from 0.20 to 34.32, and that of 158 healthy Chinese Wei subjects ranged from 0.13 to 29.73. Two phenotypes were apparent in the frequency distribution histograms with an antimode at log MR = 1.10 (MR = 12.6). Two subjects were therefore identified as poor metabolizers (PMs) of DB in 132 Zang volunteers (the frequency of PMs was found to be 1.52%), and only one in 158 Wei volunteers (0.63%). Neither sex nor smoking habit affected the DB hydroxylation (P greater than 0.2). The recoveries of DB and 4-OH-DB in Zang volunteers were 19.83 +/- 10.99 and 11.57 +/- 7.04%, and in Wei volunteers they were 22.74 +/- 14.41 and 17.77 +/- 10.82%, respectively.

The Tibet air shower array, which has an effective area of 36,900 m2, has been in operation at Yangbajing in Tibet, China at an altitude of 4,300 m above sea level. In this paper, we will briefly introduce the recent gamma-ray observation with the present Tibet air shower array and our future plan which is called the Tibet muon detector (MD) project.

Debrisoquine hydroxylation capacity determined as the ratio of debrisoquine over 4-OH-debrisoquine in 8-h urine after a single dose (10 mg) was studied in 140 unrelated Chinese Han subjects and 2 families of poor metabolizers (PM) of debrisoquine. In the 140 Chinese subjects the frequency of PM was found to be 1.43% (2/140), much lower than the 5-10% in white population reported. No sex difference was shown on the hydroxylation of debrisoquine. The recoveries of debrisoquin, 4-OH-debrisoquine in 8-h urine were 16 +/- 11 and 13 +/- 6%, respectively. None of the parents in the 2 families was PMs. Phenotype distribution in each family and population was consistent with the hypothesis that debrisoquine 4-OH-hydroxylation activity is under diallelic, monogenetic control, with the PM phenotype inheriting in an autosomal recessive trait.

We consider standing wave solutions of the linearized magnetohydrodynamic (MHD) equations describing a perfectly conducting but viscous magnetofluid in a gravitationally-stratified cylindrical plasma. We assume a relatively strong homogeneous background magnetic field within the flux tube, which is oriented along the cylinder axis; the background atmosphere is in hydrostatic equilibrium, with gravity uniform and parallel to the cylinder axis; the vertical temperature profile (constrained by the stability conditions) is arbitrary. The MHD wave equations are separable, and appropriate boundary conditions are formulated. We employ a numerical shooting scheme to solve the coupled ordinary differential equations and to obtain the damping rates and eigenfrequency spectra for the standing MHD wave modes. Three series of modes are obtained for an isothermal flux tube: Alfvtnic, quasi-fast, and quasi-slow. The quasi-slow mode series is novel, having been missed previously. In the inviscid limit, with a st...

The metabolism of antiepilepserine, 3,4-methylene dioxycinnamyl piperidine, was studied in isolated perfused rat liver. Two metabolites were separated and purified by means of HPLC. They were identified as 3,4-methylene dioxycinnamyl hydroxypiperidine and 4-hydroxy-3-methoxycinnamyl piperidine by UV and MS. The latter was further confirmed by chemical synthesis. The pharmacokinetics of antiepilepserine in isolated perfused liver was also studied. Parameters obtained include a first order elimination constant, k = 0.0157 +/- 0.0043 min-1, and a half-life, t 1/2 = 46.7 +/- 11.9 min, (n = 6). The amount of antiepilepserine lost during the perfusion could not be compensated by the increased amount of metabolites. Antiepilepserine was found to be tightly bound and stored in the liver. This might be one of the explanations of the first pass effect of antiepilepserine after oral administration.

Enpiperate, 4-(3, 5)-exocydopropyl-N-methylpiperidyl diphenyl hydroxy acetate, was synthesized in China. It has been shown to have no effect on the normal tension of rabbit aorta strips or contractions induced by NE. It inhibited the contraction of high K+-depolarized rabbit aorta strips at concentrations of 3.8 and 10.9 mumol/L. The same effect was seen on isolated guinea pig ileum, at a concentration of 10.9 mumol/L, which was depolarized by Ca2+ free high K+ Locke-Ringer's solution and the contraction was extragenous Ca2+ dependent. The inhibition was overcome by increasing the extracellular Ca2+ concentration. In the presence of EDTA (0.1 mmol/L), the NE induced intracellular Ca2+ dependent contraction was inhibited by enpiperate (3.8, 10.9 mumol/L), although no significant difference was found between enpiperate and papaverine. It is suggested that enpiperate is a calcium antagonist and that the antagonism is carried out by blocking the potential dependent calcium channel (PDC) in the membrane of vascular smooth muscles. A intracellular calcium antagonistic action may also be involved.

An HPLC method for the determination of tetramethylpyrazine in serum and application of this method to tetramethylpyrazine deposition studies in human body were described. Tetramethylpyrazine was extracted from alkalinized serum with dichloromethane using methaqualone as internal standard. A RP mu-Bondapak-C18 (10 microns) column fitted with a variable-wavelength UV spectrophotometer operated at 280 nm was used. The mobile phase was methanol-water (58:42). The detection limit of the method was 0.0174 microgram/ml serum. Assay linearity was shown over the range of 0.0291-5.816 micrograms/ml serum with a regression coefficient of 0.9999. The extraction recovery was 99.84% and no interference was found from endogenous compounds, metabolites of parent drug or other commonly used drugs. For the serum concentration following oral administration of tetramethylpyrazine capsules to healthy volunteers (n = 6), the best fit was found to be with a two compartment open model. After administration of 174.5 mg dose, the pharmacokinetic parameters were as follows: Tp = 0.5102 h, Cmax = 3.114 micrograms/ml, AUC = 5.893 mg/L.h, T1/2 (Ka) = 0.1508 h, T1/2 (alpha) = 0.4855 h, T1/2 (beta) = 2.894 h, C1 = 15.7 L.h-1, Vc = 17.70 L, V = 66.77 L. The results imply that tetramethylpyrazine is absorbed rapidly, distributed widely in the body, and also eliminated at a fairly rapid rate.