Biomedical subjects

L X Yu

Publications and source records attributed to L X Yu.

At least 19 recordsLinked to original sources

PubMed2006

Comparing microsphere deposition and flow modeling in 3D vascular trees.

Blood perfusion in organs has been shown to be heterogeneous in a number of cases. At the same time, a number of models of vascular structure and flow have been proposed that also generate heterogeneous perfusion. Although a relationship between local perfusion and vascular structure has to exist, no model has yet been validated as an accurate description of this relationship. A study of perfusion and three-dimensional (3D) arterial structure in individual rat kidneys is presented, which allows comparison between local measurements of perfusion and model-based predictions. High-resolution computed tomography is used to obtain images of both deposited microspheres and of an arterial cast in the same organ. Microsphere deposition is used as an estimate of local perfusion. A 3D cylindrical pipe model of the arterial tree is generated based on an image of the arterial cast. Results of a flow model are compared with local microsphere deposition. High correlation (r(2) > 0.94) was observed between measured and modeled flows through the vascular tree segments. However, the relative dispersion of the microsphere perfusion measurement was two- to threefold higher than perfusion heterogeneity calculated in the flow model. Also, there was no correlation in the residual deviations between the methods. This study illustrates the importance of comparing models of local perfusion with in vivo measurements of perfusion in the same biologically realistic vascular tree.

Animals↗

PubMed2005

Estimating perfusion using microCT to locate microspheres.

The injection of microspheres into the blood stream has been a common method to measure the spatial distribution of blood flow (perfusion). A technique to conduct this kind of measurement in small animal organs is presented using silver-coated microspheres with a diameter of 16 microm and high-resolution computed tomography (microCT) to detect individual microspheres. Phantom experiments demonstrate the detectability of individual spheres. The distribution of microspheres within a rat heart is given as an example. Using non-destructive, three-dimensional imaging for microsphere detection avoids the cumbersome dissection of the organ into samples or slices and their subsequent registration. The detection of individual spheres allows high-resolution measurements of perfusion and arbitrary definition of regions of interest. These, in turn, allow for accurate statistical analysis of perfusion such as relative dispersion curves.

Animals↗

PubMed2001

Effect of common excipients on Caco-2 transport of low-permeability drugs.

The Biopharmaceutics Classification System (BCS) allows waivers of in vivo bioequivalence for rapidly dissolving immediate-release (IR) formulations of drugs with high solubility and high permeability. One potential issue in possibly extending BCS biowaivers to low-permeability drugs is the potential for excipients to modulate the intestinal permeability of the drug. The objective of this work was to evaluate the effect of nine individual excipients on the Caco-2 permeability of seven low-permeable compounds that differ in their physiochemical properties. Generally, most excipients had no influence on drug permeability. With the exception of sodium lauryl sulfate, no excipient affected Caco-2 monolayer integrity. Sodium lauryl sulfate moderately increased the permeability of almost all the drugs. Tween 80 significantly increased the apical-to-basolateral direction permeability of furosemide, cimetidine, and hydrochlorothiazide, presumably by inhibiting their active efflux, without affecting mannitol permeability. Additionally, docusate sodium moderately increased cimetidine permeability. Other excipients did not have significant effect on the permeability of these three drugs. Further work is needed to interpret the in vivo consequences of these observations from cell culture.

Biological Transport↗

PubMed2001

Influence of drug release properties of conventional solid dosage forms on the systemic exposure of highly soluble drugs.

This study was designed to theoretically investigate the influence of drug release properties, characterized by the disintegration of a solid dosage form and dissolution of drug particles, on the systemic exposure of highly soluble drugs in immediate release products. An absorption model was developed by considering disintegration of a solid dosage form, dissolution of drug particles, gastrointestinal transit flow, and intestinal absorption processes. The absorption model was linked to a conventional pharmacokinetic model to evaluate the effect of disintegration and dissolution on the peak exposure (Cmax) and total exposure of area under the curve (AUC). Numerical methods were used to solve the model equations. The simulations show that the effect of disintegration of a dosage form and dissolution of drug particles depend on the permeability of a drug, with a low-permeability drug having a greater effect. To provide similar exposure to an oral solution formulation, a solid dosage form containing a low-permeability drug would need to dissolve more rapidly than a solid dosage form containing a high-permeability drug. It was shown theoretically for poorly permeable drugs that the disintegration rate constant has to be greater than 9 hour(-1)(equivalent to approximately 90% in 30 minutes) to make both AUC and Cmax ratios higher than.9, ensuring the confidence interval of.80 to 1.25. The rapid in vitro release requirement of at least 85% dissolved in 30 minutes is sufficient for highly soluble and highly permeable drugs. However, for highly soluble and poorly permeable drugs, the appropriate in vitro release requirement seems to be 90% dissolved in 30 minutes.

Algorithms↗

PubMed2001

Inhibitory effect of quercetin on cultured neonatal rat cardiomyocytes hypertrophy induced by angiotensin.

AIM: To study the inhibitory effect of quercetin on cultured neonatal rat cardiomyocytes hypertrophy induced by angiotensin II (AngII) and its mechanism. METHODS: DNA, RNA, and protein synthesis were measured by incorporation of [3H]thymidine, [14C]uridine, and [3H]tyrosine, respectively. Protein content were measured by Lowry's method. Protein kinase C (PKC) activity was assayed by incubating PKC with histone IIIS and [gamma-(32)P]ATP. Tyrosine protein kinase (TPK) activity was assayed by incubating TPK with poly glutamate/tyrosine (4:1) and [gamma-(32P]ATP. RESULTS: After treated with AngIIat 10 nmol/L for 24 h, total protein content was greatly increased as compared with untreated group (P < 0.01). Incorporation of [14C]uridine and [3H]tyrosine was also greatly increased (P < 0.01) respectively, while incorporation of [3H]thymidine remained unchanged (P > 0.05). Ang II strongly increased cardiomyocytes PKC and TPK activities at 30 min. Que (1-100 micromol/L) could inhibit the increase of total protein content, incorporation of [14C]uridine and [3H]tyrosine, and PKC and TPK activities induced by Ang II in concentration-dependent manner. CONCLUSION: The inhibitory effect of Que on the cardiomyocytes hypertrophy was related to its inhibitory effect on PKC and TPK.

Angiotensin II↗

PubMed2001

[Synthesis and antibacterial activity of 3-hydroxy-6-O-methylerythromycin-9-O-substituted oxime derivatives].

AIM: To study the antibacterial activity against erythromycin-resistant organisms of 3-hydroxy-6-O-methylerythromycin-9-O-substituted oxime derivatives, a new route of synthesis with 6 steps was designed. METHODS: The starting material, erythromycin A (1), was reacted with NH2OH.HCI to give 2, which reacted with BzBr to give 3. Selective methylation of C-6 hydroxy group using iodomethane afforded 4, which was hydrolyzed with loss of the 3-cladinosyl to give 5. Compound 5 was reduced by H2 to provide 6, which was treated with substituted benzyl chlorides to provide 7 and 8. RESULTS: Four unreported compounds (5-8) were synthesized. The antibacterial activity of the new compounds were tested in vitro against both erythromycin-susceptible and erythromycin-resistant organisms. The compounds 5 (MIC = 1 microgram.mL-1) and 6 (MIC = 1 microgram.mL-1) showed significant activity against Staphylococcus epidermidis 26,069 compared with erythromycin (MIC = 4 micrograms.mL-1). Compounds 5 (MIC = 16, 4 micrograms.mL-1), 7 (MIC = 32, 64 micrograms.mL-1) and 8 (MIC = 64, 32 micrograms.mL-1) showed better activity against Streptococcus pneumoniae 64 and Staphylococcus aureus 9525 than erythromycin (MIC > 128, 128 micrograms.mL-1). CONCLUSION: 3-hydroxy-6-O-methylerythromycin-9-O-substituted oxime derivatives have stronger antibacterial activity against some erythromycin-resistant organisms than erythromycin A.

Anti-Bacterial Agents↗

PubMed2000

Predicting human oral bioavailability of a compound: development of a novel quantitative structure-bioavailability relationship.

PURPOSE: The purpose of this investigation was to develop a quantitative structure-bioavailability relationship (QSBR) model for drug discovery and development. METHODS: A database of drugs with human oral bioavailability was assembled in electronic form with structure in SMILES format. Using that database, a stepwise regression procedure was used to link oral bioavailability in humans and substructural fragments in drugs. The regression model was compared with Lipinski's Rule of Five. RESULTS: The human oral bioavailability database contains 591 compounds. A regression model employing 85 descriptors was built to predict the human oral bioavailability of a compound based on its molecular structure. Compared to Lipinski's Rule of Five, the false negative predictions were reduced from 5% to 3% while the false positive predictions decreased from 78% to 53%. A set of substructural descriptors was identified to show which fragments tend to increase/decrease human oral bioavailability. CONCLUSIONS: A novel quantitative structure-bioavailability relationship (QSBR) was developed. Despite a large degree of experimental error, the model was reasonably predictive and stood up to cross-validation. When compared to Lipinski's Rule of Five, the QSBR model was able to reduce false positive predictions.

Administration, Oral↗

PubMed1999

A compartmental absorption and transit model for estimating oral drug absorption.

This report describes a compartmental absorption and transit model to estimate the fraction of dose absorbed and the rate of drug absorption for passively transported drugs in immediate release products. The model considers simultaneous small intestinal transit flow and drug absorption. Both analytical and numerical methods were utilized to solve the model equations. It was found that the fraction of dose absorbed can be estimated by F(a) = 1-(1+0.54 P(eff))(-7), where P(eff) is the human effective permeability in cm/h. A good correlation was found between the fraction of dose absorbed and the effective permeability for ten drugs covering a wide range of absorption characteristics. The model was able to explain the oral plasma concentration profiles of atenolol.

Adsorption↗

PubMed1999

An integrated model for determining causes of poor oral drug absorption.

PURPOSE: To develop an integrated absorption model for estimating the fraction of dose absorbed and determining the causes of poor oral drug absorption. METHODS: Both analytical and numerical methods were used to estimate the fraction of dose absorbed. RESULTS: An integrated absorption model was developed by considering transit flow, dissolution, and permeation processes, simultaneously. A framework was proposed to determine permeability-, dissolution-, and solubility-limited absorption. Digoxin, griseofulvin, and panadiplon were employed to illustrate the applications of the integrated model in identifying the causes of poor absorption and guiding formulation development. CONCLUSIONS: The integrated absorption model was successfully applied to digoxin, griseofulvin, and panadiplon to estimate the fraction dose absorbed and to roughly determine the causes of poor oral drug absorption.

Administration, Oral↗

PubMed1998

Saturable small intestinal drug absorption in humans: modeling and interpretation of cefatrizine data.

This report describes an extended compartmental absorption and transit (CAT) model to estimate saturable small intestinal absorption. This model simultaneously considers passive absorption, saturable absorption, degradation, and transit kinetics in the human small intestine. Using cefatrizine as a model drug, we demonstrated that the extended CAT model, along with intravenous pharmacokinetic parameters, was able to explain the observed oral plasma concentration-time profiles. The model predicted comparable passive and saturable absorption characteristics for cefatrizine, particularly at high dose. The predicted fraction of dose absorbed was 74% at 250 mg, 61% at 500 mg, and 48% at 1000 mg, in agreement with the reported experimental data. The simulation study showed that no single physiological factor (gastric emptying, small intestinal transit, and absorption mechanism) could account for the large variability of cefatrizine absorption observed in the literature.

Cefatrizine↗

PubMed1998

Molecular cloning and mRNA localization of tomato pollen profilin.

The actin cytoskeleton plays an important role in the growth of pollen tube. The actin-binding protein profilin could play a role in regulating the organization of the actin filaments. Using the RT-PCR technique, we isolated a cDNA clone (designated LePro 1) encoding profilin from pollen grains of tomato (Lycopersicon esculentum Mill. cv. Moneymaker). Sequence analysis of the insert shows 87% similarity to tobacco ntPro2, 78% to timothy grass profilin, 77% to Arabidopsis AthPRF4, 77% to maize ZmPro3, and 73% to birch profilin. Both quantitative PCR and RNA gel blot analyses demonstrated that LePro 1 is expressed in a tissue- or cell-type specific manner in the tomato plant. In situ hybridization of 2 microns thick anther sections using a non-radioactive labeling method reveals that LePro 1 is expressed only in pollen grains, with undetectable transcription in other parts of the anther or the other organs. Phylogenetic analysis of amino acid sequences of 18 plant profilins indicates that two distinct profilin gene classes are present in higher plants. One is pollen-specific, another is constitutive. LePro 1 belongs to the former class.

Amino Acid Sequence↗

PubMed1997

Alport syndrome with neurofibromatosis type-I: a case report.

We report a 9-year-old boy with repeated fractures of the tibia from age 6 months and microscopic hematuria from age 2 years. His maternal family has a history of nephritis and his paternal family has neurofibromatosis type-I (NF-I). The boy's renal biopsy revealed an irregular attenuation and splitting of the glomerular basement membrane. The skin biopsy was stained with monoclonal antibody against the alpha 5 chain of type IV collagen; the epidermal basement membrane was negative in the boy and segmentally positive in the boy's mother. We conclude that the patient inherited Alport syndrome from his mother and NF-I from his father. We postulate this was a chance association and that this case does not suggest any relationship between the two diseases.

Child↗

PubMed1997

[Studies on pyridonecarboxylic acids as antibacterial agents. XII. Synthesis and antibacterial activity of 6-chloro-1-cyclopropyl-7-(1-piperazinyl)-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid and analogues].

Sixteen pyridonecarboxylic acids, characterized by having a chlorine atom and a cyclopropyl group at the 6- and 1-position respectively, substituted amino groups at the 7-position, and some substituted groups (chloro, nitro, amino, dimethylamino) at the 8-position, were synthesized. In vitro antibacterial activities of these compounds were tested. The fluoroquinolones ciprofloxacin and norfloxacin were included for comparative purposes. The results showed that both 11 Ca and 11 Cc were 4-8 times more active than ciprofloxacin and norfloxacin against S. aureus-15 in vitro, but with the same activity as ciprofloxacin against E. coli-22 and P. aeruginosa-29.

Animals↗

PubMed1996

Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption.

For almost a half century scientists have striven to develop a theoretical model capable of predicting oral drug absorption in humans. From the pH-partition hypothesis to the compartmental absorption and transit (CAT) model, various qualitative/quantitative approaches have been proposed, revised and extended. In this review, these models are classified into three categories; quasi-equilibrium models, steady-state models and dynamic models. The quasi-equilibrium models include the pH-partition hypothesis and the absorption potential concept, the steady-state models include the film model and the mass balance approaches, and the dynamic models include the dispersion, mixing tank and CAT models. The quasi-equilibrium models generally provide a basic guideline for understanding drug absorption trends. The steady-state models can be used to estimate the fraction of dose absorbed. The dynamic models predict both the fraction of dose absorbed and the rate of drug absorption and can be related to pharmacokinetic models to evaluate plasma concentration profiles.

Administration, Oral↗

PubMed1996

Preparation, characterization, and in vivo evaluation of an oil suspension of a bovine growth hormone releasing factor analog.

Pharmacia & Upjohn Inc. has discovered a superior bovine growth hormone releasing factor analog, [IIe2,Ser8,28,Ala15,Leu27,Hse30] bGRF (1-30)-NH-ethyl, acetate salt (U-90699F), for enhancement of animal growth. This report delineates the preparation, characterization, and in vivo evaluation of a U-90699F oil suspension. The oil suspension formulation was selected because of its simplicity, inexpensiveness, and ability to produce sustained U-90699F release. 40% U-90699F monomers were incorporated into Miglyol oil with acceptable injectability. Both reversed-phase-high-pressure liquid chromatography (RP-HPLC) and Fourier transform infrared spectroscopy (FTIR) were utilized to evaluate its chemical and structural stability. This suspension formulation demonstrated no significant changes in concentration as determined by RP-HPLC for 10 weeks at both 25 and 39 degrees C. The U-90699F dispersed in oil also showed no signs of structural conversion from alpha-helix to beta-sheet as monitored by FTIR. However, there was an increase in alpha-helix/disordered coil structure after initial drug incorporation. The suspension was subcutaneously administered to Holstein steers. Areas under the serum somatotropin concentration curve were used to determine the duration of action. It was found that the suspension was able to effectively elevate serum somatotropin for at least 14 days.

Animals↗

PubMed1996

Negative regulation of gene expression of a novel proline-, threonine-, and glycine-rich protein by water stress in Lycopersicon chilense.

We have isolated a full length cDNA clone (designated PTGRP) encoding a proline-rich protein from leaves of Lycopersicon chilense. Sequence analysis of the 552-bp insert revealed that the open reading frame encodes a 12.6-kDa protein. The deduced amino acid sequence of PTGRP consists of a C-terminal proline-rich domain with two identical repeat motifs Phe-Pro-Met-Pro-Thr-Thr-Pro-Ser-Thr-Gly-Gly-Gly-Phe-Pro-Ser. The N terminus lacks proline and is hydrophobic. Unlike other proline-rich proteins this protein contains five glycine-rich repeat motifs (Gly-X)n representative of glycine-rich proteins. Southern blot analysis showed that PTGRP is a member of a small gene family within the L. chilense genome. Northern blot experiments revealed that the PTGRP gene is significantly down regulated by water stress. PTGRP mRNA transcription decreased 5- to 10-fold in leaves and stems after 4-8 days of water stress. The mRNA reaccumulated when the drought-stressed plants were rewatered. The in situ hybridization experiments also revealed that PTGRP mRNAs were more abundant in leaf sections of plants watered regularly compared with those of plants submitted to water stress. Down regulation of the PTGRP gene was also observed in desiccated cell suspensions of L. chilense and in those treated with abscisic acid, mannitol, and NaCl. Based on the common features of proline-rich proteins (high proline content, repeated motifs, and a putative signal peptide) and their involvement in the cell wall, it is likely that the PTGRP protein is targeted to the cell wall. Its down regulation by drought could be correlated with the remodeling of the plant cell wall in response to water stress.

Amino Acid Sequence↗

PubMed1994

Isolation of an osmotic stress- and abscisic acid-induced gene encoding an acidic endochitinase from Lycopersicon chilense.

We have identified one osmotic stress- and abscisic acid-responsive member of the endochitinase (EC 3.2.1.14) gene family from leaves of drought-stressed Lycopersicon chilense plants, a natural inhabitant of extremely arid regions in South America. The 966-bp full-length cDNA (designated pcht28) encodes an acidic chitinase precursor with an amino-terminal signal peptide. The mature protein is predicted to have 229 amino acid residues with a relative molecular mass of 24,943 and pI value of 6.2. Sequence analysis revealed that pcht28 has a high degree of homology with class II chitinases (EC 3.2.1.14) from tomato and tobacco. Expression of the pcht28 protein in Escherichia coli verified that it is indeed a chitinase. Northern blot analysis indicated that this gene has evolved a different pattern of expression from that of other family members reported thus far. It is highly induced by both osmotic stress and the plant hormone abscisic acid. Southern blot analysis of genomic DNA suggested that the pcht28-related genes may form a small multigene family in this species. The efficiency of induction of the gene by drought stress, in leaves and stems, is significantly higher in L. chilense than in the cultivated tomato. It is speculated that, besides its general defensive function, the pcht28-encoded chitinase may play a particular role in plant development or in protecting plants from pathogen attack during water stress.

Abscisic Acid↗

PubMed1994

[Treatment of refractory acute rejection after renal transplantation with lymphogloline].

156 patients received renal transplantation in the Nanfang Hospital from October 1992 to December 1993. 27 patients developed refractory acute rejection (RAR). Of them, rejection was reversed completely with lymphogloline (ATG) in 22 patients and reversed with OKT3 in 4. One patient died of cerebral hemorrhage after removal of the donor's kidney. The results suggest that ATG is safe, effective, highly specific, sensitive, and of less side-effect. The pathogenesis, diagnosis of RAR and cautions for ATG are discussed.

Adolescent↗