Biomedical subjects

Qiang Zhang

Publications and source records attributed to Qiang Zhang.

At least 145 records · Page 8Linked to original sources

PubMed2004

Transport of proteins and peptides across human cultured alveolar A549 cell monolayer.

An in vitro cultured monolayer system of alveolar epithelial cells was used as a model to investigate the transport pathway of the peptides and proteins, salmon calcitonin (sCT), insulin (INS), recombinant hirudin (rHAV2), and recombinant human growth hormone (rhGH), in pulmonary epithelium. Human lung adenocarcinoma A549 cells formed continuous monolayers when grown on the polycarbonate filters of Transwell plates. The transport of the peptides and proteins having MW of 3400-22,000 Da was studied under different conditions. The results showed that the apparent permeability coefficients (P(app)) of these macromolecules across A549 cell monolayers ranged from 2x10(-6) to 5x10(-6) cm s(-1) and exhibited a good inverse correlation with molecular weight. No concentration, direction, or temperature dependence was observed in the permeation of sCT, INS, and rHAV2. While the P(app) of rhGH in the BA direction (2.25x10(-6) cm s(-1)) was less than that in the AB direction at both concentrations (3.20x10(-6) and 3.29x10(-6) cm s(-1)). The P(app) values of rhGH were concentration and temperature independent in the AB direction. These findings suggest that the hydrophilic peptides and proteins used in this study, sCT, INS, rHAV2, and rhGH, appear to cross the A549 cell monolayers via a paracellular pathway by a passive diffusion mechanism.

Adenocarcinoma↗

PubMed2004

Separation of cefoperazone enantiomers using beta-cyclodextrin as chiral additive by capillary zone electrophoresis.

A capillary electrophoresis method was developed to separate the enantiomers of cefoperazone. Different cyclodextrins, including alpha-cyclodextrin (alpha-CD), beta-cyclodextrin (beta-CD), gamma-cyclodextrin (gamma-CD), 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and methyl-beta-cyclodextrin (Me-beta-CD), were tested as chiral additives in the running buffer. The effect of various parameters on enantioseparation such as concentration of NaH(2)PO(4), buffer pH, and CD concentration was also studied. The cefoperazone enantiomers were baseline separated under conditions of 0.04 mmol/L beta-CD, 75 mmol/L NaH(2)PO(4) buffer at pH 4.0. A fused silica capillary (40 cm effective length x 75 microm ID) was used. The applied voltage and capillary temperature were 20 kV and 25 degrees C, respectively. Under these conditions, linear calibration curves were obtained in the 5-500 microg/ml range using UV detection at 280 nm. The limit of detection for both isomers was 0.1 microg/ml. The method was used for the analysis of different pharmaceutical preparations (dose) and biological samples containing cefoperazone.

Anti-Bacterial Agents↗

PubMed2004

Embryonic development of folate binding protein-1 (Folbp1) knockout mice: Effects of the chemical form, dose, and timing of maternal folate supplementation.

Inactivation of folate binding protein-1 (Folbp1) adversely impacts murine embryonic development, as nullizygous embryos (Folbp1(-/-)) die in utero. Administration of folinic acid (N5-formyl-tetrahydrofolate) to Folbp1-deficient dams before and throughout gestation rescues the majority of embryos from premature death; however, a portion of surviving embryos develop structural malformations, including neural tube defects. We examined whether maternal supplementation with L-N5-methyl-tetrahydrofolate (L-5M-THF) has superior protective effects on embryonic development of Folbp1(-/-) fetuses compared with L-N5-formyl-tetrahydrofolate (L-5F-THF). We also examined the critical period during gestation when folate supplementation is most beneficial to the developing Folbp1(-/-) embryos. Folbp1(-/-) pups presented with a range of malformations involving the neural tube, craniofacies, eyes, and abdominal wall. The frequencies of these malformations decreased with increasing folate dose, regardless of the form used. There was no additional benefit provided by L-5M-THF compared with L-5F-THF. Despite rescuing the phenotype in Folbp1(-/-) embryos, no significant elevation of Folbp1(-/-) maternal folate levels was observed with supplementation.

Animals↗

PubMed2004

Characterization of rat liver microsomal metabolites of AM-630, a potent cannabinoid receptor antagonist, by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry.

The in vitro metabolism of AM-630 was studied by high-performance liquid chromatography coupled with tandem mass spectrometry. AM-630 is an aminoalkylindole analogue that behaves primarily as a potent CB2-selective antagonist. In this study, 17 metabolic products were identified that resulted from the incubation of AM-630 in rat liver microsome preparations. Six metabolic pathways were proposed to account for all detected metabolites: (1) o-demethylation of the methoxyphenyl group, (2) morpholinyl ring opening, (3) hydroxylation on the methoxy/hydroxyl phenyl ring, (4) hydroxylation on the indole ring, (5) hydroxylation on the morpholine ring and (6) loss of the morpholine ring leading to metabolites containing either a hydroxylated or a carboxylated alkyl terminal. Three metabolites were identified as morpholinyl ring-opening products: M1, M6 and M13. Six metabolites (M2-M5, M7 and M8) were proposed to be the products of o-demethylation, hydroxylation on the methoxyphenyl group or the morpholinyl ring, dehydration following morpholinyl ring monohydroxylation, or a combination of the above metabolic pathways. The remaining eight metabolites were attributed to a pathway involving the loss of the morpholine ring at various points during the metabolic processes.

Animals↗

PubMed2004

Automated rectilinear self-gated cardiac cine imaging.

ECG-based gating in cardiac MR imaging requires additional patient preparation time, is susceptible to RF and magnetic interference, and is ineffective in a significant percentage of patients. "Wireless" or "self-gating" techniques have been described using either interleaved central k-space lines or projection reconstruction to obtain MR signals synchronous with the cardiac cycle. However, the interleaved, central line method results in a doubling of the acquisition time, while radial streak artifacts are encountered with the projection reconstruction method. In this work, a new self-gating technique is presented to overcome these limitations. A retrospectively gated TrueFISP cine sequence was modified to acquire a short second echo after the readout and phase gradients are rewound. The information obtained from this second echo was used to derive a gating signal. This technique was compared to ECG-based gating in 10 healthy volunteers and shown to have no significant difference in image quality. The results indicate that this method could serve as an alternative gating strategy without the need for external physiological signal detection.

Electrocardiography↗

PubMed2004

Generation of marker-free transgenic maize by regular two-border Agrobacterium transformation vectors.

By introducing additional T-DNA borders into a binary plasmid used in Agrobacterium-mediated plant transformation, previous studies have demonstrated that the marker gene and the gene of interest (GOI) can be carried by independent T-strands, which sometimes integrate in unlinked loci in the plant genome. This allows the recovery of marker-free transgenic plants through genetic segregation in the next generation. In this study, we have found that by repositioning the selectable marker gene in the backbone and leaving only the GOI in the T-DNA region, a regular two-border binary plasmid was able to generate marker-free transgenic maize plants more efficiently than a conventional single binary plasmid with multiple T-DNA borders. These results also provide evidence that both the right and left borders can initiate and terminate T-strands. Such non-canonical initiation and termination of T-strands may be the basis for the elevated frequencies of cotransformation and unlinked insertions.

Agrobacterium tumefaciens↗

PubMed2004

Rapid quantification of the heteroplasmy of mutant mitochondrial DNAs in Leber's hereditary optic neuropathy using the Invader technology.

PURPOSE: To quantify the degree of heteroplasmy of a mitochondrial DNA (mtDNA) mutation in Leber's hereditary optic neuropathy (LHON) a biplex Invader assay was applied. METHODS: To determine the optimum condition for the Invader assay, mtDNAs were assayed in various amounts of total DNA in 1-4-h incubations at 63 degrees C. To evaluate the suitability of the Invader assay to detect the three mutations, G3460A, G11778A, and T14484C, 10 ng of DNAs from 224 patients with bilateral optic atrophy was assayed. To quantify mtDNA heteroplasmy, a standard curve of known mixture ratios of mutation against calculation by the Invader assay was constructed. Seventy-two of the 224 patients had one of the three mutations, which corresponded with the mutation detected earlier by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. The percentages of mutant mtDNAs were calculated by the Invader assay in five heteroplasmic families, including 30 individuals with the G11778A mutation. The results were compared with those calculated earlier by labeled polymerase chain reaction followed by single-strand conformation polymorphism (PCR-SSCP) analysis. RESULTS: In 1-8 ng of DNA, the fluorescence intensity increased near linearly during a 4-h assay. With more than 16 ng of DNA, the intensities were saturated even at the 2-h assay. A linear relationship was observed between the results obtained from separate mixtures and from the Invader assay analysis. Because two fluorescent intensities are not always the same, one of the two intensities was modified to adjust to that of the other. Complete concordance was observed between PCR-RFLP analysis and Invader assay genotyping for the 224 patients. Results of percentage of heteroplasmy in five LHON families obtained by the Invader assay were consistent with those by the PCR-SSCP analysis. CONCLUSIONS: Invader assay is a simple, rapid, and reliable method of genotyping mtDNA mutations as well as quantifying heteroplasmy simultaneously under optimum conditions.

Base Sequence↗

PubMed2004

Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose.

BACKGROUND: Commonly occurring genetic variants in CYP2C9 are known to reduce catalytic activity and are associated with enhanced patient sensitivity to warfarin. Interethnic differences in warfarin dose requirement have been described in the Asian population, and we postulate that this could be related to genetic variants of CYP2C9 that are unique to ethnic groups. METHODS: We prospectively genotyped 125 patients who were receiving a stable daily warfarin dose to maintain international normalized ratio values between 2 and 3 through comprehensive sequencing of the promoter and coding regions of the CYP2C9 gene. RESULTS: The mean weight-adjusted warfarin maintenance dose was significantly lower for Malay and Chinese subjects than Indian subjects ( P <.001 and.014, respectively). Warfarin dose negatively correlated with age (r = -0.4, P <.001) but not with sex. Multiple variants were detected in the promoter, exonic, intronic, and 3'-untranslated regions of CYP2C9, of which 16 were novel, including 7 nonsynonymous exonic variants ( 208G>C, 374G>A, 485C>A, 895A>G, 1144C>T, 1190A>C, and 1362G>C ). CYP2C9*3, but not CYP2C9*2, was found in Chinese and Malay patients, and carriers of the CYP2C9*3 variant in Chinese ( P <.01) and Indian ( P <.01) patients, but not Malay patients ( P =.77), required less warfarin. The influence of the novel exonic variants on warfarin dose requirement was unclear, because they were rare, but the lower warfarin dose requirement for Chinese and Malay patients existed despite omission of individuals with any coding region variants from analysis. CONCLUSIONS: Interethnic differences in warfarin dosing in Asian subjects may result from other genetic, dietary, or environmental influences; however, these novel variants in the gene warrant further characterization through functional studies.

Adult↗

PubMed2004

Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) on monocytic bone marrow-derived cells in the conjunctiva.

Vascular endothelial growth factor-3 (VEGFR-3), also known as Fms-like tyrosine kinase receptor 4 (FLT-4), was thought to be expressed exclusively on the lymphatic endothelium, high endothelial venules, and rarely on vascular endothelium. It plays a critical role in the development of lymphatics and cancer metastasis. Very recently, however, VEGFR-3 expression has been identified on dendritic cells (DCs) in the inflamed cornea, and related to the trafficking of these cells to lymphoid organs. The current study was performed to evaluate the expression of VEGFR-3 in the conjunctiva. The conjunctiva and limbus of normal and inflamed murine eyes were excised and stained for VEGFR-3. Immunofluorescence double staining for CD11b, CD11c, CD31, CD45, GR-1, CD3, CD80, LYVE-1 and class II major histocompatibility complex (MHC) antigen expression, using confocal microscopy, was performed to further phenotype the VEGFR-3+ cells. VEGFR-3 and LYVE-1 expression was observed on lymphatic, but not blood vessel, endothelium. In addition, we also detected expression of VEGFR-3 on non-endothelial CD45+ bone marrow-derived cells in the conjunctiva of normal and, in an increased number, in inflamed eyes. These cells were uniformly CD11b+, CD3-, and Gr-1-, suggesting a monocytic origin, similar to the VEGFR-3+ cells in the cornea. Nearly half of the VEGFR-3+ cells were also positive for MHC class II expression, and none were positive for CD80 (B7-1), indicating their relative immature status. In contrast to the recently described VEGFR3+ corneal cells, however, VEGFR-3+ conjunctival cells did not express the DC marker CD11c. We conclude that in addition to its known role in lymphangiogenesis, VEGFR-3 is also expressed by a conjunctival monocyte/macrophage lineage, implicating a potential relationship between lymphangiogenesis and leukocyte trafficking in the ocular surface.

Animals↗

PubMed2004

Lessons learned from a multiple-dose post-operative analgesic trial.

Patients undergoing major surgery often require several days of post-operative analgesic management. However, little data are available on the course of post-operative pain during this period. Such data would be extremely helpful in planning treatment, formulating pain management guidelines, and determining how to construct multiple-dose post-operative analgesic clinical trials. The objectives of this study were to determine (1) if post-operative pain severity, as measured by a modified version of the Brief Pain Inventory (BPI), can be categorized as mild, moderate, or severe in terms of modified BPI pain interference scores, (2) the relationship between modified BPI pain ratings and responses to a categorical item that specifically measures post-sternotomy pain, and (3) the relationship between global ratings of study medication effectiveness and other pain measures. This study is a reanalysis of data from patients who underwent coronary artery bypass graft procedures. We found that the pain severity level cut points developed for chronic pain apply equally well to post-operative pain. Based on this classification scheme, 18% of patients reported moderate pain after day 3, while 14% reported severe pain. Only 9% of patients reported experiencing moderate-to-severe pain approximately 2 weeks later, at the end of the study. Describing pain as mild, moderate, or severe could be a simple, meaningful clinical trial outcome measure. Because most patients experience only mild pain 6 days after surgery, long-term clinical trials of post-operative pain control may be more efficient and cost-effective if they focus on the subset of patients with persistent moderate or severe pain.

Aged↗

PubMed2004

Recombinant bivalent vaccine against foot-and-mouth disease virus serotype O/A infection in guinea pig.

In this study, two DNA fragments encoding amino acid (141-160)-(21-140)-(141-160) of the VP1 of FMDV (foot-and-mouth disease virus) serotype O and (138-160)-(21-40)-(138-160) of the serotype A FMDV were chemically synthesized. These two tandem-repeat fragments were ligated and transfected into prokaryotic expression vector pTrcHis A to construct pTH-O-A. The other vector called pTH-O-scIgG-A was constructed similarly only that the two tandem-repeat DNA fragments were linked by the bovine-IgG heavy chain coding sequence. Guinea pigs immunized with the two bivalent vaccines pTH-O-A and pTH-O-scIgG-A showed both specific antibody activity and T cell proliferation responses. FMDV challenge tests showed that 85% and 70% of guinea pigs vaccinated twice with 200 mg of the fusion protein of pTH-O-A were protected from FMDV serotype O and serotype A infection respectively. 70% and 57% of the guinea pigs immunized with the fusion protein of pTH-O-scIgG-A were protected from FMDV serotype O and serotype A infection respectively.

Animals↗

PubMed2004

Vulnerability of allogeneic retinal pigment epithelium to immune T-cell-mediated damage in vivo and in vitro.

PURPOSE: Because retinal pigment epithelium (RPE) constitutively expresses class I major histocompatibility complex (MHC) molecules, and CD95 ligand and secretes immunosuppressive factors, the vulnerability of these cells to attack by immune T cells is open to question. This study was conducted to determine the vulnerability of allogeneic RPE to damage by specifically sensitized T cells, both in vivo within the subretinal space, and in vitro. METHOD: BALB/c lymphocytes presensitized to C57BL/6 antigens were injected into the subretinal space of eyes of C57BL/6 and gld/gld mice, and the eyes were examined clinically and histologically. RPE eyecups were produced from mouse eyes by removing the anterior segment and neuronal retina, leaving an intact monolayer of RPE. Sensitized BALB/c lymphocytes were placed in the RPE eyecup and incubated for 4 hours. The RPE layer of the eyecups was assessed by confocal microscopy for viability, after staining with propidium iodide and acridine orange. RESULT: Eyes that received T cells sensitized to C57BL/6 antigens displayed a circumscribed patch of persistent choroidal "whitening" clinically and a disrupted RPE cell layer histologically at the injection site at 5 days after injection. By 14 days, only RPE cells at the injection site were lost. RPE in eyecup preparations was relatively resistant in vitro to cytolysis by sensitized T cells, whether the eyecups were obtained from CD95-deficient or wild-type mice. CONCLUSIONS: RPE monolayers, both in vivo and in vitro, are relatively resistant to immune-mediated attack by specifically sensitized T cells. This relative lack of vulnerability is independent of the expression of CD95 ligand by target RPE cells and implies that immune barriers to acceptance of allogeneic RPE transplants may be less than if transplanted cells are from nonocular tissues.

Animals↗

PubMed2004

Purification, molecular cloning, and expression of a novel growth-promoting factor for retinal pigment epithelial cells, REF-1/TFPI-2.

PURPOSE: Retinal pigment epithelial (RPE) cells are known to play important roles in maintaining the homeostasis of the retina and in controlling choroidal neovascularization. The purpose of this study was to identify a factor or factors that would stimulate RPE cells to proliferate. METHODS: To isolate such a factor, 100 L of human-fibroblast-conditioned medium underwent ion-exchange, hydrophobic, and reverse-phase chromatographies followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The growth-promoting activity of the factor was examined in a human K-1034 RPE cell line and human primary RPE cells. RESULTS: The different chromatographic processes isolated a 31-kDa factor that had RPE cell growth-promoting properties. This factor, which we have named RPE cell factor (REF)-1, promotes growth of RPE cells but not of human umbilical vein endothelial cells (HUVECs). The amino-terminal sequence and molecular cloned cDNA of REF-1 were identical with those of tissue-factor pathway inhibitor (TFPI)-2, a family of TFPIs, and placental protein (PP)-5, a serine protease inhibitor. The cDNA expression of REF-1/TFPI-2 with pcDL-pSRalpha vector in Chinese hamster ovary (CHO) cells confirmed the growth-promoting activity for RPE cells. The major component of the recombinant REF-1/TFPI-2 expressed in CHO cells had a molecular mass of 31 kDa and exerted growth-promoting activity in RPE cells but not in human endothelial cells and fibroblasts in vitro. REF-1/TFPI-2 also had protease inhibitory activity. The other family factor, TFPI-1, did not promote RPE cell growth. CONCLUSIONS: REF-1/TFPI-2 is a novel growth-promoting factor for RPE cells but not for endothelial cells and fibroblasts. Its properties make it potentially beneficial for intraocular therapy for the repair and maintenance of RPE cells.

Amino Acid Sequence↗

PubMed2004

Antipyretic, analgesic and anti-inflammatory activities of ketoprofen beta-cyclodextrin inclusion complexes in animals.

Ketoprofen is a nonsteroidal anti-inflammatory drug (NSAID) orally effective in treating fever, pain, and inflammation but gastrointestinal side effects were observed. Preparation of ketoprofen beta-cyclodextrin inclusion complexes was to increase the solubility and reduce the irritation. The complexes were prepared and preliminarily confirmed using X-ray diffraction and dissolution test. Antipyretic, analgesic and anti-inflammatory models were induced by 10% yeast using rabbits, 0.8% acetic acid using mice and 1% carrageenin using rats, respectively. Results showed that the dissolution rate of ketoprofen was significantly improved by complexation. X-Ray diffraction pattern of the complexes exhibited a diffuse pattern that differed from that of physical mixture of ketoprofen and beta-cyclodextrin. Ketoprofen markedly inhibited the fever reactions at a single dose of 2 mg/kg as follows: 64.53% (inhibition rate %) at 1 h for ketoprofen, 73.04% at 1 h for ketoprofen beta-cyclodextrin inclusion complexes, respectively. Alleviating pain reaction rates following a single dose of 8 mg/kg at 20 min were 39.25% for the inclusion complexes and 26.72% for ketoprofen, respectively. Inhibition rates to rat edema following a single dose of 5 mg/kg at 1 h were 39.47% for the inclusion complexes and 23.86% for ketoprofen. Results for antipyretic, analgesic and anti-inflammatory activities showed that the rapid and stronger effects were found in the treatment group of ketoprofen beta-cyclodextrin inclusion complexes in comparison with those of free ketoprofen.

Adjuvants, Pharmaceutic↗

PubMed2004

A pegylated liposomal platform: pharmacokinetics, pharmacodynamics, and toxicity in mice using doxorubicin as a model drug.

Aims were to observe pharmacokinetics, pharmacodynamics, and toxicity for constructing a Sino-pegylated liposomal platform. Human hepatocarcinoma cells (Bel7402) and murine hepatocarcinoma cells (H(22)) were used for the cytotoxicity assay and the in vivo solid xenograft tumor model in mice, respectively. Pharmacokinetic results in mice showed that the pegylated liposomal doxorubicin markedly prolonged the blood circulation of doxorubicin. Elimination half-time (T(1/2,gamma)) of pegylated, regular liposomal doxorubicin and free doxorubicin were 46.09 +/- 14.44, 26.04 +/- 3.34, and 23.72 +/- 5.13 h, respectively. The area under the concentration-time curves (AUC(0- infinity )) (h. microg/g) of the pegylated and regular liposomal doxorubicin were 6.8- and 2.6-fold higher than that of free doxorubicin, respectively. Cytotoxicity and antitumor activity in vivo indicated that activity of the pegylated liposomal doxorubicin was higher than that of the regular or the free one, respectively. After two weeks of tail intravenous injection of the pegylated liposomal doxorubicin at a single dose of 10 mg/kg, no significant damage was observed in gastric, intestinal mucosa, and heart muscle, but pronounced damages were found in the control group after dosing free doxorubicin. The results demonstrate that the pegylated liposomes improve the efficacy of toxics and reduce the toxicity, therefore providing favorable evidence for building a pegylated liposomal platform.

Animals↗

PubMed2004

Predicting pharmacokinetic herb-drug interactions.

In vitro and in vivo studies have indicated that the induction or inhibition of cytochrome P450 (CYP) is one of the major mechanisms for some clinically important pharmacokinetic herb-drug interactions. Thus, an attempt was made to predict pharmacokinetic herb-drug interactions using the pharmacokinetic principles that are used for predicting drug-drug interactions. The expected AUC ratio was mainly dependent on unbound herbal inhibitor concentration ([I]) and inhibition constant (Ki), hepatic fraction (fh), number of inhibitory herbal constituents (n) and metabolic pathway fraction in hepatic metabolism (fm). Herb-drug interactions would be with low risk if sigma(i=1)n [[Ii]/Ki(i)] is less than 0.1, medium risk if it is between 0.1 and 1.0, and high risk if it is greater than 1. For high clearance drugs, the change of fh x fm had minor influence on AUC ratio when sigma(i=1)n [[Ii]/Ki(i)] values were fixed. Similarly, fm did not affect the AUC ratio for low clearance drugs. It appeared likely to predict a herb-drug metabolic interaction when [I], Ki, fh, fm and n could be determined. However, many herb- and drug-related factors may cause difficulties with the prediction, and well-designed human studies are always necessary.

Area Under Curve↗

PubMed2004

Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4.

Cytochrome P450 (CYP) 3A4 is not only the most abundant isoform in human liver but also metabolizes approximately 60% of the therapeutic drugs. This feature renders CYP3A4 highly susceptible to both reversible and irreversible (mechanism-based) inhibition. The latter is characterized by NADPH-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYPs to reactive metabolites. Mechanism-based inactivation of CYP3A4 by drugs can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. The clinical pharmacokinetic effect of a CYP3A4 inactivator is a function of its KI, kinact and partition ratio and the synthesis rate of new or replacement enzyme. Predicting drug-drug interactions involving CYP3A4 inactivation is possible when proper pharmacokinetic principles are followed. However, the prediction may become difficult, since the clinical outcomes due to CYP3A4 inactivation depend on many factors associated with the enzyme, drugs and the patients. A number of clinically important drugs have been identified to be mechanism-based CYP3A4 inhibitors. These include antibiotics (e.g. erythromycin and isoniazid), anticancer drugs (e.g. tamoxifen), antidepressants (e.g. fluoxetine and midazolam), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine and verapamil), steroids and their receptor modulators (e.g. gestodene and raloxifene), and some herbal constituents (e.g. bergamottin and glabridin). Compared to reversible inhibition, mechanism-based inhibitors of CYP3A4 more frequently cause unfavorable drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesized CYP3A4 protein. Most CYP3A4 inactivators are also PgP substrates/inhibitors, confounding the in vitro-in vivo extrapolation. Clinicians should have good knowledge on these CYP3A4 inactivators and avoid their combination use.

Animals↗

PubMed2004

[Study on preparation conditions for polylactide nanoparticles loaded cyclosporine A and its oral bioavailability in rats].

AIM: To develop a less toxic alternative for sandimmun neoral (Neoral). To study the preparation conditions and to compare its pharmacokinetic characteristics with Neoral. METHODS: Polylactide nanoparticles loaded cyclosporine A was prepared by solvent-nonsolvent method. Polylactide nanoparticles were administered by oral in a dosage of 15 mg.kg-1. The CyA concentration in whole blood sample was determined by HPLC. RESULTS: The quantities of CyA, PLA and volume of acetone added had significant influence on the NP diameters. Under proper condition, the nanoparticles with diameters of 57.5 nm were obtained. The relative bioavailability in rats was 101.6%, with a smaller absorption rate (P < 0.05) and a smaller elimination rate (P < 0.1). CONCLUSION: The nanoparticles (diamater < 100 nm) with relative high bioavailability were prepared using solvent-nonsolvent method. It is suitable for further study.

Administration, Oral↗