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D Y Liu

Publications and source records attributed to D Y Liu.

At least 37 records · Page 2Linked to original sources
PubMed2000

Design, synthesis, and biological evaluation of aromatic ester prodrugs of 1-(3'-hydroxypropyl)-2-methyl-3-hydroxypyridin-4-one (CP41) as orally active iron chelators.

In order to improve chelation efficacy and to minimise toxicity, eleven aromatic ester prodrugs of 1-(3'-hydroxypropyl)-2-methyl-3-hydroxypyridin-4-one (CP41) have been synthesised. The distribution coefficients of these ester prodrugs between 1-octanol and MOPS buffer pH 7.4 were measured together with their rates of hydrolysis at pH 2 and pH 7.4, in rat blood and liver homogenate. The biliary metabolic profiles of selected ester prodrugs were investigated in rats. The in vivo iron mobilisation efficacy of these ester prodrugs has been compared with that of the parent drug using a 59Fe-ferritin loaded rat model. The hydrolytic rates of these esters vary appreciably, esters with heteroaromatic acid moieties being less stable than the corresponding benzoyl analogues. Many prodrugs were found to enhance the ability of the parent hydroxypyridinone to facilitate 59Fe excretion, the optimal effect being observed with the 4-methylbenzoyl ester derivative 8d. However, not all prodrugs provide an increased efficacy, indicating that lipophilicity is not the only factor which influences drug efficacy. Furthermore no clear correlation between lipophilicity, susceptibility towards hydrolysis and efficacy was detected.

Animals↗
PubMed2000

Defective sperm-zona pellucida interaction: a major cause of failure of fertilization in clinical in-vitro fertilization.

Sperm-zona pellucida binding and penetration were assessed on the oocytes that failed to fertilize from couples with >/=3 oocytes treated by standard in-vitro fertilization (IVF). There were four groups: fertilization rate 0% (n = 369), 1-25% (n = 194), 26-50% (n = 81) and 51-95% (n = 100). Of the couples with zero fertilization rate 70% had </=5 spermatozoa bound per zona pellucida and 42% had no spermatozoa penetrating the zona pellucida of any oocyte. In contrast, in the 51-95% fertilization rate group, only 17% had </= 5 spermatozoa bound per zona pellucida and 6% had no spermatozoa penetrating the zona pellucida. There was a significantly higher frequency of poor sperm morphology (</= 5% normal) in couples with zero fertilization rate (36%) than in the fertilization rate group 51-95% (7%). Incubation of oocytes from 68 couples with zero fertilization rate and low sperm-zonae pellucidae binding with fertile donor spermatozoa resulted in normal sperm-zona pellucida binding and most zonae pellucidae being penetrated. In conclusion, defective sperm-zona pellucida interaction was the major cause for low fertilization rates in standard IVF. This was usually because of defects of the spermatozoa rather than defects of the oocytes. Sperm defects likely to cause failure of fertilization should be diagnosed before commencing IVF and the patients directed to intracytoplasmic sperm injection.

Female↗
PubMed2000

Biliary and urinary metabolic profiles of 1,2-diethyl-3-hydroxypyridin-4-one (CP94) in the rat.

This study compares the biliary and urinary metabolic profiles of 1,2-diethyl-3-hydroxypyridin-4-one (CP94), an orally active iron chelator, in the normal rat. Surprisingly, CP94 was found to form two phase II metabolites, the 3-O- and 4-O-glucuronides. These glucuronides accounted for 38 and 28% of the administered CP94 dose, in bile and urine, respectively. Unchanged CP94 accounted for 5% of the CP94 dose in both bile and urine. The 2-(1'-hydroxy) metabolite of CP94 was found to be the dominant metabolite in urine. In addition, an unstable metabolite was detected in the bile although its structure remains unknown at the present stage. The excretion of iron in bile, after administration of CP94, was found to parallel the biliary elimination of CP94 together with its hydroxylated derivatives, indicating the importance of metabolites in iron excretion.

Animals↗
PubMed2000

The human acrosome reaction.

We developed tests of sperm-oocyte interaction: sperm-zona binding, zona-induced acrosome reaction, spermzona penetration and sperm-oolemma binding, using oocytes which failed to fertilise in clinical in vitro fertilization (IVF). Although oocyte defects contribute to failure of sperm oocyte interaction, rarely are all oocytes from one woman affected. Low or zero fertilization in standard IVF was usually caused by sperm abnormalities. Poor sperm-zona pellucida binding was frequently associated with failure of standard IVF and obvious defects of sperm motility or morphology. The size and shape of the acrosome is particularly important for sperm binding to the oocyte. The proportion of acrosome intact sperm in the insemination medium was related to the IVF rate. Inducing the acrosome reaction with a calcium ionophore reduced sperm-zona binding. Blocking acrosome dispersal with an acrosin inhibitor prevented spermzona penetration. Sperm-zona penetration was even more highly related to IVF rates than was sperm-zona binding. Some patients had low or zero fertilization rates with standard IVF but normal sperm by conventional tests and normal sperm-zona binding. Few of their sperm underwent the acrosome reaction on the surface of the zona and none penetrated the zona. In contrast, fertilization and pregnancy rates were high with intracytoplasmic sperm injection. We call this condition defective zona pellucida induced acrosome reaction. Discovery of the nature of the abnormalities in the signal transduction and effector pathways of the human zona pellucida induced acrosome reaction should result in simpler tests and treatments for the patients and also provide new leads for contraceptive development.

Acrosome Reaction↗
PubMed2000

[The treatment of hypopharyngoesophageal stenosis].

OBJECTIVE: To improve the curative effects of hypopharyngoesophageal stenosis. METHOD: 35 patients treated for hypopharyngoesophageal stenosis were retrospectively reviewed. The curative methods were selected on the stage of stenosis, including drug, dilatation, reconstruction of hypopharynx and oesophagus. RESULT: 33 patients resumed a normal oral diet, no stenosis of anastomosis occurred. CONCLUSION: For the early mild lesions, using of steroids, antibacterial and dilatation is considered to be the procedure of choice, for those severe lesions, reconstruction of hypopharynx and oesophagus with selected appropriate materials can obtain good results.

Adolescent↗
PubMed1999

Synthesis, physicochemical characterization, and biological evaluation of 2-(1'-hydroxyalkyl)-3-hydroxypyridin-4-ones: novel iron chelators with enhanced pFe(3+) values.

The synthesis of a range of 2-(1'-hydroxyalkyl)-3-hydroxypyridin-4-ones as bidentate iron(III) chelators with potential for oral administration is described. The pK(a) values of the ligands and the stability constants of their iron(III) complexes have been determined. Results indicate that the introduction of a 1'-hydroxyalkyl group at the 2-position leads to a significant improvement in the pFe(3+) values. Such an effect was found to be greater with the hydroxyethyl substituent than with the hydroxymethyl substituent, particularly in the cases of 1-ethyl-2-(1'-hydroxyethyl)-3-hydroxypyridin-4-one (pFe(3+) = 21.4) and 1,6-dimethyl-2-(1'-hydroxyethyl)-3-hydroxypyridin-4-one (pFe(3+) = 21.5) where an enhancement on pFe(3+) values in the region of two orders of magnitude is observed, as compared with Deferiprone (1, 2-dimethyl-3-hydroxypyridin-4-one) (pFe(3+) = 19.4). The ability of these novel 3-hydroxypyridin-4-ones to facilitate the iron excretion in bile was investigated using a [(59)Fe]ferritin-loaded rat model. Chelators and prodrug chelators possessing high pFe(3+) values show great promise in their ability to remove iron under in vivo conditions.

Animals↗
PubMed1999

Gradient ion-pair high-performance liquid chromatographic method for analysis of 3-hydroxypyridin-4-one iron chelators.

A gradient ion-pair HPLC separation of highly hydrophilic 3-hydroxypyridin-4-one (HPO) iron chelators is described. The separation of HPOs was performed using a reversed-phase polymer HPLC column (PLRP-S 100 A, 15x0.46 cm ID, 5 microm). The ion-pair buffer contained 1-heptanesulfonic acid (sodium salt) (5 mM) and the pH was adjusted to 2.0 using HCl. The gradient was 2%-35% CH3CN in 20 min and post-run was followed for 5 min using 2% CH3CN and 98% buffer. The flow-rate was 1 ml/min and the analytes were monitored at 280 nm. The retention times of 30 hydrophilic HPOs fell in the range of 10-18 min with sharp peak shapes, although these iron chelators possess various functional groups and distribution coefficients. The application of this HPLC method in the analysis of HPO chelators and their metabolites in rat bile and urine is described.

Animals↗
PubMed1999

Liquid extraction and ion-pair HPLC for determination of hydrophilic 3-hydroxypyridin-4-one iron chelators.

Hydrophilic 3-hydroxypyridin-4-ones (HPOs), such as 1-(2'-carboxyethyl)-2-methyl-3-hydroxypyridin-4-one (CP38), 1-(3'-hydroxypropyl)-2-methyl-3-hydroxypyridin-4-one (CP41) and 1-(2'-hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP102), are orally active iron chelators and ester prodrugs of these molecules are currently under investigation. A liquid extraction method using acetonitrile and 2-propanol (80:20 v/v) under acidic and NaCl-saturated conditions has been developed in order to efficiently extract these HPOs from various matrices. The extracted HPOs were determined using a reversed phase polymer HPLC column (PLRP-S 100 A) and the gradient ion-pair mobile phase containing tetrabutylammonium chloride (5 mM) and EDTA (0.5 mM). The extraction recovery of these chelators in phosphate buffer, rat blood and liver homogenate varied from 85 to 94%. The coefficients of variation (C.V.) for within-day determination were in the range of 1.4-3.3% at 1 mM and 2.0-4.7% at 0.1 mM. High accuracy of determination was also achieved.

Chromatography, High Pressure Liquid↗
PubMed1999

An important role of actin polymerization in the human zona pellucida-induced acrosome reaction.

The effects of inhibitors of actin polymerization and depolymerization, cytochalasins and phalloidin, on the human zona pellucida (ZP)-induced acrosome reaction (AR) were investigated. Motile spermatozoa, selected by swim-up technique from normozoospermic men, were incubated in medium with or without the actin modulators. Oocytes (four per test) which had failed to fertilize in vitro were added and incubation continued for 2 h. The spermatozoa bound to the ZP were dislodged by repeatedly aspirating the oocytes with a small-bore pipette and the status of the acrosomes was determined by fluorescein-labelled Pisum sativum agglutinin (PSA). Double immunofluorescent staining with PSA and an anti-actin monoclonal antibody illuminated the acrosomal region of acrosome-intact spermatozoa. In calcium ionophore-induced AR spermatozoa, actin staining was confined to the equatorial segment, post-acrosomal region and tail. Cytochalasins B and D significantly inhibited ZP-induced AR in a dose-dependent manner (P < 0.001). Both inhibitors had no effect on the acrosome of spermatozoa in the insemination medium. Cytochalasin B or D (10-40 micromol/l) had no effect on total percentage motile spermatozoa but decreased sperm velocity and hyperactivation. Phalloidin had no effect on the ZP-induced AR or sperm motility. In conclusion, actin polymerization plays an important role in human ZP-induced AR.

Acrosome Reaction↗
PubMed1999

Synthesis, physicochemical properties and biological evaluation of aromatic ester prodrugs of 1-(2'-hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP102): orally active iron chelators with clinical potential.

The synthesis of seven aromatic ester derivatives of 1-(2'-hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one is described. These ester prodrugs have been designed to target iron chelators to the liver, the major iron storage organ. In principle this should improve chelation efficacy and minimize toxicity. The distribution coefficients of these ester prodrugs between 1-octanol and MOPS buffer pH 7.4 were measured together with their rates of hydrolysis at pH 2 and pH 7.4, in rat blood and liver homogenate. Esters with heteroaromatic acid moieties were found to be less stable than benzoyl analogues. The in-vivo iron mobilisation efficacy of these ester prodrugs has been compared with that of the parent drug using a 59Fe-ferritin loaded rat model. Many prodrugs were found to enhance the ability of the parent hydroxypyridinone to facilitate 59Fe excretion. However, not all prodrugs provided increased efficacy, demonstrating that lipophilicity is not the only factor which influences drug efficacy. Furthermore, no clear correlation between efficacy and susceptibility to hydrolysis was detected. The picolinic and nicotinic ester derivatives appear to offer the best potential as prodrugs as they have a relatively low LogP value and yet lead to enhanced efficacy over the parent hydroxypyridinone.

Administration, Oral↗
PubMed1999

Induction and inhibition of the in vitro N1-oxidation of 9-benzyladenine and isomeric 9-(nitrobenzyl)adenines.

The present study investigated some aspects of the enzymology of the in vitro N1-oxidation of 9-benzyladenine (BA) and isomeric 9-(nitrobenzyl)adenines (NBAs) using various potential inducers and inhibitors of cytochrome P-450 (CYP). When incubated with phenobarbital-induced rabbit hepatic microsomes, the N1-oxidation rates of BA and 9-(4-nitrobenzyl)adenine were about 6- and 2-fold higher than that of the control, respectively; while the N1-oxidation of 9-(2-nitrobenzyl)adenine and 9-(3-nitrobenzyl)adenine was not markedly affected. In contrast, beta-naphthoflavone and Arochlor 1254 showed no inductive effects towards the N1-oxidation of any of these substrates. Using 12 typical CYP inhibitors, it was found that nifedipine (CYP3A inhibitor) and haloperidol (CYP2D inhibitor) showed significant inhibition towards the N1-oxidation of BA and NBAs. Therefore, the N1-oxidation of BA and NBAs is probably catalysed by CYP3A and CYP2D subfamilies. Furthermore, when 9-(4-nitrobenzyl)adenine was incubated with compounds which possessed a certain chemical similarity to the adenine substrate, various degrees of inhibition of N1-oxidation of 9-(4-nitrobenzyl)adenine were observed. These observations allowed a preliminary indication as to the structure-metabolism relationship of 9-substituted adenine derivatives.

Adenine↗
PubMed1999

Comparison of metabolic rates of some 9-aralkyladenines obtained using hamster hepatic microsomes.

Previous investigations have revealed that N1-oxidation is a major metabolic pathway in vitro for some 9-aralkyladenines (AAs) such as 9-benzyladenine (BA). However, dealkylation and other metabolic pathways are also involved. In addition, various substituents on the benzyl moiety of BA seem to have a marked effect on the metabolic rate. In order to establish the potential structure-metabolism relationship of this class of compounds, the enzyme kinetics of the substrates, which possess 2'-nitro (2NBA), 3'-nitro (3NBA), 4'nitro (4NBA), 2'-chloro (2CBA), 2'-methyl (2MBA), or 2-methoxy (2MOBA) substitution of the benzyl moiety of BA, were compared using hamster hepatic microsomes. The results show that the formation rates of the N1-oxides are in the order 2NBA > 2CBA > BA > 3NBA and 4NBA > 2MBA and 2MOBA; the formation rates of the total metabolites except N1-oxides are in the order 2MOBA and 2MBA > 2CBA > BA > 4NBA > 3NBA > 2NBA; however, the total biotransformation rates of the substrates are in the order 2MBA and 2MOBA > 2CBA > BA and 2NBA > 4NBA > 3NBA. The results strongly imply that the electronic, steric and other physicochemical properties are potential controlling factors for AA metabolism.

Adenine↗
PubMed1998

Calcium ionophore-induced acrosome reaction correlates with fertilization rates in vitro in patients with teratozoospermic semen.

The aim of this study was to determine the relationship between calcium ionophore A23187-induced acrosome reaction (AR) and sperm fertilizing ability. Semen samples remaining after preparation for standard IVF were studied in 109 patients who had sperm concentrations > or =20 x 10(6)/ml. Ionophore-induced AR was performed on motile spermatozoa selected by centrifugation on a Percoll gradient. Semen analysis was performed using standard methods. Patients with higher (>50%, n = 76) fertilization rates had significantly higher ionophore-induced AR than patients with lower (<50%, n = 33) fertilization rates (49 +/- 14 versus 38 +/- 21%, P < 0.05). When the data from all patients were analysed by logistic regression, only the percentage sperm motility in insemination medium and ionophore-induced AR were significantly related to fertilization rates. Similar results were also obtained when the data from a subgroup of patients with poor (<15% normal) sperm morphology were analysed. However, when patients with normal sperm morphology > or =15% were analysed separately, only sperm count and the percentage of spermatozoa with progressive motility in semen were significantly related to fertilization rates. In conclusion, ionophore-induced AR was significantly related to fertilization rates in vitro mainly in patients with teratozoospermic semen. Tests for ionophore-induced AR may provide additional information about sperm fertilizing ability but may not indicate specific defects of the physiological AR.

Calcimycin↗
PubMed1998

The expression of vascular endothelial growth factor isoforms in cultured human endometrial stromal cells and its regulation by 17beta-oestradiol.

Angiogenesis or formation of new blood vessels is required for regeneration of the endometrium after its breakdown during each menstruation. Vascular endothelial growth factor (VEGF), a family of recently discovered angiogenic factors, may be involved in the repair and growth of the endometrium. In this study reverse transcription-polymerase chain reaction (PCR) was used to confirm the presence of VEGF mRNA and restriction enzyme digestion to confirm the identity of PCR products generated from different VEGF isoforms in cultured human endometrial stromal cells. The shortest isoform, VEGF 121, was the most abundant in quiescent stromal cells. It was about one-and-a-half times that of VEGF 165. The longest isoform, VEGF 206, was not detected; only a relatively weak signal for VEGF 189 was detectable. The mRNA for VEGF increased 2-fold after stimulation by 17beta-oestradiol (10 nM) for 30 min. A further increase to 3-fold above baseline occurred after 2 h incubation and remained steady at 6 h incubation, but decreased to 2-fold of baseline after 15 h. There was no differential stimulation of mRNA for VEGF isoforms: the ratio of VEGF 121 to 165 remained constant at 3:2 during the course of the incubation, with the exception at 15 h incubation when the ratio was 2:1. The VEGF protein, determined by specific enzyme immunoassay, increased from undetectable at baseline to 79.8 +/- 18.9 pg/ml (n = 4, mean +/- SD, 9.6 cm2/well/ml) after 2 h, with a further significant increase to 249.5 +/- 27.3 pg/ml after 15 h and 695.0 +/- 41.4 pg/well after 39 h. At 15 h incubation, the specific oestradiol antagonist ICI 182,780 (1 microM) significantly reduced VEGF secretion by 25% from 249.5 +/- 27.3 to 189.0 +/- 26.6 pg/ml. Thus, VEGF showed specific patterns of isoform expression in the human endometrial stromal cells; oestradiol (10 microM) stimulated, but not differentially, the mRNA for VEGF isoforms.

Cells, Cultured↗
PubMed1998

Reduction of acute and reactivated colitis in rats by an inhibitor of neutrophil activation.

Neutrophils have been implicated as major contributors to tissue injury in inflammatory bowel disease. In this study, we have assessed the effects of an inhibitor of neutrophil activation and adherence, NPC-18915 (4-¿2-[2-(2-benzofuranyl)phenyl]-(E)-ethenyl¿benzoic acid sodium salt), in models of both acute and reactivated colitis. Acute colitis was induced by intracolonic administration of a hapten. In other rats, colitis was reactivated 6 wk after a bout of acute colitis by subcutaneous administration of the hapten. NPC-18915 given during the first 4 days after induction of acute colitis significantly reduced tissue injury and the incidence of diarrhea and adhesions. When treatment of NPC-18915 was initiated after colitis was firmly established (48 h posthapten), it did not produce a significant effect. NPC-18915 was effective at significantly reducing colonic injury and granulocyte infiltration in the reactivated colitis model, and a similar effect could be observed in rats treated with antineutrophil serum. These results demonstrate that an inhibitor of neutrophil activation is effective in both acute and reactivated colitis, although in the former case, effectiveness is only seen when the drug is given before full establishment of colitis. These results also suggest that neutrophils, are a critical effector cell of hapten-induced colitis in the rat, particularly in the case of reactivated colitis.

Acute Disease↗
PubMed1998

Interleukin-1 beta induces cyclooxygenase-2 gene expression in cultured endometrial stromal cells.

Increasing evidence indicates that PGs may play an obligatory role in blastocyst implantation. Cyclooxygenase (also known as PGH synthase) isozymes 1 and 2 catalyze the rate limiting steps in the biosynthesis of PGs. The ubiquitous cyclooxygenase-1 (COX-1) subserves housekeeping functions, whereas the inducible cyclooxygenase-2 (COX-2) is expressed by limited cell types and tightly controlled. Here we report the induction of COX-2 gene expression by interleukin-1 beta (IL-1 beta) in cultured human endometrial stromal cells. COX-2 activity was induced by IL-1 beta (1 ng/mL); conversion of exogenous arachidonic acid to PGF2 alpha increased from 2.6 +/- 0.6 ng/well (mean +/- SEM; n = 6) to 22.2 +/- 5.6 ng, but was completely blocked (2.8 +/- 0.7 ng/well) by NS-398, a specific COX-2 inhibitor. Undetectable in quiescent stromal cells, messenger ribonucleic acid for COX-2 was induced 30 min after IL-1 beta treatment, reached a maximum at 4 h, and decreased after 15 h. Protein synthesis was not required for induction of the COX-2 gene, as it was blocked by actinomycin D but not by cycloheximide. The 70-kDa COX-2 protein was not detected in quiescent cells, became detectable 6 h after IL-1 beta treatment, and remained detectable even after 15 h. IL-1 beta (0.1-100 ng/mL) increased the luciferase activity in promoterless luciferase reporter containing the 900-bp 5'-flanking sequence (-891 to +9) of the COX-2 gene in a dose-dependent manner, with an ED50 of 0.1-1 ng/mL.

Arachidonic Acid↗
PubMed1998

Delayed administration of low-dose NPC18915 ameliorates lung ischemia-reperfusion injury.

BACKGROUND: NPC18915, a member of new antiinflammatory agent called nactins (neutrophil activation inhibitors), has been shown to reduce reperfusion injury in rat lung transplantation at high dosage. In vitro studies have demonstrated effectiveness of this compound even at low dosage. We hypothesized that this compound ameliorates lung ischemia reperfusion injury even at low dosage levels if administration is optimally timed. The aim of this study was to determine the efficacy and the best timing for administration of low-dose NPC18915. METHODS: Forty syngeneic rat left lung transplantations were performed. All isografts were flushed with low-potassium dextran-1% glucose solution 20 ml and preserved for 18 hours at 4 degrees C. Animals were divided into four groups. Group I animals (n = 10) served as control subjects. In groups II (n = 10), III (n = 10), and IV (n = 10), NPC18915 (0.04 mg) was added to the flush solution and was administered intravenously (0.4 mg/kg) immediately before reperfusion (group II) and 60 minutes (group III) and 120 minutes (group IV) after reperfusion. Pulmonary function was assessed 24 hours after reperfusion. RESULTS: In group III, oxygenation improved in comparison to group I (247.2 +/- 59.8 versus 76.6 +/- 16.0 mm Hg, p < 0.002). Wet-to-dry weight ratio and graft myeloperoxidase activity were significantly improved (group III versus group I, 6.02 +/- 0.21 versus 7.19 +/- 0.41, p = 0.013) (group III versus group I, 0.093 +/- 0.019 versus 0.207 +/- 0.023 delta optical density/min/mg, p < 0.002). There were no significant differences in CD11b expression. CONCLUSION: These data suggest that delayed administration of NPC18915, 60 minutes after reperfusion, dramatically improves pulmonary graft function.

Animals↗