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Biomedical subjects

C M Lai

Publications and source records attributed to C M Lai.

At least 37 records · Page 2Linked to original sources
PubMed1996

Production of monoclonal and polyclonal antibodies against various haemoglobins for the detection of thalassaemias.

The thalassaemias are a major group of genetic disorders in Southeast Asia that affect the production of the alpha-globin chain (alpha-thalassaemia) or the beta-globin chain (beta-thalassaemia) of the haemoglobin. As a result of defective globin chain synthesis, individuals with this disorder show varying degrees of anaemia due to ineffective erythropoiesis and haemolysis. The presence of abnormal haemoglobins in thalassaemia patients has enabled the detection of thalassaemia using immunological methods which have certain advantages over the conventional diagnostic methods. This paper reviews the application of various types of antibodies against the different types of haemoglobins used for the detection of thalassaemia. The developed antibodies include the polyclonal antibodies against Hb Bart's and Hb H; monoclonal antibodies (mab) against Hb H, used in a sandwich enzyme-linked immunosorbent assay (ELISA), for detecting carriers of (--SEA/) deletion and deletions involving the complete zeta-alpha-globin gene cluster, such as (--alpha FIL/), (--alpha THAI/) and (--HW/), which are the common deletional alpha-thalassaemias in Southeast Asians; mab against zeta-globin chains used in an immunocytological test, for the detection of adult carriers of (--SEA/) deletion except for (alpha 20.5/), (--alpha FIL/) and (--alpha THAI/) (this simple test is useful in identifying couples at risk of conceiving foetuses afflicted with the Hb Bart's hydrops foetalis syndrome due to homozygous alpha-thalassaemia); mab against Hb A2 and beta- and gamma-globin chains used for the quantitation of Hb A2 in beta-thalassaemia and the diagnosis of beta-thalassaemia major in foetuses respectively; other mabs produced to date include those specific to haemoglobins D-Los Angeles, J-Baltimore, O-Arab and J-Paris-I.

Antibodies, Monoclonal↗
PubMed1995

Interferon-alpha inhibits erythropoietin-induced proliferation, but not differentiation, and restricts erythroleukemia development.

The immature erythroid cell line J2E responds to erythropoietin (Epo) by proliferating and terminally differentiating into hemoglobin-synthesizing red blood cells. These cells produce a rapid, fatal erythroleukemia in mice characterized by hepatosplenomegaly and severe anemia. The aim of this study was to investigate the effects of murine interferons-alpha (MuIFN-alpha) on J2E cells in vitro and in vivo. Here we show that in culture MuIFN-alpha inhibited the Epo-induced proliferation of J2E cells but did not interfere with differentiation. When mice with J2E erythroleukemias were treated with MuIFNs in vivo, an extension of their life span was observed. Moreover, numerous necrotic lesions of infiltrating leukemic cells were detected in the spleens of these mice. Finally, ex vivo treatment of leukemic bone marrow cells with Epo and MuIFNs delayed mortality even further. It was concluded that MuIFNs (1) suppressed the proliferation of J2E cells in vitro but did not affect Epo-induced differentiation, and (2) inhibited the progress of erythroleukemias, especially in combination with Epo.

Animals↗
PubMed1995

Binding of fosphenytoin, phosphate ester pro drug of phenytoin, to human serum proteins and competitive binding with carbamazepine, diazepam, phenobarbital, phenylbutazone, phenytoin, valproic acid or warfarin.

The protein binding of [14C]fosphenytoin, (3-phosphoryloxy-methyl phenytoin disodium), a phosphate ester prodrug of phenytoin sodium, to human serum proteins, serum albumin and alpha 1-acid glycoprotein was determined by ultrafiltration. The mean +/- SD% of fosphenytoin bound to human serum proteins was 95.7 +/- 0.48%. Binding to albumin (36.5 mg/ml) decreased linearly from 89.2 to 67.3% when the fosphenytoin concentration was increased from 6 to 200 micrograms/ml. Fosphenytoin was weakly bound to alpha 1-acid glycoprotein (13.3%). Simultaneous incubation with high concentrations of carbamazepine (10 micrograms/ml) and diazepam (5 micrograms/ml) or therapeutic concentrations of phenytoin (10 micrograms/ml) had no effect on the binding of fosphenytoin to human serum proteins. High concentrations of phenobarbital (160 micrograms/ml), phenytoin (50 micrograms/ml), or valproic acid (500 micrograms/ml), however, caused slight, but significant, increases in the free fraction of fosphenytoin in serum protein. Phenylbutazone and sulfisoxazole resulted in a 48% increase in fosphenytoin free fraction while warfarin had a slight (8%), but significant, increase in free fraction of fosphenytoin. It was concluded that the concentration of albumin was the most important determinant for the plasma free fraction of fosphenytoin in man. Potential increase in fosphenytoin clearance may be observed in hypoalbuminemia.

Adult↗
PubMed1995

A rapid fatal erythroleukemia caused by J2E cells can be treated ex vivo with erythropoietin.

The J2E cell line is an immature erythroid line which terminally differentiates in response to erythropoietin (epo), producing mature, hemoglobin-synthesizing red blood cells. We have shown that when these cells were injected into mice a rapid and fatal erythroleukemia developed with symptoms of severe anemia and hepatosplenomegaly. Southern blotting demonstrated that the leukemic cells were the introduced J2E cells. In addition to spleen and liver, the bone marrow was a major site of leukemic cell infiltration, and when grown in vitro leukemic cells from bone marrow remained responsive to erythropoietin. We reasoned, therefore, that treatment of mice with this hormone should alleviate the erythroleukemia, but regular injections of epo in vivo failed to arrest the progress of the disease. However, when bone marrow from leukemic mice was exposed continuously to the hormone ex vivo, before reinfusion into naive recipients, a marked extension in life span was observed. It was concluded that ex vivo epo treatment could be used therapeutically for J2E cell erythroleukemias.

Animals↗
PubMed1994

Determination of DuP 128, an ACAT inhibitor and its sulphoxide and sulphone metabolites in human plasma by liquid chromatography.

A sensitive and specific high-performance liquid chromatographic (HPLC) method with fluorescence detection was developed for the simultaneous determination of DuP 128 (N'-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)p entyl]-N- hepthylurea), an ACAT inhibitor, its sulphone metabolite (XB277), and the separate determination of sulphoxide metabolite (XC164) in human plasma. After deproteinizing plasma samples with acetonitrile, the organic layer, created by adding approximately 0.25 g of NaCl, was removed, evaporated to dryness, and the residue then reconstituted with 400 microliters of acetonitrile. The acetonitrile layer was washed with 5 ml of hexane and then 50 microliters was injected into the HPLC. DuP 128 and XB277 were simultaneously quantified using a YMC basic column and fluorescence detection (lambda Ex = 270 nm and lambda Em = 385 nm). XC164 was quantified using a Waters microBondpack C18 reversed-phase column and fluorescence detection (lambda Ex = 270 nm and lambda Em = 365 nm). The relationship between the peak height and plasma concentrations best fit a power curve and showed an average correlation coefficient of > 0.99 over a concentration range of 1-200 ng ml-1 for DuP 128 and XC164 and 2.5-200 ng ml-1 for XB277. Good intraday and interday assay precisions (RSD < 10%) and accuracy (< 14%) for all three compounds were observed. The methods were sufficiently sensitive and selective to quantify plasma concentrations of DuP 128 and its sulphoxide and sulphone metabolites after oral administration of single or multiple dose(s) of > 350 mg of DuP 128 to healthy subjects.

Administration, Oral↗
PubMed1992

Biological activities of recombinant murine interferons alpha 1 and alpha 4: large difference in antiproliferative effect.

The mature forms of two recombinant murine interferons alpha, alpha 1 and alpha 4, have been expressed in vitro using an established transcription and translation system. The relative specific antiviral activity, antiproliferative activity and the natural killer cell stimulating activity of both subtypes were compared in vitro. While the antiviral and natural killer cell stimulating activities of the 2 subtypes were similar, the relative antiproliferative activities varied markedly. On the basis of equal molar inputs, MuIFN-alpha 1 had less than 8% of the antiproliferative activity of MuIFN-alpha 4. This data shows that a large functional difference exists between these two subtypes which are known to be expressed at different levels in mouse L-cells in vitro.

Animals↗
PubMed1991

Relative antiviral activity of in vitro-synthesized murine interferon-alpha 4 and -alpha 1.

Murine interferon-alpha 4 (MuIFN-alpha 4) is notable among the MuIFN-alpha subtypes because it lacks 5 amino acids corresponding to positions 103-107 of the other subtypes, yet is the most highly expressed subtype. Site-directed in vitro mutagenesis has been used to modify the genes coding for MuIFN-alpha 4 and MuIFN-alpha 1. The modifications have allowed (i) the in vitro expression of the mature form of each MuIFN-alpha subtype and (ii) the insertion of five amino acids, corresponding to amino acid positions 103-107 of MuIFN-alpha 1, into the MuIFN-alpha 4 sequence. In contrast to previously published data MuIFN-alpha 4 and MuIFN-alpha 1 show only a twofold difference in antiviral activity, with MuIFN-alpha 4 being the more active subtype. In keeping with this observation, it was also found that insertion of the five "missing" amino acids into MuIFN-alpha 4 resulted in an analogue MuIFN-alpha with antiviral activity equivalent to MuIFN-alpha 1. It may be inferred from this work that the deletion of amino acids 103-107 (QVGVQ) is solely responsible for the difference in antiviral activity between MuIFN-alpha 4 and MuIFN-alpha 1.

Animals↗
PubMed1990

Pharmacokinetics, pharmacodynamics, and minimum effective clinical dose of intravenous nicardipine.

Nicardipine hydrochloride was administered intravenously to two groups of hypertensive patients: one group of 37 patients with mild to moderate hypertension and one group of 20 patients with severe hypertension. In the first group, doses of 0.5, 1, 2, and 4 mg/hr, as well as placebo, were infused for 48 hours in a double-blind fashion. Blood pressure and heart rate were monitored for this period and for the 24 hours after the infusion was discontinued. Significant decrements in blood pressure were noted with all doses; 4 mg/hr produced lowering that was greater than all other doses; 1 and 2 mg/hr produced lowering that was greater than 0.5 mg/hr but that were not different from each other. Excellent correlation of blood pressure reduction and plasma level was observed and linear kinetics existed. In the severe hypertensive patients, 1, 2, 4, 5, and 8 mg/hr were infused to established minimal and ineffective doses. One milligram per hour was an ineffective dose; 4, 5, and 8 mg/hr all produced significant reductions over the course of the study that were undistinguishable from each other. Two milligrams per hour produced modest reductions in blood pressure. Blood pressure reduction also correlated with plasma levels in the severe hypertensive group.

Analysis of Variance↗
PubMed1988

Hepatic arterial embolization in patients with unresectable hepatocellular carcinoma--a randomized controlled trial.

A randomized controlled trial of hepatic arterial embolization was conducted in 63 consecutive patients who had unresectable but still embolizable hepatocellular carcinoma. Patients were randomized into three groups. Patients in group 1 received multiple hepatic arterial embolizations; patients in group 2 were given hepatic arterial embolization once, followed by monthly chemotherapy with high doses of 5-fluorouracil; and patients in group 3 received only monthly chemotherapy with high doses of 5-fluorouracil. Complete response was achieved in only 1 patient who received multiple hepatic arterial embolizations. Partial responses were observed in 13 patients (61.9%) in group 1, 10 patients (47.6%) in group 2, and 2 patients (9.5%) in group 3. The survival rates of patients in group 1 at the end of the ninth, 12th, 15th, 18th, and 21st months were 53.2%, 42.2%, 42.2%, 42.2%, and 42.2%, respectively, which were not significantly different from those of patients in group 2 but were better than the survival rates of patients in group 3. The results suggest that hepatic arterial embolization is an effective palliative treatment that prolongs survival of patients with unresectable hepatocellular carcinoma.

Adult↗
PubMed1986

Quantitation of the ultra short acting beta-adrenergic antagonist flestolol in blood by liquid chromatography.

A sensitive, specific, reproducible, and convenient high-performance liquid chromatographic (HPLC) assay was developed for quantitation of the new ultra short acting beta-adrenergic antagonist, flestolol (1), in whole blood. The instability of the compound in blood was overcome by the esterase inhibitor, NaF, and deproteinization of blood samples with CH3CN:CH2Cl2 (2:5). The internal standard was p-ethoxyphenethyl alcohol. The compounds were back extracted from the CH3CN:CH2Cl2 phase into a small volume of pH 3-4 phosphate buffer and then separated on a reversed-phase C18 column with 0.05 M phosphate buffer (pH 3-4) in acetonitrile (4.6:1) as the mobile phase, and detected with an UV detector at 229 nm. The assay was linear with a blood concentration range from 10 to 1270 ng/mL (r2 greater than 0.998, p greater than 0.01), and reproducible with an overall CV of 8%. The assay procedure was used to determine the blood levels of flestolol intravenously infused into a male dog for 105 min at 230 micrograms/kg/min. The steady-state unchanged drug concentration of 5 micrograms/mL in blood was achieved within 10-20 min and declined biexponentially to 0.02 microgram/mL at 6 h following termination of the infusion.

Adrenergic beta-Antagonists↗
PubMed1985

Effect of infusion administration set on the delivery rate and plasma concentration of nitroglycerin in dogs.

A randomized crossover study with eight dogs was carried out to determine whether the in vitro difference observed in the delivery of nitroglycerin using polyvinyl chloride (PVC) and polyethylene (PE) infusion sets would result in a measurable difference in steady-state plasma concentration. At the same apparent infusion rate of 40 micrograms/min, PVC infusion sets produced steady-state plasma nitroglycerin concentrations that were only 40% of those generated with PE sets (p less than 0.0001). Attainment of steady-state drug levels appeared more rapid with the PE administration sets, but in three out of eight animals, these infusion systems appeared to produce a "bolus" dosing effect. PE sets did not reduce the variability in plasma nitroglycerin concentration observed with PVC sets.

Animals↗
PubMed1984

Pharmacokinetic and pharmacodynamic studies of acute interaction between warfarin enantiomers and metronidazole in rats.

This investigation was designed to determine if the reported stereoselectivity of the pharmacokinetic interaction between warfarin and metronidazole in humans occurs also in rats and if the potentiation of the anticoagulant effect of warfarin can be ascribed solely to inhibition of warfarin metabolism by metronidazole. Metronidazole had no effect on the serum protein binding of racemic warfarin in vitro over a wide concentration range but decreased the protein binding of R-(+)-warfarin and S-(-)-warfarin in vivo, perhaps indirectly through metabolite(s). Treatment with i.p. metronidazole, 100 mg/kg every 6 hr, decreased the plasma clearance of free warfarin ("intrinsic clearance"). This inhibitory effect was more pronounced with S-(-)-warfarin than with R-(+)-warfarin (congruent to 60 and congruent to 30%, respectively). Metronidazole did not affect plasma prothrombin complex activity in vitro but reduced it in vivo. Metronidazole treatment increased the elimination rate constant for endogenous prothrombin complex activity and decreased the plasma concentration of free R-(+)-warfarin required to decrease prothrombin complex activity synthesis rate to one-half of normal (there were insufficient data to determine the effect of metronidazole on the activity of the other enantiomer). It is concluded that metronidazole preferentially inhibits the metabolism of S-(-)-warfarin in rats as in humans but that (at least in rats) the stereoselectivity is not absolute. Moreover, metronidazole has an indirect inhibitory effect on warfarin protein binding in vivo and also affects the pharmacodynamics of warfarin as well as the blood clotting process per se.

Animals↗
PubMed1984

Pharmacokinetic and pharmacodynamic studies of acute interaction between warfarin enantiomers and chloramphenicol in rats.

The purpose of this investigation was to explore the mechanisms and possible stereoselectivity of the interaction between warfarin and chloramphenicol in rats. Chloramphenicol had no apparent effect on the serum protein binding of R-(+)-warfarin or S-(-)-warfarin in vitro or in vivo. Treatment with i.p. chloramphenicol, 50 mg/kg every 4 hr or 30 mg/kg every 6 hr, decreased the plasma clearance of free warfarin by one-half or more, with no apparent stereoselectivity. The volume of distribution was not significantly affected; the half-life of each warfarin enantiomer was appreciably increased by chloramphenicol. Treatment with chloramphenicol had no apparent effect on relative liver size and on serum aspartate aminotransferase activity. Prothrombin complex activity in plasma was not affected by in vitro addition or in vivo administration of chloramphenicol alone. Chloramphenicol treatment did not affect significantly the elimination kinetics of endogenous prothrombin complex activity and the plasma concentration of free R-(+)-warfarin or S-(-)-warfarin required to decrease prothrombin complex activity synthesis rate to one-half of normal. It appears that the pronounced potentiation of the anticoagulant effect of warfarin by chloramphenicol is due only to inhibition of warfarin metabolism and that this effect is not stereoselective.

Animals↗
PubMed1983

Chemical characterization of the persistent fraction of hydroxyethyl starch in rat serum and spleen.

Hydroxyethyl starch (HES) found in rat serum and spleen after single and daily administrations of 0.9 g/kg for 1 week was characterized by gas-liquid chromatography. There was very little difference in the degree of substitution (D.S.) and molar substitution (M.S.) of HES in serum samples obtained at 1 hour and 57 days after multiple doses and of HES in spleen samples obtained at 1 hour and 168 days after a single dose of HES. The small increase in D.S. and M.S. was due to a decrease in the glucose content and not due to a change in the ratio of mono- to poly-substituted glucoses.

Animals↗
PubMed1983

Tissue distribution of [14C]bretylium tosylate in rats.

The distribution of [14C]bretylium tosylate in the body and the relationship between tissue and plasma concentrations was determined following intravenous administration of the drug to Charles River rats. The renal excretion of bretylium was rapid in rats and follows an active process. On the average, 50% of the administered dose was excreted in the urine within 1 hr. In the postequilibrium phase, the plasma concentration declined with a half-life of 5 hr. Bretylium concentrations in all tissues, except the heart, declined rapidly according to a triexponential equation. The liver and kidney bretylium concentrations declined in parallel to the plasma concentration with mean tissue-plasma concentration ratios of 6.04 and 12.3, respectively, in the beta phase. However, the concentration of bretylium in the heart increased gradually and peaked at 2 hr, with a tissue-plasma concentration ratio of 121, which, in turn, declined to a value of greater than 60 after 8 hr. The data indicated that (a) bretylium is rapidly distributed into the liver and kidney immediately after reaching the systemic circulation; (b) the distribution into the heart occurs at a slower rate compared with the other organs, and the drug has a high affinity to the myocardium; and (c) since the heart is the site of action and there is no direct correlation between the concentrations in myocardium and plasma, the antiarrhythmic effect of bretylium may not be related to the plasma concentration.

Animals↗
PubMed1983

Esmolol: a pharmacokinetic profile of a new cardioselective beta-blocking agent.

beta-Adrenergic blocking agents--esmolol hydrochloride, pharmacokinetic profile, metabolism. Pharmacokinetic profile--cardioselective beta-adrenergic blocking agent, methyl 3-[4-(2-hydroxy-3-(isopropylamino)propoxy]phenylpropionate hydrochloride. Esmolol--cardioselective beta-adrenergic blocking agent, pharmacokinetic profile.

Adrenergic beta-Antagonists↗
PubMed1983

Age-related pharmacokinetics of N-acetylprocainamide in rats.

The pharmacokinetics of N-acetylprocainamide, administered orally or intravenously, were studied in 3-, 6-, and 12-month-old rats using a two-way crossover study design. At 3, 6, and 12 months of age, the half-life values of N-acetylprocainamide were 1.66, 1.82, and 2.29 hr, respectively; the apparent volumes of distribution were 4.75, 3.35, and 1.98 liter/kg, respectively. The elimination rate constant, clearance, and absolute bioavailability of the drug (determined by AUC measurements and the amounts excreted unchanged in the urine) decreased significantly with age. The rate of absorption remained unchanged. The amounts of N-acetylprocainamide in the liver and kidneys were significantly higher in the 12-month-old animals. These results clearly demonstrate a significant alteration with age in the bioavailability, distribution, and elimination of N-acetylprocainamide in rats. In long-term toxicity studies of this and other drugs that show age-dependent pharmacokinetics, an adjustment in the chronically administered dose is essential.

Acecainide↗