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Biomedical subjects

J Tse

Publications and source records attributed to J Tse.

At least 55 records · Page 3Linked to original sources
PubMed1994

Effects of topical methylene blue on cyclic GMP level, blood flow, and O2 consumption in focal cerebral ischaemia.

We hypothesized that a decrease in cyclic GMP, a second messenger in the glutamate-nitric oxide pathway, would reduce oxygen consumption and improve O2 balance in the ischaemic cerebral cortex. To test this hypothesis, a study was performed in unilateral middle cerebral artery occluded rats which were assigned to either a control or methylene blue (10(-3) M) group. Regional cerebral blood flow was determined using 14C-iodoantipyrine and regional arterial and venous O2 saturations were determined by microspectrophotometry (n = 6). Cyclic GMP level was measured by radioimmunoassay (n = 8). Guanylate cyclase and cyclic GMP-phosphodiesterase activities were determined in an additional set of control rats (n = 10). The cyclic GMP levels were not different between the ischaemic and contralateral areas in the control group. Compared to the cyclic GMP in the control ischaemic cortex, topical methylene blue significantly decreased the cyclic GMP level by 56% in the ischaemic cortex of the methylene blue group. Ischaemia did not alter the activities of guanylate cyclase but mildly decreased cyclic GMP-phosphodiesterase. The regional cerebral blood flow and O2 consumption in the control group were 50% and 32% lower than those in corresponding contralateral cortex. Topical methylene blue did not alter regional cerebral blood flow and O2 consumption in the ischaemic cortex. Our data showed that cyclic GMP is not a major controller on O2 supply or O2 consumption in the ischaemic brain.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1994

Milrinone, a cyclic AMP-phosphodiesterase inhibitor, has differential effects on regional myocardial work and oxygen consumption in experimental left ventricular hypertrophy.

OBJECTIVE: The aim was to test the hypothesis that local myocardial work and O2 consumption would respond differentially to milrinone, a selective cyclic AMP-phosphodiesterase inhibitor, in left ventricular hypertrophy due to differences in myocardial cyclic AMP-phosphodiesterase activity. METHODS: The effect of milrinone on regional segment work and regional O2 consumption was measured in 12 open chest anaesthetised dogs with left ventricular hypertrophy induced by valvular aortic stenosis and in 10 age matched control dogs. Regional myocardial work was calculated as the integrated product of instantaneous force development (miniature transducer) and segment shortening (sonomicrometer). Regional O2 consumption was calculated from coronary blood flow (radiolabelled microspheres) and O2 saturations in small regional vessels (microspectrophotometry). Low Km phosphodiesterase activity was assayed by measuring the hydrolysis of radiolabelled cyclic AMP. RESULTS: Milrinone increased left ventricular dP/dtmax by approximately 60-70% in both control [2808(SEM 314) to 4584(660) mm Hg.s-1] and left ventricular hypertrophy [3279(258) to 5589(470) mm-Hg.s-1]. Regional work increased significantly in control [612(88) to 955(101) g.mm.min-1], while the increase was not significant in left ventricular hypertrophy [859(139) to 974(172) g.mm.min-1]. Regional O2 consumption increased significantly with milrinone in left ventricular hypertrophy [8.1(1.2) to 13.1(2.4) ml O2.min-1.100 g-1], but the increase was not significant in control [6.9(1.2) to 7.4(1.0) ml O2.min-1.100 g-1]. Myocardial stiffness during ejection was increased by milrinone to a significantly greater extent in animals with left ventricular hypertrophy. These effects were not related to differences in cyclic AMP-phosphodiesterase activity between control hearts and hearts with left ventricular hypertrophy [393(45) v 402(36) pmol.mg protein-1.1]. CONCLUSIONS: Differences between the hypertrophied and normal canine myocardium in response to milrinone are either due to altered levels of cyclic AMP production in left ventricular hypertrophy, to effects of milrinone that are unrelated to cyclic AMP-phosphodiesterase inhibition, or to other differences in hypertrophied hearts. The greater stiffness of the myocardium in left ventricular hypertrophy may require a greater energy expenditure to increase the amount of work it performs.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Effect of increased myocardial cyclic GMP induced by cyclic GMP-phosphodiesterase inhibition on oxygen consumption and supply of rabbit hearts.

1. We tested the hypothesis that increasing myocardial cyclic GMP levels would reduce myocardial O2 consumption and areas of low O2 supply/consumption balance, using zaprinast, a selective cyclic GMP-phosphodiesterase inhibitor. 2. The study was conducted in three groups (vehicle, 10(-3) and 3 x 10(-3) mol/L zaprinast) of anaesthetized open-chest New Zealand white rabbits (n = 24). Coronary blood flow (radioactive microspheres), arterial and venous O2 saturation (microspectrophotometry), O2 consumption, cyclic GMP content (competitive binding) and cyclic GMP-phosphodiesterase activity (conversion of 3H-cyclic GMP to 3H-GMP) were determined. 3. Agents were applied to a patch on the myocardial surface and did not cause significant haemodynamic changes, except for bradycardia in the vehicle and low dose group. 4. The total myocardial cyclic GMP-phosphodiesterase activity was 148 +/- 14 while the zaprinast (10 mumol/L) inhibitable activity averaged 63 +/- 8 pmol/mg protein per min. Cyclic GMP content was increased with increasing doses of zaprinast (vehicle, 4.308 +/- 0.349 pmol/g; low dose zaprinast, 4.803 +/- 0.279 and high dose zaprinast, 7.938 +/- 1.304 pmol/g). 5. Coronary blood flow was not different after treatment (198 +/- 11, 209 +/- 10 and 153 +/- 9 mL/min per 100 g for the vehicle, low and high dose zaprinast, respectively). 6. Under control conditions, 48% of the small veins had O2 saturations below 50%. With zaprinast, this value was reduced to 19% for the low and 24% for the high dose. 7. Average venous O2 saturation increased with zaprinast (49 +/- 2%, 61 +/- 3% and 59 +/- 1%).(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1993

Effect of isoproterenol on coronary blood flow and signal transduction responses in thyroxine-treated rabbit hearts.

This study examined the hypothesis that treatment with thyroxine (T4) would alter the coronary blood flow and signal transduction responses of the rabbit heart. T4 was administered for 16 days by subcutaneous time-release pellets (3 mg/kg/day) in 3 kg New Zealand white rabbits. Four groups of anesthetized open-chest rabbits (control, control+isoproterenol (ISO, 0.5 microgram/kg/min for 15 min), T4, and T4 + ISO) were used to determine coronary blood flow (radioactive microspheres), cyclic AMP content (competitive binding), low Km cyclic-AMP-phosphodiesterase activity (cyclic AMP-PDE, conversion of 3H-cyclic AMP to 3H-AMP) and beta-adrenoceptor number and affinity (125I-iodocyano-pindolol). Coronary blood flow was increased from control by ISO from 167 +/- 59 to 354 +/- 157 ml/min/100 g. T4 did not cause cardiac hypertrophy, but increased baseline coronary blood flow to 269 +/- 115 ml/min/100 g. The ISO response was attenuated in terms of blood flow (448 +/- 118) and heart rate with T4. Beta-adrenoceptor numbers increased significantly from 65.7 +/- 9.2 to 81.9 +/- 4.4 fmol/mg protein, while neither soluble (126 +/- 39 vs 119 +/- 15 pmol/mg protein/min) nor particulate cyclic AMP-PDE activity were different between control and T4 animals. Cyclic AMP content was increased from control by both ISO (779 +/- 239 to 1371 +/- 672 pmol/g) and T4 (1143 +/- 244). T4 animals showed a smaller increase in cyclic AMP following ISO (1391 +/- 261). There was not a significant difference between the control and T4 group cyclic AMP level following ISO. Thus, despite increased beta-adrenoceptor numbers, there was a diminished responsiveness of heart rate, coronary blood flow and cyclic AMP levels to isoproterenol in the T4-treated rabbit hearts.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

Role of ischemia-reperfusion on myocardial cyclic AMP and cyclic AMP phosphodiesterase: effects of amrinone on regional myocardial force and shortening.

This study tested the hypothesis that a reperfused ischemic myocardial region of the dog heart would be unable to increase its function in response to amrinone, a specific cyclic AMP phosphodiesterase (cAMP-PDE) inhibitor, due to loss of cAMP-PDE activity in the region. The global contractility (+dp/dtmax), regional percent shortening (ultrasonic crystals), and developed force (miniature force gauge) were measured on a continuous basis throughout a 6-hour experiment and regional blood flow (radioactive microspheres) in open-chest pentobarbital-anesthetized mongrel dogs. The left anterior descending coronary artery (LAD) was isolated and ligated for 2 hours and allowed to reperfuse for 4 hours. This myocardial region was compared to a nonischemic region supplied by the circumflex artery. At the end of the 4-hour reperfusion period, 9 dogs were treated with amrinone (5 mg/kg) and three dogs were not treated with amrinone. The hearts were rapidly excised and frozen in liquid nitrogen. Cyclic AMP and cAMP-PDE activity was determined in homogenates of myocardial tissue. Blood flow decreased during occlusion in the LAD region and returned toward control with reperfusion. Flow increased nonsignificantly with amrinone. the basal cyclic AMP content of the two regions was not different. The cAMP-PDE activity was reduced 24% in the LAD region compared to the control region. There were no ischemia-induced changes in the enzyme characteristics. These experiments demonstrated increased global function in the ischemic reperfused myocardium after amrinone was administered (dP/dtmax: 2092 +/- 538 to 3277 +/- 688 mmHg/sec).(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

Autoradiographic evidence of estrogen binding sites in nuclei of diethylstilbesterol induced hamster renal carcinomas.

Estrogen binding sites were demonstrated by autoradiography in one transplantable and five primary diethylstilbesterol induced renal carcinomas in three hamsters. Radiolabelling, following the in vivo injection of 3H-17 beta estradiol, was increased only over the nuclei of tumor cells; stereologic analysis revealed a 4.5- to 6.7-times higher concentration of reduced silver grains over nuclei than cytoplasm of these cells. Despite rapid tubular excretion of estradiol which peaked in less than 1 h, the normal cells did not appear to bind the ligand. This is the first published report documenting the preferential in vivo binding of estrogen to nuclei of cells in estrogen induced hamster renal carcinomas.

Animals↗
PubMed1989

A preliminary study on the link between PUVA and skin cancer.

One hundred four psoriatic patients who had 8-methoxypsoralen-ultraviolet light A (PUVA) treatment between 1975-1987 were investigated to determine if skin cancer had ever occurred during or after the therapeutic period. Incidence data of skin cancer was applied to this group of patients to measure the expected number of patients with skin cancer. The significance of observed number versus expected of PUVA-treated patients with skin cancer was analyzed. The authors did not observe a significant increase of patients with skin cancer.

Adult↗
PubMed1988

Immunohistochemical demonstration of estrophilin in mouse tissues using a biotinylated monoclonal antibody.

We have developed a direct avidin-biotin-peroxidase complex (ABC) immunohistochemical method for localization of estrophilin in mouse tissues. The method has been found especially useful for microscopic demonstration of the receptor in mouse liver, since the indirect alternative, autoradiography after injection of radiolabeled estrogens, is of no value in this organ. The ABC technique employs a biotinylated monoclonal antibody to human estrophilin (Abbot H222) which was previously shown to crossreact with the murine receptor. Cryostat-cut tissue sections which were briefly fixed were incubated with the modified antibody, and the estrophilin was revealed by subsequent exposure to ABC followed by H2O2/diaminobenzidine.

Animals↗
PubMed1987

Pharmacokinetics of low-dose intravenous pethidine in patients with renal dysfunction.

The kinetics and elimination of pethidine (meperidine) after intravenous administration (150 micrograms/kg) to ten healthy volunteer subjects were compared with those obtained from 18 patients who suffered from varying degrees of renal dysfunction. In both groups of subjects, pethidine was eliminated triexponentially from plasma. However, plasma concentrations in the patients (who were subdivided into patients with severe dysfunction, moderate dysfunction, and mild dysfunction) were consistently higher. The mean +/- SEM elimination half-life (t1/2) of pethidine was significantly longer in the three groups of renal patients: 7.9 +/- 1.1, 20.2 +/- 13.6, 16.6 +/- 5.4, and 14.3 +/- 3.1 hr, respectively, for healthy volunteers, patients with severe, moderate, and mild dysfunction; their mean +/- SEM creatinine clearances were 97.3 +/- 7.5, less than 9.5, 30.0 (3.7), and 63.3 +/- 8.5 mL/min respectively. The mean plasma clearance of the drug was higher in healthy subjects (342.7 +/- 62.5 mL/min) than various groups of renal patients (99.9 +/- 11.6, 120.9 +/- 45.8, and 123.8 +/- 34.1, respectively, for patients with severe, moderate, and mild dysfunction). Impairment of renal function also reduced total plasma protein binding: 58.2 +/- 5.0% in healthy subjects and 31.8 +/- 3.9%, 44.5 +/- 5.0%, and 42.5 +/- 5.6%, respectively, for the three renal patient groups. The percentage of pethidine recovered in the urine was significantly lower in the severe dysfunction group while norpethidine recovery was significantly lower in all three groups of renal patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Influence of urinary pH on pethidine kinetics in healthy volunteer subjects. 2. A study of ten Chinese subjects.

The pharmacokinetics of intravenous pethidine (150 micrograms kg-1) were determined in 10 healthy Chinese subjects under controlled (acidic and alkaline) and uncontrolled urinary pH. Large variations in the 48 hr urinary recoveries of pethidine and norpethidine were induced by change in urinary pH: (mean +/- S.D.): 24.3 +/- 7.3% & 33.0 +/- 11.4%, 0.4 +/- 0.3% & 3.8 +/- 2.2%, 11.4 +/- 6.9% & 13.9 +/- 2.5%, respectively, under acidic, alkaline and uncontrolled urinary pH for pethidine and norpethidine. There was no significant difference in the terminal half-lives, t 1/2 (6.1 to 7.0 hr) of pethidine, although the area under the plasma concentration-time curve under acidic urinary conditions was slightly lower and renal clearance of the drug higher than those under alkaline and uncontrolled urinary conditions. Confirming previous results from Caucasian subjects, under all 3 conditions pethidine disappeared from the plasma tri-exponentially and acidification of the urine may increase body clearance of unchanged pethidine due mainly to greater renal clearance of the drug; this may be useful clinically to treat acute pethidine poisoning. However, under acidic urinary conditions, Chinese subjects excreted more norpethidine than Caucasians (33.0 +/- 11.4% and 23.4 +/- 4.6%, respectively).

Adult↗
PubMed1987

Disposition of pethidine in man under acidic urinary pH. 3. A comparison of pharmacokinetics among Caucasian, Chinese and Indian subjects.

The pharmacokinetics of low dose pethidine (150 micrograms kg-1) after intravenous administration were determined in 10 Caucasian, 10 Chinese and 10 Indian healthy volunteers under conditions of acidic urinary pH. Plasma and urine concentrations of pethidine and norpethidine were measured by gas liquid chromatography. In all 3 ethnic groups, the disappearance of pethidine from plasma was best described by a tri-exponential function. No significant differences were observed in the elimination half life, renal clearance and total plasma clearance of the drug. The significantly lower AUC and higher (approaching significance) apparent volume of distribution in the 2 Asian groups may be explained in terms of more readily distribution of the drug (significantly higher K21 rate constants were obtained from both Chinese and Indian subjects according to a 3-compartment open model) due possibly to more frequent movement of these subjects during the early part of experiment. More norpethidine was recovered in the urine of the Chinese and Indian subjects; this may suggest an interethnic difference in the oxidative demethylation of pethidine.

Adult↗
PubMed1986

Inhibition of the biosynthesis of uroporphyrinogen and heme in rat liver during obstructive jaundice produced by bile duct ligation.

Altered hepatic microsomal drug metabolism has been reported to occur in afflicted with hyperbilirubinemia. Similarities of the chemical structures of hydroxymethylbilane, an intermediate in the biosynthesis of uroporphyrinogen, to bilirubin prompted investigations of the effect of bilirubin on the activity of uroporphyrinogen I synthase (porphobilinogen deaminase, EC 4.3.1.8) and the biosynthesis of heme. Bilirubin was found to be a reversible, noncompetitive inhibitor of uroporphyrinogen I synthase. The inhibition constant (Ki) for bilirubin was 1.5 microM. Bile acids had no effect on rat hepatic uroporphyrinogen I synthase activity. Hyperbilirubinemia was achieved in rats by biliary ligation in order to investigate whether elevated levels of bilirubin impair the biosynthesis of hepatic heme in vivo. The relative rate of heme biosynthesis, as measured by the rate of incorporation of delta-[4-14C]aminolevulinic acid into heme, was decreased 59% 24 h after biliary obstruction. The levels of hepatic microsomal heme and cytochrome P-450 were decreased by 43 and 40%, respectively, 72 h after biliary obstruction. The activities of hepatic delta-aminolevulinic acid synthase and uroporphyrinogen I synthase were increased by 39 and 46%, respectively, 72 h after biliary obstruction. During the 48- to 72-h period following biliary obstruction, the urinary excretion of porphobilinogen and uroporphyrin was increased 3.0- and 3.5-fold, respectively, whereas, the urinary excretion of delta-aminolevulinic acid was not altered. During this 48-to 72-h time interval following biliary obstruction, 100% of the uroporphyrin was excreted as isomer I. These results indicate that bilirubin is capable of depressing the biosynthesis of rat hepatic heme and thus cytochrome P-450-mediated drug metabolism by inhibition of the formation of uroporphyrinogen. These findings are a plausible mechanism for reports of impaired clearance of various drugs in patients afflicted with hyperbilirubinemic disease states.

5-Aminolevulinate Synthetase↗
PubMed1986

Characterization of estrogen binding proteins in mouse liver cytosol: absence of sexual dimorphism.

Estrogen binding proteins in mouse liver cytosol were characterized by separation on Sephadex G-75 columns, by Scatchard plot analysis, and by hormonal competition studies. A high affinity receptor (56-70 fmol/mg cytosolic protein) with a mol. wt greater than 75,000, Kd of 5.7-8.4 X 10(-10) M was identified in male and female C3H liver. A second high capacity low affinity (HCLA) binder (200-300 fmol/mg cytosolic protein) with a mol. wt of about 50,000, Kd of 1.7-7.2 X 10(-8) was also identified. Following partial purification of the estrogen binders by ammonium sulfate precipitation, Scatchard plot analysis revealed selective removal of HCLA. On Sephadex G-75 filtration, the purification also resulted in selective removal of the 17 beta-estradiol binding component with a mol. wt of 50,000. Comparison with rat cytosol separations show that the sexual dimorphism in HCLA binding proteins (5 times higher in male than female rat liver) was absent in the mouse liver. These studies document the presence of a specific high affinity estrogen binding protein in mouse liver and indicate that the sexual dimorphism in HCLA proteins is not a universal feature of all rodent species.

Animals↗
PubMed1985

Influence of urinary pH on pethidine kinetics in healthy volunteer subjects.

The kinetics of intravenous pethidine (150 micrograms kg-1) were determined in 10 healthy Caucasian subjects under uncontrolled and controlled (acidic and alkaline) urinary pH. Although large variations in the 48 hr urinary recovery of pethidine and norpethidine (26.9 +/- 5.9% & 23.4 +/- 4.6%, 0.6 +/- 0.3% & 3.6 +/- 1.6%, 6.9 +/- 3.2% & 17.4 +/- 6.6%, respectively, under acidic, alkaline and uncontrolled urinary pH were induced by change in urinary pH, the terminal t1/2 (7-8 hr), the AUC and the plasma concentration-time profiles were not affected. Under all these conditions, the disappearance of pethidine from the plasma was described by a triexponential function. A 3-compartment open model with input into the central compartment and elimination from both the central and the fast accessible (metabolising) compartment was proposed to interpret pethidine distribution in the body. This model explains the complimentary elimination of pethidine by renal excretion and metabolism. Under alkaline urinary pH, the hydrolytic route predominates as recovery of pethidine and norpethidine in the urine is significantly lower under this condition. Acidification of the urine may increase body clearance of the unchanged drug due mainly to greater renal clearance, and this may be useful clinically to treat acute pethidine poisoning and when the complimentary hepatic metabolism is impaired.

Adult↗
PubMed1984

Rat hepatic uroporphyrinogen III co-synthase. Purification and evidence for a bound folate coenzyme participating in the biosynthesis of uroporphyrinogen III.

Rat hepatic uroporphyrinogen III co-synthase was isolated and purified 73-fold with a 13% yield by (NH4)2SO4 fractionation and sequential chromatography on DEAE-Sephacel, Sephadex G-100 (superfine grade) and folate-AH-Sepharose 4B. The purified co-synthase has an Mr of approx. 42 000, and is resolved into two bands, each possessing co-synthase activity, by polyacrylamide-gel electrophoresis. A factor was dissociated from the purified co-synthase. Results of both microbiological and competitive protein-binding assays suggest that it is a pteroylpolyglutamate. The isolated pteroylpolyglutamate factor was co-eluted with authentic N5-methyltetrahydropteroylheptaglutamate on DEAE-Sephacel. Uroporphyrinogen III is formed by cosynthase-free preparations of uroporphyrinogen I synthase in the presence of tetrahydropteroylglutamate. Tetrahydropeteroylheptaglutamate is also able to direct the formation of equivalent amounts of uroporphyrinogen III at a concentration approximately one-hundredth that of tetrahydropteroylmonoglutamate. These results suggest that a reduced pteroylpolyglutamate factor is associated with rat hepatic uroporphyrinogen III co-synthase, and that this may function as a coenzyme for the biosynthesis of uroporphyrinogen III.

Animals↗
PubMed1984

Inhibition of uroporphyrinogen I synthase activity and depression of microsomal heme and cytochrome P-450 in rat liver by bilirubin.

Purified rat hepatic uroporphyrinogen (UROgen) I synthase (URO-S) was inhibited by bilirubin or the ditaurine derivative. Inhibition was reversible and non-competitive to the substrate porphobilinogen (PBG). The inhibition constants (Ki values) for bilirubin and the conjugate were 1.5 microM and 0.26 microM respectively. Rats afflicted with hyperbilirubinemia caused by biliary obstruction had decreased levels of hepatic microsomal heme (58% of control) and cytochrome P-450 (60% of control) at day 3. Hepatic delta-aminolevulinic acid synthetase (ALAS) activity was increased (39% of control) at day 3.

5-Aminolevulinate Synthetase↗
PubMed1983

The dissolution and oral bioavailability of mexiletine capsules modified for clinical trial. A preliminary report.

The dissolution and bioavailability of two preparations of mexiletine hydrochloride (200 mg), one available commercially as Mexitil and one modified by the Hospital Pharmacy for a clinical trial, were investigated in a cross-over study with healthy volunteer subjects. The evaluation of bioavailability was based on comparisons of the mean residence time (MRTp.o.) and mean absorption time (MATp.o.), areas under the plasma mexiletine concentration time-curve (AUC) and urinary recovery of unchanged mexiletine under controlled condition of acidic urinary pH after oral administration of single doses of either 400 mg or 200 mg as mexiletine hydrochloride. Three different methods of calculation were used to account for possible changes in clearance of the drug in between treatments. Bioavailability data were available from 3 cross-over studies as the investigation was terminated because one subject experienced idiosyncratic reactions to mexiletine. The mean-transit-time, T DISSOLVED-IN VITRO, for the hospital-modified capsules (2.8 min) was longer than that of the Mexitil capsule (2.0 min) in 0.1 HCl. This delay in dissolution was complemented by an increase in MATp.o. (0.43 and 0.58 hr respectively for Mexitil and hospital-modified capsules) obtained in one subject. The bioavailabilities of the two preparations were comparable from AUC between 0 to 6 hr, but the plasma curves from 6 to 48 hr were not followed. The mean times in vivo, T MEAN-IN VIVO (determined from urinary elimination curves in a cross-over study of 3 subjects) were consistently shorter after ingestion of Mexitil capsules though the significance was difficult to obtain due to small sample size.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗