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Biomedical subjects

D Chung

Publications and source records attributed to D Chung.

At least 55 records · Page 3Linked to original sources
PubMed1992

The effects of cardiac transplantation and cyclosporine therapy on digoxin pharmacokinetics.

Most patients needing cardiac transplantation are treated with digoxin for heart failure. Because of its narrow therapeutic range, even recommended doses of digoxin may cause severe toxicity. Several drugs, including quinidine, amiodarone, verapamil, and propafenone can interact with digoxin, leading to toxic accumulation of the glycoside. The authors have recently reported two cases of severe digitalis toxicity after the initiation of cyclosporine treatment in patients awaiting cardiac transplantation. A preliminary study on two additional patients suggested that cyclosporine reduced the plasma clearance and volume of distribution of digoxin. To assess the mechanism of this interaction, the authors studied digoxin pharmacokinetics in patients awaiting cardiac transplantation and again after the surgery, during chronic cyclosporine therapy. To separate the effects of transplantation and cyclosporine on digoxin pharmacokinetics, pharmacokinetic studies were subsequently performed in dogs to allow controlled experimental conditions for evaluation of the digoxin-cyclosporine interaction.

Administration, Oral↗
PubMed1992

Activated conformations of the ras-gene-encoded p21 protein. 1. An energy-refined structure for the normal p21 protein complexed with GDP.

A complete three-dimensional structure for the ras-gene-encoded p21 protein with Gly 12 and Gln 61, bound to GDP, has been constructed in four stages using the available alpha-carbon coordinates as deposited in the Brookhaven National Laboratories Protein Data Bank. No all-atom structure has been made available despite the fact that the first crystallographic structure for the p21 protein was reported almost four years ago. In the p21 protein, if amino acid substitutions are made at any one of a number of different positions in the amino acid sequence, the protein becomes permanently activated and causes malignant transformation of normal cells or, in some cell lines, differentiation and maturation. For example, all amino acids except Gly and Pro at position 12 result in an oncogenic protein; all amino acids except Gln, Glu and Pro at position 61 likewise cause malignant transformation of cells. We have constructed our all-atom structure of the non-oncogenic protein from the x-ray structure in order to determine how oncogenic amino acid substitutions affect the three-dimensional structure of this protein. In Stage 1 we generated a poly-alanine backbone (except at Gly and Pro residues) through the alpha-carbon structure, requiring the individual Ala, Pro or Gly residues to conform to standard amino acid geometry and to form trans-planar peptide bonds. Since no alpha-carbon coordinates for residues 60-65 have been determined, these residues were modeled by generating them in the extended conformation and then subjecting them to molecular dynamics using the computer application DISCOVER and energy minimization using DISCOVER and the ECEPP (Empirical Conformational Energies for Peptides Program). In Stage 2, the positions of residues that are homologous to corresponding residues of bacterial elongation factor Tu (EF-Tu) to which p21 bears an overall 40% sequence homology, were determined from their corresponding positions in a high-resolution structure of EF-Tu. Non-homologous loops were taken from the structure generated in Stage 1 and were placed between the appropriate homologous segments so as to connect them. In Stage 3, all bad contacts that occurred in this resulting structure were removed, and the coordinates of the alpha-carbon atoms were forced to superimpose as closely as possible on the corresponding atoms of the reference (x-ray) structure. Then the side chain positions of residues of the non-homologous loop regions were modeled using a combination of molecular dynamics and energy minimization using DISCOVER and ECEPP respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1991

Relationship between the pharmacokinetics and iron excretion pharmacodynamics of the new oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one in patients with thalassemia.

Single-dose and steady-state pharmacokinetics of the new oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1) were studied in 14 patients with thalassemia and correlated with iron excretion. Food prolongs the rate of absorption of L1, but it does not affect significantly the extent of absorption measured by the area under the plasma concentration-time curve. Similarly, it does not affect the chelation potential of the drug. The mean elimination half-life of the drug is 3 hours, suggesting that a divided dose every 8 hours may assure better chelation. Our steady-state studies reveal that urinary iron excretion is independently influenced by body iron load (measured by ferritin levels) and by steady-state trough concentrations of the drug. While patients were receiving an unchanged regimen of 75 mg/kg/day, we have detected a gradual and significant decrease in trough concentrations in the presence of unchanged patients' compliance monitored by the Medication Event Monitoring System, diaries, and pill count. These findings suggest self-induction of L1 metabolism or decreased absorption during long-term therapy. Because of the concentration-dependent iron excretion, patients may need increasing doses to achieve negative iron balance.

Adolescent↗
PubMed1991

Aging and the trophic effects of cholecystokinin, bombesin and pentagastrin on the rat pancreas.

We examined the effect of age on the trophic response of the pancreas to chronic treatment with cholecystokinin (CCK), bombesin, or pentagastrin. Three age groups (3-, 12-, and 24-months) male F344 rats received saline; CCK-8 (5 ng/kg), bombesin (10 micrograms/kg), or pentagastrin (100 micrograms/kg) by intraperitoneal injection t.i.d. for 2 weeks. Rats were then killed and the pancreases excised, weighed, and assayed for DNA, RNA, protein, and polyamine (putrescine, spermidine, and spermine) concentrations and contents. We found that none of the treatments altered body weight at any age. All three hormones increased pancreas size and cell number in 3-month old rats, but by 12 months, all three had increased only pancreatic RNA content. Pancreatic spermidine concentration was decreased by all three hormone regimens in 3- but not in 12-month old rats, and pancreatic putrescine concentration and content were increased in 12-month old rats receiving all three hormones. There was no change in any parameter following any of the three hormones, tested at 24 months of age. We conclude that, at the dosages tested, the trophic response of pancreas to chronic administration of CCK, bombesin, and pentagastrin, which is normally present in young adult rats, is lost with aging.

Aging↗
PubMed1991

A high-performance liquid chromatographic method for the measurement of the iron chelator 1,2-dimethyl-3-hydroxypyridin-4-one in human plasma.

1,2-Dimethyl-3-hydroxypyridin-4-one (CP020 or L1) is a novel oral iron chelator that has proved to be effective in animals and humans. A rapid, accurate, and sensitive high-performance liquid chromatography method is described for measuring L1 in human plasma using a Hypercarb 7 microns column and monitoring the column eluent by ultraviolet absorption at 280 nm. CP020 and the internal standard (CP094) were extracted into dichloromethane (2 x 5 ml) from plasma at neutral pH [0.25 ml of plasma + 0.75 ml of 60 mM 3-(N-morpholino)propanesulfonic acid buffer, pH 7.4]. The method proved to be linear (r2 = 0.998) in the clinical range of 0.5-50 micrograms/ml when 0.25 ml of plasma was used, with the coefficient of variation less than 10% even at the lower concentration range.

Adolescent↗
PubMed1990

Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients.

The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) was compared with that of subcutaneous desferrioxamine in 26 patients with transfusional iron overload. Immediately after red-cell transfusion, 20 patients were randomised to receive either desferrioxamine (50 mg/kg daily as a 12 h subcutaneous infusion), or L1 (50 mg/kg daily by mouth). Patients were evaluated during treatment with the other drug after transfusion the next month. Mean (SD) daily urinary iron excretion was lower during L1 than during desferrioxamine (12.3 [6.7] vs 18.2 [15.3] mg/day). In 5 patients the dose of L1 was raised from 50 to 75 mg/kg daily; mean urinary iron excretion rose from 13.8 (7.0) mg/day to 26.7 (17.8) mg/day, comparable with that during desferrioxamine (24.9 [24.3] mg/day). Faecal iron excretion rose slightly over baseline in 6 patients studied during L1 administration (from 8.5 [0.9] mg/day to 12.2 [0.9] mg/day). Pharmacokinetic studies showed an elimination half-life for L1 of 117-237 min. Studies in dogs and in volunteers showed no absorption of the L1-iron complex, excluding a contribution of absorption of intraluminal complexes of L1 and food iron to urinary iron excretion. Further animal toxicity testing is needed before L1 can be studied in a broader group of patients.

Adolescent↗
PubMed1990

In vivo incorporation of N-acetyl-D-[U-14C]mannosamine into brain gangliosides of rats with quinolinic acid-induced lesions of the forebrain nucleus basalis magnocellularis.

Quinolinic acid, an excitotoxic agent, was applied unilaterally to the nucleus basalis magnocellularis of the rat forebrain, which resulted in neuronal destructions and consequently, loss of cholinergic projections to the cortex. The effects on ganglioside metabolism in brain cortical matter were studied. Total ganglioside contents in lesioned brains (n = 8) were found to be significantly decreased (range, 20-60%) but changes in brain ganglioside patterns on thin layer chromatograms were not apparent. On the other hand, in vivo incorporation of N-acetyl-D-[U-14C]mannosamine into brain gangliosides ranged from 19 to 36% (mean, 26%) of radiolabel in controls, and 5 to 21% (mean, 13%), a significant reduction in lesioned brains. Labeling of brain glycoproteins or of nonganglioside lipids was not affected. Since central cholinergic hypofunctions are also important neurochemical characteristics of Alzheimer's disease, abnormal ganglioside metabolism found in the lesioned rats may be of significance in the human disorder, where reduced brain ganglioside contents have also been reported.

Animals↗
PubMed1990

Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia.

Because trimethoprim-sulfamethoxazole (TMP-SMX) causes neutropenia in children with leukemia, we investigated the possibility that pharmacokinetic interaction between methotrexate (MTX) and TMP-SMX causes accumulation of the antileukemia agent. We studied the pharmacokinetics of MTX given intravenously or orally to nine children with acute lymphoblastic leukemia, once with and once without TMP-SMX. There was an increase in free MTX fraction during TMP-SMX therapy in all patients, from (mean +/- SD) 37.4 +/- 11% without TMP-SMX to 52.2 +/- 6.4% with TMP-SMX (p less than 0.01). Plasma clearance of total MTX did not change significantly, whereas clearance of free MTX decreased significantly (from 12.5 +/- 4 to 7.6 +/- 1.5 ml/kg/min; p less than 0.05). There was a consistent decrease in the renal clearance of free MTX (from 12.1 +/- 6.8 to 5.6 +/- 2.4 ml/kg/min; p less than 0.05). Elimination half-life of MTX was not affected significantly by TMP-SMX. There was a significant correlation between serum concentrations of TMP-SMX and the percentage of decrease in the renal clearance of free MTX (r = 0.91; p less than 0.05). These changes in protein binding and tubular clearance of MTX, caused by competition with TMP-SMX, result in a mean 66% increase in systemic exposure to MTX and may explain the myelotoxicity often observed with the coadministration of the two drugs.

Bone Marrow↗
PubMed1990

Preliminary study on the antinociceptive effect of elephant beta-endorphin.

1. Intraventricular administration of human beta-endorphin and elephant beta-endorphin significantly prolonged the tail flick response tested 30 min later. However, elephant beta-endorphin was about 7-8 times more potent than human beta-endorphin in the tail flick test. 2. beta-Endorphin antagonized the antinociceptive effect of both human beta-endorphin and elephant beta-endorphin by the same extent. Naloxone also antagonized the antinociceptive effects of the beta-endorphins but it was less effective than beta-endorphin. 3. Human beta-endorphin and elephant beta-endorphin were of equal potency in inhibiting the abdominal constriction response induced by intraperitoneal (i.p.) acetic acid. Both beta-endorphin and naloxone antagonized these effects of the beta-endorphins with naloxone being more effective. 4. The present study showed that different opioid receptor subtypes may be involved in the tail flick test and the abdominal constriction test. Furthermore, elephant beta-endorphin was a better antinociceptive agent than human beta-endorphin in the tail flick test.

Analgesics↗
PubMed1989

Primary structure of elephant pituitary prolactin.

Tryptic digests of elephant pituitary prolactin (elePRL) were separated by reverse phase high performance liquid chromatography (HPLC) and paper electrophoresis. From the amino acid composition, the amino acid sequencing of selected peptides, and from their alignment with expected tryptic peptides from ovine prolactin (oPRL), the primary sequence of elePRL is proposed.

Amino Acid Sequence↗
PubMed1989

Primary structure of fox pituitary growth hormone.

Tryptic digests of fox growth hormone (fGH) were separated by reverse phase high performance liquid chromatography (HPLC) and by paper electrophoresis. From the amino acid composition of these tryptic peptides and from their alignment with the expected tryptic peptides from bovine growth hormone (bGH), the primary structure of fGH is proposed. There are only 17 amino acid residues which are different in these two growth hormone molecules.

Amino Acid Sequence↗
PubMed1988

Isolation and characterization of growth hormone from blue fox pituitary glands.

Growth hormone has been purified to homogeneity from blue fox pituitary glands. It has 191 amino acids with two disulfide bridges and a single tryptophan residue. The somatotropin activity is only 8% when compared with the bovine hormone in the receptor-binding assay. From radioimmunoassay data using baboon antisera to porcine or bovine growth hormone, the fox hormone has 14-17% immunoreactivity of bovine or porcine hormone.

Amino Acid Sequence↗
PubMed1988

Isolation and primary structures of elephant adrenocorticotropin and beta-lipotropin.

Adrenocorticotropin and beta-lipotropin have been isolated and purified from elephant pituitary glands. The primary structures of these two hormones were determined by amino acid and sequence analyses of enzymatically cleaved peptides from the hormones. Peptide purification involved the use of gel filtration, reverse phase high performance liquid chromatography, and paper electrophoresis.

Adrenocorticotropic Hormone↗
PubMed1987

Gonadotropin-releasing peptide from human follicular fluid: isolation, characterization, and chemical synthesis.

A gonadotropin-releasing peptide has been isolated from human follicular fluid. Its amino acid composition and sequence are completely different from the hypothalamic lutropin-releasing hormone. It is designated human follicular gonadotropin-releasing peptide and abbreviated as hF-GRP. The primary structure of this peptide (H-Thr-Asp-Thr-Ser-His-His-Asp-Gln-Asp-His-Pro-Thr-Phe-Asn-OH) has been confirmed by chemical synthesis. In the mouse pituitary incubation assay, the ED50 value for follitropin or lutropin release is estimated to be 1.2-1.6 nM.

Body Fluids↗
PubMed1987

Elephant growth hormone. Isolation and characterization.

Growth hormone has been purified to homogeneity from elephant pituitary glands. It has 191 amino acids with two disulfide bridges and a single tryptophan residue. The somatotropin activity is only 15% when compared with the bovine hormone in the radioreceptor binding assay. From circular dichroism spectra alpha-helical content of elephant growth hormone is estimated to be 50%. Difference absorption spectra of the hormone suggest the presence of a hydrogen bond between the single Trp and a carboxylate ion.

Amino Acids↗
PubMed1987

Elephant prolactin: isolation and characterization.

Prolactin was isolated from anterior lobes of elephant pituitary glands. It consisted of 199 amino acids with three disulfide bridges and two tryptophan residues as found in prolactin from other species. The sequence of the NH2-terminal 28 amino acids was determined and shown homologous with the ovine hormone. In comparison with ovine prolactin, a marked difference was seen in the methionine content; the elephant hormone possessed only 18-34% lactogenic potency. The conformation of elephant prolactin was examined by zero order, second order and circular dichroism spectroscopy. The alpha helical content was estimated to be about 60%. In comparison with prolactins from other species, the second order spectra of elephant prolactin suggest that the local microenvironment for one or both tryptophan residues is somewhat different.

Amino Acids↗