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Biomedical subjects

C E Costello

Publications and source records attributed to C E Costello.

At least 91 records · Page 5Linked to original sources
PubMed1985

Production and purification of a peptide of Fusarium tricinctum that causes conidia of Penicillium to swell.

A process is described for production of a cyclodepsipeptide complex (CDPC) from autoclaved white corn grits fermented with Fusarium tricinctum NRRL 3510. Yields of more than 2.5 g CDPC/kg of medium were obtained. Previously, we described the conspicuous swelling of Penicillium digitatum conidia and hyphal tips incubating in a medium supplemented with the CDPC, a trio of metabolites produced by strains of F. tricinctum and F. roseum. Analysis of the CDPC mass spectra and the amino acid composition indicated one major and two minor cyclodepsipeptides. The two major products differed from the major cyclodepsipeptide only in the substitution of either isoleucine or valine for leucine in the threonyl-alanyl-alanyl-glutaminyl-tyrosyl-leucine peptide portion of the molecule.

Antifungal Agents↗
PubMed1984

Structural elucidation of a unique macrocyclic membrane lipid from a new, extremely thermophilic, deep-sea hydrothermal vent archaebacterium, Methanococcus jannaschii.

The membrane lipid of a new deep-sea hydrothermal vent methanogen, Methanococcus jannaschii, was isolated, purified, and structurally characterized. The total lipid extract, amounting to 32.2 micrograms/mg, dry cell weight, was fractionated on silica gel into a neutral lipid and polar lipid fraction. The neutral lipid fraction consisted of a series of isoprenoid hydrocarbons and free (nonphospholipid) alkylglycerol ethers. The polar phospholipid and glycolipid fraction (8.44 micrograms/mg, dry cell weight) was hydrolyzed with methanolic HCl, and the resulting alkylglycerol ethers were analyzed by a combination of chemical and spectroscopic techniques. The hydrolyzed polar lipid was primarily (95%) a unique, macrocyclic glycerol diether, heretofore unknown. High-field (250 MHz) proton nuclear magnetic resonance and infrared spectra of this novel macrocyclic compound are nearly identical and overlapping those of the known bis-(phytanyl)glycerol diether and bis-(diphytanyl)diglycerol tetraether. A field desorption mass spectrum revealed a molecular weight of 650 for the macrocyclic glycerol diether, 2 mass units less than that of bis-(phytanyl)glycerol diether. Degradation of the macrocyclic ether with boron tribromide resulted in diphytanyl dibromide, and further reaction of this dibromide with lithium aluminium hydride resulted in diphytane as determined by gas chromatography-mass spectrometry. The significance of the predominance of this structure in M. jannaschii is discussed. A survey of selected methanogenic Archaebacteria, including three thermophiles, failed to indicate the presence of the macrocyclic glycerol diether in any other microorganism, including two species of order Methanococcales, one species of Methanobacteriales, and three strains belonging to the order Methanomicrobiales.

Chemical Phenomena↗
PubMed1984

Identification of methylphosphomannosyl residues as components of the high mannose oligosaccharides of Dictyostelium discoideum glycoproteins.

Lysosomal enzymes isolated from the slime mold Dictyostelium discoideum bind to the mannose 6-phosphate receptor which is present in many mammalian cells. While binding to the receptor suggests that the slime mold enzymes possess the same mannose 6-phosphate recognition marker as their mammalian counterparts, initial structural studies of the phosphorylated oligosaccharides have indicated that the phosphate is attached to high mannose-type units via an unusual phosphodiester linkage (Freeze, H.H., Yeh, R., Miller, A.L., and Kornfeld, S. (1983) J. Biol. Chem. 258, 14874-14879). To identify the components of the phosphodiester group we have isolated the phosphorylated high-mannose oligosaccharides from D. discoideum AX3 cells labeled with [2-3H]mannose or [6-3H]glucosamine and from the differentiation medium of unlabeled cells. The major phosphorylated species contain one or two phosphodiester groups and an average of 6 or 7 mannose residues. The phosphodiesters are relatively stable to both acid and base hydrolysis, but upon strong acid hydrolysis (conditions that completely hydrolyze the oligosaccharide) mannose 6-phosphate residues are liberated. Through a combination of techniques, including fast atom bombardment and direct chemical ionization mass spectrometry, it is shown that the mannose 6-phosphate residues of the intact oligosaccharide are diesterified to methyl groups. This indicates that slime mold possesses a different biosynthetic pathway for the formation of phosphorylated high mannose-type oligosaccharides than is utilized by higher organisms.

Chromatography, High Pressure Liquid↗
PubMed1983

Synthesis of a cyclic fibrin-like peptide and its analysis by fast atom bombardment mass spectrometry.

For immunochemical purposes, a cyclic 12-peptide was synthesized to model the gamma-gamma-chain cross-link site in human fibrin. The model was based upon the structure proposed by Chen & Doolittle (Biochemistry (1971) 10, 4486-4491) which is characterized by two reciprocating epsilon-(gamma-Glu)Lys bonds between adjacent fibrin gamma-chains oriented in an antiparallel manner. To achieve the antiparallel orientation of the peptide backbone, Pro and Gly were inserted at positions 6 and 7 of the linear 12-peptide: acetyl-Gly-Glu-Gln-His-His-Pro-Gly-Gly-Gly-Ala-Lys-Gly-amide. The insertions were made to facilitate a reverse turn of the peptide during the last synthetic step, which was formation of the epsilon-(gamma-Glu)Lys bond between Glu at position 2 and Lys at position 11 with diphenylphosphorylazide. The resulting cyclic peptide represented half of the symmetrical cross-linked region in clotted fibrin. Following purification by HPLC, both linear and cyclic 12-peptides were analyzed by fast atom bombardment mass spectrometry. Abundant molecular protonated ions were observed for both peptides. In addition, the amino acid sequence of the linear peptide and the location of the epsilon-(gamma-Glu)Lys bond in the cyclized peptide could be verified.

Amino Acid Sequence↗
PubMed1983

The investigation of radiopharmaceutical components by fast atom bombardment mass spectrometry: the identification of Tc-HIDA and the epimers of Tc-CO2DADS.

The nature of two technetium-labeled radiopharmaceutical components has been established by means of fast-atom-bombardment mass spectrometry (FABMS) in combination with carrier-added (CA) and no-carrier-added (NCA) reversed-phase high-pressure liquid chromatography (HPLC). Negative-ion FABMS was used to determine that the epimers of Tc-CO2DADS are the oxo[N,N'-(1-carboxyethylene)-bis-(2-mercaptoacetimido)]technetate(V) ions; positive-ion FABMS showed that Tc-HIDA is bis[N-(2,6-dimethylphenyl-carbamoylmethyliminodiaceto]technetate(III).

Chromatography, High Pressure Liquid↗
PubMed1982

Pharmacokinetic equivalence of stable-isotope-labeled and unlabeled drugs. Phenobarbital in man.

Stable isotope labeling of drugs has been used in human metabolism studies because it eliminates the risk of radiation exposure accompanying use of radioactive tracers. The labeled drug can be measured by gas-chromatographic mass spectrometry (GCMS). However, if reliable pharmacokinetic data are to be obtained, one has to be certain the rate of metabolism of labeled and unlabeled drug is the same, i.e., there is no kinetic isotope effect. To evaluate this for phenobarbital (PB), three humans were infused with a 1:1 mixture of phenobarbital and 1,3-15N2-2-13C-PB. Serum was collected at regular intervals. Concentrations of labeled and unlabeled phenobarbital were determined by GCMS. Within each subject, there was no trend for concentrations of labeled phenobarbital to be higher or lower than concentrations of unlabeled phenobarbital (P greater than 0.90 for all three subjects). There was no difference in the zero time intercepts, distribution and elimination time constants and half-lives, volumes of distribution and central compartment, or clearance of the two forms of phenobarbital. Thus, no isotope effect was found. Published data on other labeled drugs and the likelihood of encountering an isotope effect based on type of isotope and its location in the molecule are discussed.

Adult↗
PubMed1982

Chemical and in vivo studies of the anion oxo[N,N'-ethylenebis(2-mercaptoacetimido)]Technetate(V).

Studies of the anionic coordination complex 99Tc-oxo[N,N'-ethylene-bis(2-mercaptoacetimido)]technetate(V) ([TcO(ema)]-) are described. Syntheses performed both at carrier levels (10(-5)M) and with no carrier added (less than 10(-8)M) indicate that the complex is formed virtually quantitatively from pertechnetate ion over this range. Tissue distributions in normal rats are similar at both concentrations up to one hour after administration. It has been shown--using a combination of high-pressure liquid chromatography and field-desorption mass spectrometry--that the anion is excreted unchanged into both urine and bile. The effectiveness of this N2S2 donor set in sequestering Tc-99m, and the in vivo stability of the resulting complex, suggest that modified chelates of this structural class could provide a series of useful diagnostic agents.

Animals↗
PubMed1981

A gas chromatographic/mass spectrometric method for the simultaneous quantitation of 5,5-diphenylhydantoin (phenytoin), its para-hydroxylated metabolite and their stable isotope labelled analogs.

A stable isotope dilution method for the quantitation by GC-MS of 5,5-diphenylhydantoin, its major metabolite (5-(4-hydroxyphenyl)-5-phenylhydantoin), and, simultaneously, their stable isotope labelled analogs (5,5-diphenyl-2-(13)C-1,3-(15)N2-hydantoin and 5-(4-hydroxyphenyl)-5-phenyl-2-(13)C-1,3-(15)N2-hydantoin) is discussed and evaluated. 5,5-di-(pentadeuterophenyl)hydantoin and 5-(4-hydroxy-3,5-dideuterophenyl)-5-phenyl-2-(13)C-1,3(15)N2-hydantoin are used as internal standards. The chemical work-up procedure of serum (1.0 ml) and urine (0.5 ml) involves acid hydrolysis, extraction at pH 7.4 and permethylation of drug and metabolite analogs by extractive methylation. The mass spectrometric technique consists of repetitive scanning over the molecular ion region of the permethylated derivatives of the phenytoin and para-hydroxy metabolite analogs as they elute from the gas chromatograph. Molecular ion abundances are measured. Reproducibility, selectivity and linearity of the method are discussed in the light of the planned applications.

Carbon Radioisotopes↗
PubMed1981

Kinetic equivalence of stable-isotope-labeled and unlabeled phenytoin.

Stable isotope labeling (SIL) of a drug results in a higher molecular weight than that of the unlabeled drug. SIL tracer doses can be quantitated separately from unlabeled drug by gas chromatography-mass spectrometry (GC-MS) without exposing the patient to radiation. The higher molecular weight of SIL drug could cause a higher energy of activation for (and slowing of) metabolic reactions ("isotope effect"). To evaluate possible isotope effect, three dogs and three men were infused with a mixture containing equal amounts of SIL (2-13C-1,3-15N2) and unlabeled phenytoin (PHT). Plasma and urine were collected at regular intervals. Concentrations of SIL and unlabeled PHT and HPPH (the major metabolite of PHT) were determined by GC-MS. Within each subject there was no trend for concentrations of SIL PHT or HPPH to be higher or lower than concentrations of their unlabeled analogs (greater than 0.20 to 0.90). There was no difference in the distribution and elimination half-lifes (t 1/2s), volume of distribution, volume of central compartment, or clearance of the two forms of PHT. Thus, no isotope effect was found.

Animals↗
PubMed1981

Reliability of the toxic screen in drug overdose.

To determine the reliability of the laboratory in detecting drugs taken by overdosed patients, we evaluated laboratory performance on an unbiased sample of actual clinical specimens. Replicate serum and urine samples from a series of 20 consecutive clinically overdosed patients were sent to three commercial laboratories and one academic research laboratory for identification and quantification of intoxicating agents. All laboratories used the advance analytical techniques of gas chromatography-mass spectrometry. The results suggest that laboratories do not reliably identify drugs in the serum of overdosed patients, partly because of technical limitation, partly because of laboratory error, and possibly because of inadequate specimens. Drugs judged responsible for the overdose were identified in only 50% to 70% of the cases, depending on the laboratory. Reported concentrations sometimes varied over a 10-fold range.

Evaluation Studies as Topic↗
PubMed1980

A mass spectrometric method for the determination of stable isotope labeled phenytoin suitable for pulse dosing studies.

A gas chromatographic mass spectrometric method has been developed for the determination in biological fluids of phenytoin (5,5-diphenylhydantoin), 5-(4-hydroxyphenyl)-5-phenylhydantoin (the major metabolite of phenytoin), and simultaneously, their stable isotope labeled analogs [5,5-diphenyl-2-13C-1,3-15N2-hydantoin and 5-(4-hydroxyphenyl)-5-phenyl-2-13C-1,3-15N2-hydantoin]. Quantification was achieved by an isotopic dilution technique: 5,5-di(pentadeuterophenyl)-hydantoin and 5-(4-hydroxy-3,5-dideuterophenyl)-5-phenyl-2-13C-1,3-15N2-hydantoin were used as internal standards. Molecular ion abundances of the permethylated derivatives were measured using a limited mass range repetitive scanning technique. The method is accurate, selective, reproducible and linear for analysis of 1.0 ml of serum and 0.5 ml of urine samples at the expected concentrations of drug (serum: 0.1-30.0 micrograms ml-1) and metabolite (serum: 0.1-10.0 micrograms ml-1; urine: 5.0-200.0 micrograms ml-1). The pharmacological equivalence of labeled and unlabeled phenytoin is demonstrated for a human volunteer. The results are discussed in the light of the further applications of the method, i.e. determination of the pharmacokinetics of a pulse dose of the labeled drug administered to patients who are taking a steady state dose of the unlabeled drug.

Animals↗
PubMed1979

Sites of intermolecular crosslinking of fatty acyl chains in phospholipids carrying a photoactivable carbene precursor.

Sonicated vesicles of 1-fatty acyl-2-omega-(2-diazo-3,3,3-trifluoropropionoxy) fatty acyl sn-glycero-3-phosphoryl-cholines were shown recently to form intermolecular crosslinks by insertion of the photogenerated carbene into a C-H bond of a neighboring hydrocarbon chain. We now report that photolysis of multilamellar dispersions gives a second series of products in which carbene insertion is accompanied by elimination of a molecule of hydrogen fluoride. The sites of crosslinking in the latter compounds have been studied by mass spectrometry using phospholipids with varying chain lengths of the fatty acyl groups carrying the carbene precursor. The patterns observed show that the point of maximum crosslinking is consistent with the recent conclusion that in phospholipids the sn-2 fatty acyl chain trails the sn-1 chain by 2-4 atoms.

Journal Article↗
PubMed1978

Occurrence of novel branched-chain fatty acids in Refsum's disease.

Two novel branched-chain fatty acids, which appear to be unsaturated analogs of phytanic acid, have been observed in sera and urine of patients with Refsum's disease. They occur in both phospholipids and neutral lipids, and have been isolated and characterized.

Eicosanoic Acids↗
PubMed1976

Methylation artifacts in the gas chromatography of serum extracts. Competitive suppression with trimethyl-d9 anilinium hydroxide.

In the course of the identification of drugs in body fluids by gas chromatography-mass spectrometry we have observed the appearance of N-methyl derivatives of certain compounds such as phenobarbital and diphenylhydantoin, especially in extracts of serum. With the aid of deuterium labelled phenobarbital it could, however, be shown that the N-methyl derivatives are not endogenous metabolites but artifacts generated upon injection of the serum extract into the gas chromatograph. Conversely, derivatization with trimethyl-d9 anilinium hydroxide (TMAH-d9) demonstrated the absence of any undeuterated methyl derivative and this reagent should be useful for the detection of endogenous N-methyl derivative which would, of course, remain undetected when using unlabelled TMAH in the course of the conventional methylation technique. There are good indications that lecithin is the methylating agent in serum responsible for the formation of these artifacts.

Aniline Compounds↗
PubMed1975

Phencyclidine. Nine cases of poisoning.

In nine cases of phencyclidine hydrochloride poisoning, early signs of overdose included drowsiness, nystagmus, miotic pupils, blood pressure elevation, increased deep tendon reflexes, ataxia, anxiety, and agitation. In more severe cases, seizures, spasticity, and opisthotonos were seen in addition to deep coma and respiratory depression. Treatment included removal by emetics or lavage, hydration, and a quiet, reassuring environment. Spasticity, agitation, and ocular manifestions responded to diazepam. Psychiatric intervention was instituted after the patients were stable and no longer agitated.

Adolescent↗