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J M Ziegler

Publications and source records attributed to J M Ziegler.

16 recordsLinked to original sources
PubMed1995

Application of high-performance computing to numerical simulation of human movement.

We have examined the feasibility of using massively-parallel and vector-processing supercomputers to solve large-scale optimization problems for human movement. Specifically, we compared the computational expense of determining the optimal controls for the single support phase of gait using a conventional serial machine (SGI Iris 4D25), a MIMD parallel machine (Intel iPSC/860), and a parallel-vector-processing machine (Cray Y-MP 8/864). With the human body modeled as a 14 degree-of-freedom linkage actuated by 46 musculotendinous units, computation of the optimal controls for gait could take up to 3 months of CPU time on the Iris. Both the Cray and the Intel are able to reduce this time to practical levels. The optimal solution for gait can be found with about 77 hours of CPU on the Cray and with about 88 hours of CPU on the Intel. Although the overall speeds of the Cray and the Intel were found to be similar, the unique capabilities of each machine are better suited to different portions of the computational algorithm used. The Intel was best suited to computing the derivatives of the performance criterion and the constraints whereas the Cray was best suited to parameter optimization of the controls. These results suggest that the ideal computer architecture for solving very large-scale optimal control problems is a hybrid system in which a vector-processing machine is integrated into the communication network of a MIMD parallel machine.

Computer Systems↗
PubMed1991

Identification of novel phencyclidine metabolites formed in vitro by rabbit microsomal metabolism.

1. Phencyclidine (PCP) was incubated with rabbit liver and brain microsomal fractions, and the structures of metabolites formed by oxidation determined by g.l.c.-mass spectrometry. 2. The formation of several known mono- and di-hydroxylated metabolites, as well as two new metabolites, was seen in the liver preparations. 3. Hydroxylated PCP metabolites were also formed after incubation of PCP with brain microsomes, indicating that PCP biotransformation may occur in the brain itself.

Animals↗
PubMed1990

Phenobarbital inducible UDP-glucuronosyltransferase is responsible for glucuronidation of 3'-azido-3'-deoxythymidine: characterization of the enzyme in human and rat liver microsomes.

Glucuronidation by liver microsomes of 3'-azido-3'-deoxythymidine (AZT) was characterized in human and in various animal species. The glucuronide isolated by HPLC, was identified by mass spectrometry (fast atom bombardment, desorption in chemical ionization), and beta-glucuronidase hydrolysis. AZT glucuronidation reaction in liver microsomes of human and monkey proceeded similarly with an apparent Vmax of 0.98 nmol/min/mg protein and apparent Km of 13 mM. Oleoyl lysophosphatidylcholine activated more than twofold the formation of the glucuronide. Human kidney microsomes could also biosynthesize AZT glucuronide, although to a lower extent (six times less than the corresponding liver). Probenecid, which is administered to AIDS patients, decreased hepatic AZT glucuronidation in vitro (I50 = 1.5 mM), whereas paracetamol did not exert any effect at concentrations up to 21.5 mM. Morphine also inhibited the reaction (I50 = 2.7 mM). AZT glucuronidation presented the highest rate in human and in monkey (0.50 nmol/min/mg protein); pig and rat glucuronidated the drug two and three times less, respectively. In Gunn rat, the specific activity in liver microsomes was similar (0.18 nmol/min/mg protein) to that of the congenic normal strain; this suggests that an isozyme other than bilirubin UDP-glucuronosyltransferase catalyzed the reaction. In rats, AZT glucuronidation was stimulated fourfold by phenobarbital; 3-methylcholanthrene or clofibrate failed to increase this activity. This result was consistent with the bulkiness of the AZT molecule (thickness 6.7 A), which is a critical structural factor for glucuronidation of the drug by phenobarbital-induced isozymes. Altogether, the results strongly indicate that UDP-glucuronosyltransferase (phenobarbital inducible forms) is responsible for AZT glucuronidation.

Animals↗
PubMed1989

The secret.

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Attitude to Death↗
PubMed1988

Negative ion mass spectra of dihydropyridine calcium-channel blockers.

The negative ion mass spectra of some dihydropyridine analogues of nifedipine are studied; they show a fragmentation which is highly dependent on the position of the nitro group on the phenyl ring: 3'-nitro derivatives give essentially the molecular anion, whereas 2'-nitro derivatives lose successively H2O, RO and O. In addition, (2,1,3-benzoxadiazol-4-yl) derivatives show essentially a [M-ROH]- peak. Possible pathways for these fragmentations are given.

Calcium Channel Blockers↗
PubMed1987

High-performance liquid chromatographic analysis of glucuronic acid conjugates after derivatization with 4-bromomethyl-7-methoxycoumarin.

In order to enhance the detection sensitivity of various glucuronic acid conjugates (phenol, menthol borneol, estrone and testosterone) in high-performance liquid chromatography (HPLC), the compounds were esterified with 4-bromomethyl-7-methoxycoumarin in the presence of potassium carbonate and 18-crown-6 in acetone. The resulting esters were chromatographed on either a normal-phase (NP) column (LiChrospher DIOL) with hexane-ethanol mixtures as eluents or a reversed-phase column (LiChrospher CH-18) with methanol-water mixtures. They were detected by UV spectrophotometry at 328 nm. The structure of the derivatives was confirmed by mass spectrometry by direct introduction and chemical ionization. Prior to this step, their isolation on a semi-preparative scale was performed by NP-HPLC. The extraction of the studied glucuronides from microsomal solutions was tested by ion-suppression and ion-pair liquid-liquid partition and liquid-solid chromatography (on octadecylsilica cartridges). Extraction and chromatographic data are discussed with regard to the determination of glucuronyltransferase activity towards the aglycones cited above.

Chromatography, High Pressure Liquid↗
PubMed1986

Interactions of perhexiline maleate and arylalkylamine derivatives with cytochrome P-450 and in-vitro hydroxylation.

In order to find a substitute for perhexiline maleate, an antiangina drug, for which several side effects due to poor hydroxylation have been reported, an arylalkylamine series with antianginal properties has been synthesized. The aim of the present work was to select a more rapidly hydroxylated compound than perhexiline maleate in this series. Two criteria have been retained. The binding of the molecules to liver microsomal cytochrome P-450 and their rate of hydroxylation were both studied in vitro using phenobarbital induced rat liver microsomes. Incubation with cofactors and extraction procedures have been tested on one of the molecules of the series taken as example: N-2-dicyclohexyl-2-phenethylamine. All of the molecules tested in the series substrates were type I substrates; nevertheless, no correlation was found between binding on cytochrome P-450 and oxidative metabolism of the drugs. Two of the studied molecules were more easily hydroxylated than the others and than perhexiline maleate: (N-2-dicyclohexyl-2-phenethylamine) and (II) (N-cyclohexyl-2-diphenylethylamine) with the following respective kinetics: Apparent Vmax: 0.073 and 0.32 units, apparent Km: 6.9 X 10(-5) M and 22.2 X 10(-5) M.

Animals↗
PubMed1986

Rotavirus fecal IgA antibody response in adults challenged with human rotavirus.

Our studies of rotavirus challenge in adult volunteers enabled us to evaluate the relationship of pre-existing antirotavirus fecal IgA antibody to infection and illness and to investigate the local response to this infection. No relationship could be found between the pre-existing levels of fecal antirotavirus IgA antibody and protection from infection or illness. A greater than six-fold increase in the level of antibody was seen in 16/19 infected volunteers with determinable increases but in 0/15 controls who received less than the minimal infectious dose of rotavirus. Antibody levels increased rapidly in infected volunteers and were consistent with an anamnestic response. Two of seven volunteers who received an infectious dose of rotavirus but were considered uninfected on the basis of other laboratory methods had greater than or equal to six-fold increases of fecal antibody and one of these experienced symptoms compatible with a rotavirus infection. This finding indicates that an increase in fecal antibody may be a reliable indicator of rotavirus infection even in the absence of detectable shedding or seroconversion.

Adolescent↗
PubMed1985

Plasma uric acid: mass spectrometric method for control and comparison of intra- and interlaboratory studies.

We propose a preliminary study for the utilization of isotope dilution and mass fragmentography for the measurement of plasma uric acid. Using stable isotopes it is possible to measure this compound in comparison with the molecule labelled with three 15N atoms (1,3,9). We achieved the determination at the molecular peak. A linear calibration curve is obtained from standard solutions between 0 and 600 mumol/l. The method has good precision and the results obtained with different quality control materials demonstrate the need for better accuracy. This method could, after more detailed studies, be a good candidate for a definitive method.

Gas Chromatography-Mass Spectrometry↗
PubMedDate not supplied

Identification of cytochrome P-450 isozymes involved in the hydroxylation of dantrolene by rat liver microsomes.

The role of individual rat liver cytochrome P-450 isozymes in the metabolism of the skeletal muscle relaxant, dantrolene, was studied. Following incubation of dantrolene with hepatic microsomes from 3-methylcholanthrene-treated rats, two major hydroxylated metabolites were identified. Using inhibitory antibodies specific for individual cytochrome P-450 isozymes, cytochromes P-450 1A1, 1A2, and 3A were identified to be involved in dantrolene hydroxylations. In liver microsomes from 3-methylcholanthrene-treated rats, antibodies specific for cytochrome P-450 1A1 and 1A2 inhibited hydroxylation of dantrolene by 60% and 20%, respectively. Kinetics studies using these microsomes showed that dantrolene hydroxylation was biphasic with a low KM (0.06-0.08 microM) and high KM (5-7 microM). Cytochrome P-450 1A1 was responsible for the low KM hydroxylation of dantrolene, whereas cytochrome P-450 1A2 was responsible for the high KM. In hepatic microsomes from pregnenolone-16 alpha-carbonitrile-treated rats, an antibody specific for cytochrome P-450 3A completely inhibited the formation of 5-hydroxydantrolene, the major metabolite formed by these microsomes.

Animals↗