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Biomedical subjects

J A Todhunter

Publications and source records attributed to J A Todhunter.

16 recordsLinked to original sources

Societal considerations in implementing risk management decisions: towards improving the process.

The risk management process can be seen as a public health activity which requires the expenditure of both public and private resources. As such, an effective risk management system must actually produce gains in public health to justify its cost. Similarly, the system should not force risk managers into decisions which are counterproductive. This requires that risk management take into consideration a variety of societal and technical factors. Among these are the actual nature of the risk involved and the risk trade-offs inherent in a management decision; the benefits associated with the risk generating activity; the practicality of various control options; and the nature of the various parties interested in the control decision. The degree of flexibility with which risk managers have to consider the various factors above depends on the risk management style under which they are constrained to operate. This is usually determined by the governing statutes or policies of the relevant regulatory agencies. These risk management styles run the gamut from zero risk approaches to risk/risk and risk/benefit balancing. Assuming that the risk manager has sufficient flexibility to produce cost effective decisions, the risk management process must still be sufficiently defined, procedurally and technically, to be accessible to interested parties. It also needs to effectively distinguish between risks which can be calculated or postulated and those which can have a practical outcome.

Decision Making

Synthesis of 3-hydroxycyclophosphamide and studies related to its possible role in the metabolism of cyclophosphamide.

Hydrogenolysis of 3-(benzyloxy)cyclophosphamide (10) using Pd/C catalyst and ethyl acetate as solvent leads to the formation of 3-hydroxycyclophosphamide (3, approximately 20%) and cyclophosphamide (1, approximately 10%), accompanied by regioselective hydrogen-exchange reactions at the C-4 and C-5 positions in 3 and 1. A variety of oxidizing reagents and liver microsomal incubation failed to provide evidence (31P NMR) for conversion of 1 into 3, whereas identical incubation of 3 led to its reduction to 1. Compound 3 is stable at pH 6.5-8.2, 37 degrees C, and exhibits anticancer activity comparable to 1 when tested against L1210 leukemia in mice. Data are discussed with regard to a previously reported suggestion that metabolism of 1 may involved oxidation to give 3 followed by rearrangement of 3 to 2.

Animals

Subchronic administration of caffeine and theophylline in drinking water: effects on rat liver RNA polymerase I activity.

Administration of caffeine or theophylline, 0.2 mg/ml (an average of 20 mg/kg/d) of drinking water, to male CD rats, 2 months of age, over a 15 week period resulted in the elevation of liver RNA polymerase I activity by 2-3 fold as assayed in isolated nuclei. This increase in activity was already apparent by the fourth week of exposure. The changes in RNA polymerase I activity were accompanied by moderate liver hypertrophy.

Animals

Modification of rat liver RNA polymerase I after in vivo stimulation by hydrocortisone or methylisobutylxanthine.

Following in vivo administration of hydrocortisone or methylisobutylxanthine to rats, higher levels (1.5- to 2.3-fold) of RNA polymerase I activity are present in liver nuclei and nucleoli of the treated animals as compared to control animals. The elevated specific activity is retained after purification of the enzyme under conditions where the enzyme is dependent on exogenous template for activity. The elevated polymerase activity in nuclei, nucleoli, and soluble enzyme can be destroyed by mild trypsin treatment which results in a rapid decay of the specific activity to the control level. Under these conditions, the control polymerase I activity is stable. The results indicate that in vivo stimulation by hydrocortisone or methylisobutylxanthine results in a conversion of the enzyme to a form that is catalytically more active but has an increased sensitivity to proteolysis.

Animals

Autophosphorylation of cardiac 3',5'-cyclic AMP-stimulated protein kinase. Kinetic evidence for the regulatory subunit directly acting at the active site in the R2C2 complex.

The mechanism of the autophosphorylation reaction of bovine heart cyclic AMP-dependent protein kinase (ATP: protein phosphotranferase, EC 2.7.1.31) has been further examined using a kinetic approach. The reaction is first order in both ATP and protein kinase when both are present at comparable concentrations. Dilution has no effect on the fraction of regulatory subunit phosphorylated over a given interval of time, and this finding is in accord with the autophosphorylation proceeding via an intramolecular (or, more appropriately in this case, by an intracomplex) reaction. The possibility of regulatory subunit phosphorylation by uncomplex catalytic subunit or another R2C2 complex (the protein kinase complex of two catalytic subunits and the regulatory dimer) was clearly eliminated. These results are compatible with a subunit geometry permitting the regulatory subunit to bind at the protein substrate region of the kinase's active site and to undergo subsequent phosphorylation.

Animals

Steady state and equilibrium exchange kinetic studies of the sheep brain glutamine synthetase reaction.

The kinetic mechanism of the sheep brain glutamine synthetase has been examined by both initial rate kinetics using the glutamate analog beta-glutamate and by isotope exchange measurements at equilibrium. Results of the initial rate studies were compatible with a number of sequential mechanisms but not with a partially or fully ordered rapid equilibrium or a ping-pong mechanism. Kinetic parameters at 37 degrees and pH 7.2 were K beta-Glu = 16 mM, KATP = 0.28 mM, and KNH2OH = 1.4 mM. For all equilibrium exchanges studied (ATP in equilibrium ADP, ATP in equilibrium Pi, and Glu in equilibrium Gln), the rate of exchange rose smoothly to a maximum as all substrates and products were simultaneously raised in a constant ratio. This result is in accord with a random order of substrate addition. A brief treatment of equilibrium exchange rates in cases where all substrate/product pairs are varied together is also presented.

Adenosine Diphosphate

Use of the sodium borohydride reduction technique to identify a gamma-glutamyl phosphate intermediary in the Escherichia coli glutamine synthetase reaction.

Incubation of unadenylylated Escherichia coli glutamine synthetase with ATP, L-[14C]glutamate and metal ion results in the formation of gamma-glutamyl-P which can under appropriate conditions be reduced by sodium borohydride. The acyl-P compound is formed catalytically as judged by the quantity of radioactive alpha-amino-delta-hydroxyvalerate produced compared to the concentration of enzyme subunits. Formation of the glutamyl-P compound occurs in the presence of magnesium or manganous ions, and the relation of this apparent lack of metal ion specificity with regard to the highly specific Mg2+-supported biosynthetic activity of the unadenylylated form is discussed.

Adenosine Triphosphate