Biomedical subjects
Publications and source records attributed to M J Bargetzi.
Intrapulmonary sequestration is a rare disorder which should be considered when an intrathoracic mass is found in the lower part of the lungs. The clinical symptoms range, as in our two patients, from an asymptomatic mass in the chest X-ray film to frequent pulmonary infections. A definite diagnosis is possible only by visualization of the aberrant artery by arteriography, which is also helpful to the surgeon at lobectomy.
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Flecainide acetate, a class Ic antiarrhythmic agent, is eliminated to a larger extent by renal excretion and to a minor extent by the liver. In patients with impaired renal function or with elevated urinary pH, however, its elimination is dominated by hepatic metabolism. Recent evidence suggests that the in vivo metabolism of flecainide is controlled by the genetic polymorphism of the debrisoquin/sparteine type; i.e., it is a substrate of cytochrome P450IID6. We investigated the inhibitory effect of flecainide on bufuralol 1'-hydroxylation in human liver microsomes in vitro and on the metabolic dextromethorphan urinary ratio in eight healthy male volunteers. Both bufuralol and dextromethorphan are well-known substrates of cytochrome P450IID6. Microsomal bufuralol 1-hydroxylation was competitively inhibited by flecainide with an apparent Ki of 0.954 mumol/L. Moreover, a statistically significant increase in the urinary metabolic ratio (MR) of dextromethorphan/dextrorphan after 1 week of administration of oral flecainide was observed (p = 0.013) in all subjects. One individual increased the urinary MR to a value consistent with the poor metabolizer phenotype. We conclude that flecainide is a potent inhibitor of cytochrome P450IID6 in vitro and in vivo and that careful drug monitoring is required with respect to renal function, debrisoquine phenotype, and concomitant drug administration.
A new nitrocellulose-based ELISA technique, the line immunobinding assay (LIBA), permits the quantitative detection of multiple antigen-antibody reactions in one single assay. The antigen solutions are sprayed in thin lines onto a nitrocellulose sheet which is then cut into several strips before incubation in a multi-channel tray with serially diluted serum. The reacting antibodies are visualized by a peroxidase system. Comparison with other techniques routinely used for the detection of antibodies against measles, mumps and rubella, suggest that the LIBA offers specificity with sensitivity and may have a broad range of applications.
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The metabolism of lidocaine to its major metabolite monoethylglycinexylidide (MEGX) was studied in human liver microsomes of 13 kidney transplant donors and of one patient with liver cirrhosis. Interindividual variation in metabolite formation was considerable. Biphasic kinetics indicated the involvement of at least two distinct enzymatic activities. With use of a series of antisera that recognize different human cytochrome P450 isozymes, we were able to identify an enzyme of the P450III gene family as one of two enzymes. By expressing human P450IIIA4 complementary deoxyribonucleic acid (cDNA) in HepG2 cells, we directly demonstrated lidocaine-deethylase activity for this P450 isozyme. These data suggest that P450IIIA4 is at least in part responsible for microsomal MEGX formation.
In human liver microsomal preparations the neurotoxic chemical N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and several of its analogs competitively inhibited bufuralol 1'-hydroxylase activity of cytochrome P450bufI. This enzyme is the target of the common genetic polymorphism of drug oxidation known as debrisoquine polymorphism. Bufuralol 1'-hydroxylase activity was detectable in rat brain tissue. The activity was inhibited by antisera raised against a rat liver cytochrome P450 called P450db1. Immunoblotting experiments revealed the presence of a protein in rat and human brain microsomes with the same electrophoretic properties as the liver enzyme. These data suggest that P450bufI may be involved in the metabolism and neurotoxicity of MPTP.
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