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P Goldman

Publications and source records attributed to P Goldman.

At least 55 records · Page 3Linked to original sources
PubMed1985

Structural analysis of both products of a reciprocal translocation between c-myc and immunoglobulin loci in Burkitt lymphoma.

The balanced translocations that occur between the c-myc and immunoglobulin loci in Burkitt lymphoma provide an unusual opportunity to analyze both products of a reciprocal recombination. Accordingly, we have determined the structure of the two reciprocal products of a translocation that joins the 5' portion of the c-myc gene on chromosome 8 to the immunoglobulin mu switch recombination signal on chromosome 14. By determining the nucleotide sequences at the translocation crossover points of both product chromosomes, we precisely locate these points with respect to nearby genes. This determination allows us to conclude that translocation involves nonhomologous recombination, is highly conservative of c-myc sequences (deleting only 16 bp at the crossover point), but deletes over 2 Kb of immunoglobulin sequences from the mu switch signal. The mu constant and c-myc genes are joined head-to-head about 3 Kb apart, while the IgH enhancer and an aberrantly rearranged D/J region are linked to sequences 5' of c-myc on the reciprocal product.

Burkitt Lymphoma↗
PubMed1985

Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18.

Specific chromosomal translocations found in distinct neoplasms suggest that genes that flank such breakpoints play a critical role in transformation. We have characterized the t(14;18)(q32;q21) chromosomal translocation present in over 60% of human follicular lymphomas. We exploited an unexpected rearrangement of an Ig heavy-chain gene to clone the chromosomal breakpoint. An element isolated from 18q21 mediated translocations in all four t(14;18) bearing cell lines and in six of 11 follicular lymphomas, but did not normally rearrange in other B or non-B cells. The breakpoints clustered within a small 4.3 kb region on chromosome 18. The breakpoints on chromosome 14 were focused within or immediately 5' to JH. These breakpoints retained the Ig enhancer region close to a new transcriptional unit identified on chromosome segment 18q21. Since none of the cellular oncogenes are known to map to 18q21, cloning this element provides an opportunity to characterize a potentially new transforming gene.

Cell Line↗
PubMed1984

Effect of bioavailability on dose-response relationships.

To achieve the goals of drug therapy one must not only select the appropriate drug but also ensure that it is administered in the proper dose. Sufficient drug should be administered to achieve a therapeutic effect, yet not so much as to produce unwanted side effects. One desirable effect of hydrochlorothiazide, for example, is the control of hypertension. An undesirable effect is excessive potassium loss. The dosage range that is likely to cause the hypotensive effect without the potassium loss has been called the "therapeutic window." In principle, hydrochlorothiazide can be combined with a potassium-sparing diuretic, such as triamterene, to lower blood pressure with a decreased risk of hypokalemia, and thus to "widen" the therapeutic window. The term "dose," however, requires further description. Because of compliance problems we know that the patient does not necessarily adhere to the prescribed dosage schedule. Furthermore, because of the bioavailability of the pharmaceutical formulation, the dose the patient "takes" may not be the one that he or she actually gets. The formulation of the drug product determines how rapidly and completely the active ingredient of the drug dissolves in the gastrointestinal tract and subsequently gets absorbed into the bloodstream. Thus, the time course of the drug concentration in serum has become the measure of dose that is most directly related to dose-response relationships. Incompletely absorbed drug products are said to be poorly bioavailable. Such products are undesirable, not only because the patient receives a dosage that is on the average less than that expected, but also because poor bioavailability may lead to a great variation in dose. Thus, poorly bioavailable drug formulations increase the variability in dose-response relationships among patients and as a result jeopardize the attainment of therapeutic objectives.

Biological Availability↗
PubMed1984

Interaction of metronidazole with DNA repair mutants of Escherichia coli.

It has been proposed that one of metronidazole's partially reduced intermediates interacts either with DNA to exert a bactericidal effect or with water to form acetamide. To test this hypothesis we have examined the effect of metronidazole on several mutants of Escherichia coli that are defective in DNA repair. UV-susceptible RecA- and UvrB- point mutants have an increased susceptibility to metronidazole as manifested by both a decreased minimal inhibitory concentration and a greater bactericidal response to metronidazole in resting cultures. By these criteria, however, we find that UvrB- deletion mutants, which lack the ability to reduce nitrate and chlorate, are no more susceptible to metronidazole than is the wild type. We find, however, that these deletion mutants also lack the ability to reduce metronidazole and thus possibly to form its reactive species. When metronidazole's bactericidal effect is expressed in terms of the concurrent accumulation of acetamide derived from metronidazole, then all RecA- and UvrB- mutants are killed more efficiently than their wild types. The data are consistent, therefore, with metronidazole's lethal effect being mediated by a partially reduced intermediate on the metabolic pathway between metronidazole and acetamide. Defects in other aspects of the DNA repair system do not confer this increased susceptibility to the proposed intermediate. A Tag- mutant, for example, which is defective in 3-methyl-adenine-DNA glycosylase, does not have this increased susceptibility to the presumed precursor of acetamide. Thus, these results provide further support for the hypothesis that the bactericidal effect of metronidazole is mediated by a partially reduced intermediate in the metabolic conversion of metronidazole to acetamide and suggest that this intermediate interacts with DNA to produce a lesion similar to that caused by UV light.

Acetamides↗
PubMed1983

Role of sulfhydryl compounds in the bactericidal effect of metronidazole.

The bactericidal effect of metronidazole on Escherichia coli and Bacteroides fragilis can be partially reversed by cysteamine under conditions that lead to the formation of an adduct, the thioether, 4-(2-aminoethyl)thio-2-methylimidazole-1-ethanol (4-ATME). This adduct, which is not mutagenic for the Ames histidine auxotrophs of Salmonella typhimurium, forms at a rate that is independent of live bacterial cells and, therefore, can not be shown to relate to the biological effect of cysteamine. When treated with Raney nickel, this adduct yields 2-methylimidazole-1-ethanol. To determine whether a structurally related adduct forms with bacterial protein, a culture of B. fragilis was incubated with radiolabelled metronidazole and then treated with 5% trichloroacetic acid. That the radiolabel in the precipitate did not yield 2-methylimidazole-1-ethanol when treated with Raney nickel suggests that binding of metronidazole to cellular macromolecules does not involve thioether formation.

Bacteria↗
PubMed1983

Reduction of nitroheterocyclic compounds by mammalian tissues in vivo.

To determine whether nitro group reduction occurs in mammalian tissues, metronidazole (0.021, 0.064 and 10 mg/kg), misonidazole (0.015 mg/kg) and nitrofurazone (0.13 mg/kg), respectively, were administered to germfree rats. A reduced metabolite [1-(2-aminoimidazol-1-yl)-3-methoxypropan-2-ol] and two of its hydrolysis products, urea and (2-hydroxy-3-methoxypropyl)-guanidine, were found in the urines of germfree rats that received misonidazole. When nitrofurazone was administered, a reduced metabolite, 4-cyano-2-oxobutyraldehyde semicarbazone, was detected in the urines. However, acetamide and N-(2-hydroxyethyl)oxamic acid, fragmentation products from the reduction of metronidazole, were not found in significant concentrations in the urine when germfree rats received metronidazole. Apparently metronidazole is reduced so much more slowly than misonidazole and nitrofurazone in the tissues of germfree rats that its reductive metabolites are not detectable. This observation may be explained by the one-electron reduction potentials (E1 7) of these drugs, that of metronidazole (E1 7 = -486 mV) being lower than those of either misonidazole (E1 7 = -389 mV) or nitrofurazone (E1 7 = -257 mV). Under these circumstances, metronidazole reduction is not detected, either because its radical anion forms more slowly than that of the other nitroheterocyclic compounds or because its radical anion interacts more rapidly with oxygen to restore the parent compound.

Acetamides↗
PubMed1983

Drug residue formation from ronidazole, a 5-nitro-imidazole. IV. The role of the microflora.

When radioactive 1-methyl-5-nitroimidazole-2-methanol carbamate, ronidazole, labeled at the 4,5-ring positions was administered orally to germ-free and conventional rats, a much larger fraction of the radioactivity was excreted in the feces of the conventional animals. Determination of the total radioactive residues present in the carcass, blood, plasma, liver, fat and kidney 5 days after dosing indicated that the carcass of the germ-free animals contained a greater quantity of residue than that of conventional rats. On the other hand, the blood of the conventional animals contained a much higher level of radioactivity than that of the germ-free animals. These results show that while the microflora influence the distribution of the drug their presence is not obligating for the formation of persistent tissue residues in rats dosed with ronidazole.

Adipose Tissue↗
PubMed1983

Studies on avian erythrocyte metabolism. XIII. Changing organic phosphate composition in age-dependent density populations of chicken erythrocytes.

These studies were performed to determine whether the erythrocytes (RBC's) of chickens are able to alter the concentrations of organic phosphates, particularly inositol pentakis (dihydrogen phosphate) (inositol-P5), in response to anemia. Acute anemia with 33.5% reticulocytes (retics) in the peripheral blood of 4-month-old White Leghorn cockerels was produced after two successive days of controlled bleeding. Five populations of RBC's were prepared from blood of these anemic birds based upon age-dependent density by angle rotor centrifugation. The relative increase in age of Fraction 1 (younger cells) through Fraction 5 (oldest cells) was verified by increased hemoglobin concentration and decreased retic count and cell volume. The acid aqueous-soluble phosphates from each RBC fraction were extracted, fractionated by ion exchange column chromatography, and the concentration of inorganic phosphate (Pi), adenosine triphosphate (ATP), and inositol-P5 quantitated by wet-ash phosphate analysis. Determination of Pi, ATP, and inositol-P5 in Fraction 1 (younger cells, 7.4% retics) from the initial (Day 1) blood withdrawn gave 4.3, 5.7, and 18.6 mumoles Pi/ml RBC, respectively. On Day 4 of controlled-bleeding, Pi, ATP, and inositol-P5 concentrations in Fraction 1 (95.1% retics) were 12.7, 10.6, and 12.3 mumoles Pi/ml RBC, respectively. On Day 11, after 1 week recovery from controlled-bleeding, the values for Pi, ATP, and inositol-P5 in Fraction 1 (37.7% retics) were 5.0, 5.4, and 19.0 mumoles Pi/ml RBC, respectively, which were similar to the values before bleeding.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3-Diphosphoglycerate↗
PubMed1982

Age-dependency of vascular phospholipid deacylation-reacylation in spontaneously hypertensive rats.

We have studied the temporal relation of phospholipid turnover and prostaglandin synthesis to the evolution of hypertensive vascular disease in the spontaneously hypertensive rat. The incorporation of arachidonate into aortic phospholipids, its release by phospholipase A2 and its utilization for prostaglandin synthesis were compared in spontaneously hypertensive and Wistar-Kyoto rats aged 7, 20 and 42 weeks. When expressed per mg of protein in the assay medium, arachidonate incorporation into aortic phospholipids decreased, while prostaglandin synthesis increased, with age in both rat strains. No significant differences were noted between hypertensive and normotensive animals at 7 weeks of age whereas both enhanced phospholipid turnover and prostaglandin synthesis was demonstrated in hypertensive rats at 20 and 42 weeks of age. The higher phospholipase activity in hypertensive aortas was associated with a significant increase in the capacity for exogenous lysophosphatide hydrolysis. Transacylation and reacylation of lysolecithin, however, were not significantly enhanced in hypertensive aortas. These biochemical changes accompany, and may be related to, structural modifications of the aortic wall in the course of hypertension.

Acylation↗
PubMed1982

Risks to children from computed tomographic scan premedication.

We observed serious adverse reactions after premedication for computed tomographic (CT) head scans and therefore determined rates and risk factors for such reactions among 106 hospitalized children monitored by an intensive drug surveillance program. Reactions occurred in 13 patients (13%), including four cases of life-threatening cardiorespiratory depression or arrest after narcotic premedication. Other reactions included CNS depression, behavior changes, voiding problems, and vomiting. The risk of reaction was elevated in subjects who received high doses of a premedication drug (relative risk, 5.2) and in those who received four or more premedication (relative risk, 3.7). All life-threatening reactions occurred among infants younger than 3 months, and two of these followed medication with only morphine sulfate, in the recommended dose. Risks of adverse reactions from premedication should be considered by physicians who order CT scans for hospitalized children.

Adolescent↗
PubMed1982

Comparative misonidazole metabolism in anaerobic bacteria and hypoxic Chinese hamster lung fibroblast (V-79-473) cells.

The metabolism of the radiation sensitizer misonidazole was similar in anaerobic cecal contents and hypoxic Chinese hamster lung fibroblasts (V-79-473). Both systems formed the amino derivative of misonidazole, [1-(2-aminoimidazol-1-yl)-3-methoxypropan-2-ol] (AIM), and urea, as well as a metabolite, (2-hydroxy-3-methoxypropyl)-guanidine (G), which has not been described previously. It appears that the nitro group of misonidazole was reduced to form AIM and that this compound was then hydrolyzed to yield either urea or G, the latter in yields of 25% (tissue culture) to 55% (cecal contents). When tested with the Ames tester strain, both G and AIM were slightly mutagenic only for strain TA 98 and then only in the presence of the system for microsomal activation.

Animals↗
PubMed1982

Interaction of metronidazole with resistant and susceptible Bacteroides fragilis.

The kinetics of the lethal action of metronidazole and the formation of acetamide have been studied in a strain of Bacteroides fragilis which is relatively resistant to metronidazole. As with a susceptible strain of B. fragilis, the data are consistent with a model in which a labile intermediate in metronidazole metabolism interacts either with water to form acetamide or with a bacterium to cause its death. Although the relatively resistant strain grows more slowly than the susceptible one and is killed less rapidly by metronidazole, the resistant strain displays the same relationship between the lethal action of metronidazole and metronidazole metabolism to acetamide. The relatively resistant strain, like the susceptible one, has an enhanced lethal response to metronidazole in the presence of a strain of Escherichia coli. The results suggest that the proposed labile reactive intermediate of metronidazole forms more slowly in the resistant strains.

Acetamides↗