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Biomedical subjects

D E Duggan

Publications and source records attributed to D E Duggan.

At least 37 records · Page 2Linked to original sources
PubMed1977

The disposition of sulindac.

The disposition of sulindac, a new nonsteroid anti-inflammatory drug, has been studied in normal volunteers in five separate clinical studies. Based upon material balance considerations, a minimum of approximately 88% of an oral dose is absorbed. The major biotransformations involve irreversible oxidation of the sulfinyl group of sulindac to sulfone and reduction to the corresponding sulfide. The latter, which all available evidence indicates to be the pharmacologically active form of sulindac, is not excreted in urine, and has an apparent terminal half-life of 18.2 hr, well suited to twice daily dosage of its pro-drug. Following twice daily dosage of sulindac for 5 days, plasma levels of sulfide approach an apparent steady state with concentrations varying only within a twofold range over each dosage interval. The reversible biotransformation between sulindac and its active sulfide metabolite provides the basis for two therapeutic advantages relating to the gastrointestinal intolerance usually associated with anti-inflammatory drugs: (1) circumvention of initial exposure of gastric and small intestinal mucosa to the active form of the drug and (2) maintenance of systemic levels of active drug by means of enterohepatic recycling, principally of inactive pro-drug.

Adult↗
PubMed1977

Analysis of sulindac and metabolites by combined isotope dilution-radioimmunoassay.

Sulindac, a new anti-inflammatory agent, and its sulfone and sulfide metabolites were conjugated to bovine serum albumin by the N-hydroxysuccinimide active ester procedure. Antiserum from rabbits immunized with each of these haptens exhibited extensive cross-reactivity, precluding differential analyses of the three species by displacement assay without prior separation. Therefore, an analytical method based on a combination of isotope dilution and radioimmunoassay was devised. A known mixture of the three chemical species, each labeled with tritium, was equilibrated with plasma or urine samples, reisolated chromatographically, and quantitated by binding to an appropriate immunoglobulin. The radiolabeled materials thus served as recovery standards as well as labeled antigens for each displacement assay. Sulindac and each of its metabolites in plasma or urine at concentrations as low as 500 ng/sample were differentially determined by this procedure. However, since an extraction is required, several milliliters of plasma can be used for each sample, thus increasing the actual sensitivity of the assay.

Animals↗
PubMed1977

Radioimmunoassay of indomethacin in biological fluids.

A radioimmunoassay was developed for the determination of indomethacin in biological fluids at concentrations as low as 50 ng/ml. Antibodies were produced in rabbits immunized with a conjugate of bovine serum albumin and indomethacin. This conjugate was prepared by an N-hydroxysuccinimide active ester procedure. Antiserums exhibited minimal cross-reactivity with the O-desmethyl and deschlorobenzoyl metabolites. However, the glucuronide conjugate was about three times as reactive as indomethacin, thus invalidating direct determinations of indomethacin in urine. This difficulty was circumvented by analyzing urine aliquots before and after conjugate hydrolysis. Concentrations of free and conjugated indomethacin were calculated by difference.

Animals↗
PubMed1977

2-pyridylimidazoles as inhibitors of xanthine oxidase.

A series of 28 4-substituted and 4,5-disubstituted 2-pyridylimidazoles was synthesized and evaluated in vitro for inhibition of xanthine oxidase. Included within this group are examples of 2-pyridylimidazopyridines and halo-substituted 2-pyridylbenzimidazoles. Five compounds exhibited inhibitory activity in the same range as the standards, 4-hydroxypyrazolo[3,4-d]pyrimidine and 2-(4-pyridyl)-4-trifluoromethylimidazole (22). Two examples, 2-(4-pyridyl)-4,5-dicyanoimidazole (16) and 2-(4-pyridyl)-4-nitroimidazole (3), were at least an order of magnitude more active than the standards and therefore rank among the most potent known inhibitors of the enzyme.

Chemical Phenomena↗
PubMed1977

The effects of probenecid upon the individual components of indomethacin elimination.

The effects of probenecid upon plasma profiles for indomethacin and upon the individual components of total plasma clearance have been evaluated in dogs, monkeys and rats. These three species cover the wide spectrum of species differences with respect to the relative contribution of renal, biliary and metabolic clearances to elimination of indomethacin. In dogs, in which biliary clearance is the major component of elimination, probenecid raised incremental values for area under the plasma curve [AUC] greater than 2-fold and completely obliterated the normal portal: peripheral gradient of drug after i.v. dosage. Biliary clearance, measured directly, was inhibited 70%. In rats, in which metabolic clearance is predominant, probenecid had no significant effect upon plasma clearance. In rhesus and spider monkeys, in which renal, metabolic and biliary clearances are all significant, as in man, areas under the plasma curve for indomethacin were more than doubled by probenecid, concomitant with profound depressions of both renal and biliary clearances. If plasma levels are a valid index of pharmacological availabiltiy and amount of drug secreted in bile a correlate of intestinal irritation, probenecid increases therapeutic ratio with respect to intestinal toxicity ca. 5-fold in spider monkeys and 10-fold in rhesus monkeys.

Animals↗
PubMed1977

Identification of the biologically active form of sulindac.

In five animal species, the only quantitatively significant biotransformations undergone by cis-5-fluoro-2-methyl-1-[p-(methylsulfinyl) benzylidene]indene-3-acetic acid (sulindac) are oxidation of its sulfinyl substituent to sulfone, and reduction to sulfide. The former metabolite is eliminated unchanged and elicits no pharmacological response. The sulfide, on the other hand, is readily reoxidized in vivo to sulindac. In each of seven in vivo models of inflammation, sulfide administered as such is more active than sulindac. The inference that the activity of sulindac might be attributed in whole or in part to the sulfide was tested directly by comparison of responses with concentrations of each reduction oxidation species in appropriate biological fluids. Regression analyses of circulation levels of sunlindac and sulfide vs. inhibition of rat paw edema, and of their levels in synovial fluid vs. response in the dog knee joint assay, show highly significant correlations only for sulfide. Sulindac thus appears to be a "latentiated" or "pro-drug," oral dosage with chich may circumvent the gastrointestinal side effects commonly associated with nonsteriod anti-inflammatory agents.

Administration, Oral↗
PubMed1976

Novel genotypes among transductants made with bacteriophage P1 lysates from an F14 merogenote strain of Escherichia coli K-12.

Among P1 transductants in Escherichia coli K-12 that were selected for the proximal and distal markers from the large F14 merogenote, a variety of unusual genotypes were found. As earlier workers had found, one class of these could transfer the proximal genes (argH, metB) and distal genes (ilvEDAC) of the F14 during conjugation. These F14 genes could be transferred into RecA recipients, indicating that they were carried on an F-merogenote rather than on an Hfr chromosome. The transduced F-merogenotes could transfer other F14 genes (metE, rha) as well. Transfer kinetic analysis showed that all of the latter transduced F-merogenotes that were examined were indistinguishable from the parental F14 in the order of transfer and the genetic distance between proximal and distal markers. This suggests that the whole F14 had been received somehow by the primary transductional recipients, a remarkable possibility since the F14 is much larger than the largest deoxyribonucleic acid segment normally transduced by P1. The mechanism of this phenomenon is not yet known. Many of the transductants did not transfer any of the F14 markers tested. Some of these transductants segregated certain F14 genes, indicating they were carried on self-replicating genetic elements, but others were not cured of F14 markers, even by acridine orange. Cotransductional analysis of this group was consistent with the hypothesis that the F14 markers in some of these strains had integrated into the chromosome in the expected manner, since in these latter the F14 alleles were linked to the expected chromosomal genes. Other strains among the stable transductants had acquired new linkages in that genes previously separated by several minutes could now be cotransduced. These latter included the novel cotransductional linkages of rbs-ilv-argH, rbs-ilv-argH-metB, and ilvD-argH-purD. Such strains might have been formed as a result of insertion into the chromosome of small circles derived from F14.

Acridines↗
PubMed1975

Bioavailability of oral dexamethasone.

Bioavailabilities of dexamethasone tablets and elixir in man were evaluated by each of 3 model-independent methods of pharmacokinetic analysis employing plasma and urinary values as determined by radioimmune assay. There were no significant differences among the results determined by the 3 methods nor between the respective availabilities of the two formulations; the latter averaged 82.6 +/- 17.7% for the elixir formulation and 78.0 +/- 12.1% for tablets.

Administration, Oral↗
PubMed1975

Bioavailability of dexamethasone. II. Dexamethasone phosphate.

Plasma levels of dexamethasone phosphate (DP) and dexamethasone free alcohol (DA) were determined by a modification of existing radioimmunoassay methodology following intravenous administration of DP in man. Areas under DA plasma profiles were a linear function of DP dosage over the 40-fold range 0.05 to 2.0 mg/kg, and, by comparison with values obtained after DA was intravenously administered, indicated an overall conversion of DP to DA of 90%. The first-order rate constant for the conversion, 4.03 hr-1, was approximately 25 times that for hydrolysis in whole blood incubated in vitro. This relationship as well as disposition kinetics suggested that the major component of DP hydrolysis occurs within highly perfused organ(s) comprising the central kinetic compartment. Eighteen subjects were studied in a crossover experiment, and no significant differences were observed in best-fit parameters for the 4 mg/ml parenteral solution of DP in current use and an experimental high potency preparation of 24 mg/ml.

Adolescent↗
PubMed1975

4-Trifluoromethylimidazoles and 5-(4-pyridyl)-1,2,4-triazoles, new classes of xanthine oxidase inhibitors.

The syntheses of a number of 2-substituted 4-trifluoromethylimidazoles and 3-substituted 5-(4-pyridyl)-1,2,4-triazoles are described. The trifluoromethylimidazoles were prepared from 3,3-dibromo-1,1,1-trifluoroacetone after hydrolysis with aqueous sodium acetate solution and condensation with an aldehyde in the presence of ammonia. Basic hydrolysis of the trifluoromethyl group was found to provide a facile method for the synthesis of imidazole-4-carboxylic acids. In the imidazole series a 2-aryl substituent and a free imino group were required for xanthine oxidase inhibitory activity. The triazoles were obtained through the reaction of an aroylhydrazine and an imino ether followed by thermal ring closure of the intermediate acylamidrazone. As in the imidazole series, a free imino group is an absolute requirement for in vitro activity. Additional structure-activity relationships of these compounds are presented.

Animals↗
PubMed1975

3,5-disubstituted 1,2,3,4-triazoles, 1 new class of xanthine oxidase inhibitor.

3,5-Bis(4-pyridyl)-1,2,4-triazole (PPT), 3-(4-pyrimidinyl)-5-(4-pyridyl)-1,2,4-triazole (PMPT), and 3-(4-pyridazinyl)-5-(4-pyridyl)-1,2,4-triazole (PZPT) are among the most active competitive inhibitors of xanthine oxidase among a series of 3,5-disubstituted triazoles synthesized for this purpose, inhibition constants being less than 1 times 10(-7) M for each. ED50 values in squirrel monkeys derived from first-order rate constants for the first and rate-limiting step of the sequence, xanthine leads to uric acid leads to allantoin plus CO2, range from 0.04 to 0.08 mg kg-1 orally, with unusually long durations of action attributable to asymmetric distribution of inhibitor within liver and gut as a consequence of enterohepatic recirculation. Sensitivity of rats, dogs, and anthropoid species to these, as to other xanthine oxidase inhibitors, is markedly less than that of the squirrel monkey, but the triazoles are at least an order of magnitude more active than the representative purine analogs tested.

Aerobiosis↗