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B M Sweeney

Publications and source records attributed to B M Sweeney.

16 recordsLinked to original sources
PubMed1991

Metabolism of the platelet-activating factor antagonist (+/-)-trans-2-(3'-methoxy-5'-methylsulphonyl-4'-propoxyphenyl)-5-(3",4" ,5"- trimethoxyphenyl)tetrahydrofuran (L-659,989) in rhesus monkeys.

1. The plasma concentration, main route of metabolism and excretion of 3H-L-659,989 were studied in male and female rhesus monkeys by dosing either i.v. or orally at 10 mg/kg. 2. The percentage of the AUC for the plasma radioactivity concentration-time curve of oral vs i.v. dosed monkeys was 78% for males and 90% for females, indicating that the dose was well absorbed. 3. The bioavailability of the drug was low (less than or equal to 10%) for all monkeys, probably due to rapid first pass metabolism. The drug was metabolized-predominantly at the C-4'-propoxy side-chain. The two major plasma metabolites were identified as the 4'-2-(hydroxy)propoxy metabolite (3H-trans-4'-HP) and the 4'-hydroxy metabolite (3H-4'-hydroxy) which was isolated as a 2:1 mixture of (+/-)trans: (+/-)cis. 4. Approx. 80% of the radiolabelled dose was excreted equally in the urine and faeces in 96 h, with the largest percentage of the tritiated dose (31 +/- 4%) in the 0-24 h urine. 5. The major metabolites in the excreta were the (+/-)trans/(+/-)cis mixture of 3H-4'-hydroxy and the glucuronide conjugate of 3H-trans-4'-hydroxy. The glucuronide conjugate of 3H-trans-4'-hydroxy was excreted in the urine of i.v. and orally dosed monkeys and represented an average of 21% and 5.1% of the dose, respectively. 3H-4'-Hydroxy was excreted in both the urine and faeces, accounting for less than or equal to 0.1% and 7.4% of the dose in i.v. and orally dosed monkeys, respectively.

Animals↗
PubMed1988

A peripherally acting alpha-2 adrenoceptor antagonist: L-659,066.

L-659,066 has been characterized as a potent and selective alpha-2 adrenoceptor antagonist. Both in vitro and in vivo, L-659,066 exhibited specificity (comparable to rauwolscine) for alpha-2 over alpha-1 adrenoceptors. Studies comparing L-659,066 with a previously described antagonist, L-657,743, demonstrate that the new compound penetrates the blood-brain barrier only poorly after systemic administration. With a pA2 of 8.44 at alpha-2 adrenoceptors in the isolated rat vas deferens and an IC50 of 3.0 nM against the binding of [3H]rauwolscine to rat cerebrocortical membranes, L-659,066 possessed, respectively, about one-eighth and one-third of the potency of L-657,743. Similar relative potencies were obtained in vivo in pithed rats with regard to blocking peripherally located postjunctional and prejunctional alpha-2 adrenoceptors (L-659,066 = one-seventh and one-fourth of L-657,743, respectively). In tests carried out in vivo with rats for ascertaining alpha-2 adrenoceptor antagonism in the central nervous system--namely, accumulation of cortical dopa and antagonism of mydriasis induced by the alpha-2 agonist, clonidine--L-659,066 had, respectively, less than 1/345th and about 1/5000th of the potency of L-657,743. In mice, L-659,066 had, respectively, approximately 1/29th and 1/1400th of the potency of L-657,743 as an antagonist in vivo of the predominately peripherally mediated inhibition of colonic propulsion caused by clonidine as compared with the mainly centrally mediated antinocisponsive action elicited by the alpha-2 agonist UK 14,304. The foregoing findings are consistent with poor penetration of the blood-brain barrier by L-659,066.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1987

The ultrastructural localization of luciferase in three bioluminescent dinoflagellates, two species of Pyrocystis, and Noctiluca, using anti-luciferase and immunogold labelling.

In order to discover the intracellular location of luciferase in dinoflagellates, sections from a number of species were treated with a polyclonal anti-luciferase and the bound antibody was visualized at the electron-microscope level by indirect immunogold labelling. In two species of Pyrocystis and in Noctiluca, as in Gonyaulax, antibody became bound to dense vesicles, which correspond in size and position to light-emitting bodies detected in previous work. These vesicles resemble microsomes, are bounded by a single membrane and sometimes project into the vacuole. Unexpectedly, the trichocysts of Gonyaulax and Noctiluca and the related mucocysts of Pyrocystis also bound the antibody. This cross-reaction seems quite independent of bioluminescence, since the trichocysts of the non-luminous Cachonina also reacted positively. The possibility is discussed that a protein, different from luciferase but having some antigenic similarity, is present in trichocysts and related organelles.

Animals↗
PubMed1976

Freeze-fracture studies of the thecal membranes of Gonyaulax polyedra: circadian changes in the particles of one membrane face.

Intramembrane faces were visualized in the marine dinoflagellate Gonyaulax polyedra by the freeze-fracture technique, in order to test a prediction of a membrane model for circadian oscillations--i.e;, that membrane particle distribution and size change with time in the circadian cycle. Cells from each of four cell suspensions in continuous light (500 1x, 20-21 degrees C) were frozen, without fixation or cryoprotection, at four circadian times in a cycle. This paper reports findings concerning the membranes associated with the theca, particularly the cytoplasmic membrane and the membrane of the large peripheral vesicle. While the number and size distribution of the particles of the PF face of the cytoplasmic membrane were constant with time, those of the EF face of the peripheral vesicle doubled in number at 18 h circadian time as compared with 06 h. Particles of the 120-A size class, in particular, were more numerous at 12 and 18 h circadian time than at 00 and 06 h. While the finding does not provide definitive confirmation of the membrane hypothesis for circadian rhythms, it is consistent with this model. It is suggested that the peripheral vesicle may be the site of bioluminescence in Gonyaulax.

Animals↗
PubMed1967

The circadian rhythm in photosynthesis in Acetabularia in the presence of actinomycin D, puromycin, and chloramphenicol.

Anucleate Acetabularia crenulata shows a circadian rhythm in photosynthesis. In this study, an oxygen electrode was employed to measure this photosynthetic rhythm in the presence and absence of the inhibitors, actinomycin D, chloramphenicol, and puromycin. High concentrations of the inhibitors were used: actinomycin D, 20-40 micrograms ml-1; puromycin, 30 and 100 micrograms ml-1; and chloramphenicol, 250 micrograms ml-1. The effectiveness of these inhibitors on protein synthesis was also measured under the same conditions used for the determination of rhythmicity. In spite of large effects of all three inhibitors on the incorporation of 14C leucine, no effect on the period or the phase of the photosynthetic rhythm was observed. The higher concentration of puromycin and chloramphenicol produced toxic effects which were expressed as a reduction in the amount of photosynthesis, but rhythmicity was still apparent. After 3 or 4 days' exposure to actinomycin, Acetabularia became resistant to its effect. Recovery was also observed in the ability to incorporate leucine. The implications of these results for theories of the basic oscillator responsible for circadian rhythmicity are discussed.

Acetabularia↗
PubMedDate not supplied

Metabolism of kadsurenone and 9,10-dihydrokadsurenone in rhesus monkeys and rat liver microsomes.

The metabolism of the PAF antagonists kadsurenone and tritium-labeled 9,10-dihydrokadsurenone was studied in rhesus monkeys and rat liver microsomes. The monkey metabolites of the two drugs were isolated as their glucuronide conjugates from the urine of iv dosed males. The metabolites from both monkey and microsomal metabolism were purified by reverse phase HPLC and identified by spectral (NMR, UV, and mass spectrometric) analysis. The principal pathway of biotransformation of the tritium-labeled 9,10-dihydrokadsurenone in monkeys was hydroxylation of the C-5 propyl side chain to give two metabolites, 10-hydroxy-9,10-dihydrokadsurenone and 9-hydroxy-9,10-dihydrokadsurenone. These compounds were excreted as glucuronides. Microsomal incubation of tritium-labeled 9,10-dihydrokadsurenone yielded the 10-, 9-, and 8-hydroxy-9,10-dihydrokadsurenone as major metabolites. Kadsurenone was also metabolized at the C-5 side chain, an allyl group. The monoglucuronide of 9,10-dihydroxykadsurenone was isolated from monkey urine. Spectral analysis was not definitive as to the site of conjugation, and the structure of the metabolite was assigned as the C-10 conjugate. A major metabolite of rat liver microsomal incubation of kadsurenone was 9,10-dihydroxykadsurenone.

Animals↗