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Biomedical subjects

R R Brooks

Publications and source records attributed to R R Brooks.

At least 37 records · Page 2Linked to original sources
PubMed1988

Effects of orpanoxin on arachidonic acid metabolism of human polymorphonuclear leucocytes and platelets in vitro.

1. The effect of orpanoxin, a nonsteroidal anti-inflammatory drug, on cyclo-oxygenase and lipoxygenase activity in human polymorphonuclear leucocytes (PMNL) and platelets was studied ex vivo to see if lipoxygenase inhibition contributed to orpanoxin's mechanism of action. 2. In PMNL, orpanoxin (50, 100, and 200 mumols/l), like indomethacin (100 mumols/l), had little effect on synthesis of leukotriene B4 or 5S-hydroxy-6-trans,8,11,14-cis-eicosatetraenoic acid. BW755c at 100 mumols/l inhibited synthesis of both. 3. In PLT, orpanoxin (100 mumols/l) inhibited formation of cyclo-oxygenase products (thromboxanes, prostaglandins, and 12-L-hydroxy-5,8,10-heptadecatrienoic acid) and increased synthesis of the lipoxygenase product, 12S-hydroxy-5,8-cis,10-trans,14-cis-eicosatetraenoic acid. Effects of indomethacin (100 mumols/l) and benoxaprofen (100 mumols/l) in platelets were qualitatively similar to those of orpanoxin. 4. These results indicate that the discrepancy between the low potency of orpanoxin in inhibiting bovine seminal vesicle cyclo-oxygenase in vitro and its high potency as an anti-inflammatory agent in vivo is not explained by its having an additional lipoxygenase inhibitory mechanism.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1988

Characterization of 5-[5-(4-chlorophenyl-2-furanyl)]dihydro-2(3H)-furanone as a nonsteroidal antiinflammatory drug.

5-[5-(4-Chlorophenyl-2-furanyl)]dihydro-2(3H)-furanone (F-1044), a nonsteroidal antiinflammatory drug related to orpanoxin, lacks the usual acid moiety of such agents. F-1044 had antiinflammatory activity equivalent to ibuprofen's and orpanoxin's in the carrageenin-induced paw edema model in normal and adrenalectomized rats. Antiinflammatory activity was also expressed in the guinea pig UV-induced erythema and rat established arthritis models. F-1044 was a more potent analgesic than ibuprofen and orpanoxin in the rat paw pressure assay. In contrast to the reference agents, F-1044 raised the pain threshold of both the yeast-injected and non-injected paws, suggesting a central component to its analgesic action. F-1044 was more potent than ibuprofen and orpanoxin in the rat brewer's yeast pyresis model. Based on its low activity in inhibiting bradykinin-induced bronchoconstriction in guinea pigs and low gastric irritation activity in rats. F-1044 appears to have a mechanisms of action that involves more than simple inhibition of prostaglandin synthesis. Thus F-1044 is a nonsteroidal antiinflammatory agent with unique chemical and pharmacological features.

Animals↗
PubMed1985

Anti-inflammatory activity of orpanoxin administered orally and topically to rodents.

Orpanoxin, a nonsteroidal anti-inflammatory drug (NSAID) lacking gastric ulcerogenic effects in the therapeutic dose range in rats, was compared with six reference NSAIDs for oral activity in the rat paw carrageenin-induced edema assay. Tested NSAIDs were ranked on the basis of oral mg/kg ED50 values: piroxicam, 0.55; orpanoxin, 35.6; diflunisal, 59.6; benoxaprofen, greater than 300; tolmetin sodium, greater than 300; and sulindac, greater than 300. Zomepirac sodium was inactive. Only the three most potent compounds produced greater than 60% inhibition of edema. Inhibition was generally greater at 4 h than at 6 h post carrageenin for all compounds. Oral activity of orpanoxin was also demonstrated in the guinea-pig u.v.-induced erythema model (ED50 = 24.2 mg/kg p.o. when given 1 h before irradiation) and in the mouse ear croton oil induced edema test (ED50 value = 131 mg/kg p.o.). Topical activity of orpanoxin was assessed in both the guinea-pig and mouse models. In the guinea-pig u.v.-induced erythema model, application (1 h after u.v.) of 1, 5, and 10% (w/v) orpanoxin creams (containing 10% urea) significantly inhibited erythema at 2, 3, and 4 h post-irradiation. Orpanoxin, mefenamic acid, and indomethacin as 1% creams inhibited total erythema scores 70, 92 and 74%, respectively. Evidence for topical activity in the mouse ear assay was also obtained for orpanoxin in diethyl ether or 10% urea cream, but not in dimethylsulfoxide. It was concluded that orpanoxin has anti-inflammatory activity comparable to reference NSAIDs in the rat paw edema test, is active orally in rat, mouse, and guinea-pig models, and shows topical activity in the guinea-pig and the mouse.

Administration, Oral↗
PubMed1985

Correlation between anti-hypertensive activity in rats and plasma angiotensin I-converting enzyme (ACE) inhibition in mice following oral administration of ACE inhibitors.

Thirty-four ACE inhibitors were evaluated to determine the concentration giving 50% inhibition of purified rabbit lung ACE (IC50 microM) using benzyloxycarboxyl-p-NO2-Phe-His-Leu as substrate, to determine the oral dose causing a lowering in blood pressure of 30 mm Hg (ED30 mumol/kg) in acute aortic coarctate (AAC) rats, and to determine inhibition of plasma ACE (PACE) activity in mice after oral dosing. Mouse PACE activity was determined with 14C-Hip-His-Leu as substrate one hour after oral dosing of 3 animals/group with 5 or 50 mumol ACE inhibitor per kg. Data from mice were expressed as percent of control group PACE activity. Least squares regression analysis showed the IC50 data to be poorly correlated with either rat data or mouse PACE data at 50 mumol/kg p.o. However, correlation was significant between log rat ED30 and mouse PACE at 5 (p less than 0.001, r = 0.570) and 50 (p less than 0.025, r = 0.387) mumol/kg p.o. Thus, the simple mouse plasma ACE determination after a dose of 5 mumol/kg is a convenient supplement to the AAC rat model for showing oral activity of ACE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Effect of nolinium bromide on vascular smooth muscle.

Nolinium bromide inhibits gastric acid secretion and gastrointestinal smooth muscle contraction. While the compound's gastric antisecretory action has been attributed in part to inhibition of gastric adenylate cyclase and the gastric proton-transport ATPase, the mechanism of nolinium bromide's relaxant effect on smooth muscle has not been elucidated. We have determined that nolinium bromide inhibits contraction of vascular smooth muscle, using isolated rabbit aortic strips. This report characterizes the specificity of this inhibition (by using several agonists) and its Ca2+ dependence (by using contractile conditions of known dependence on various Ca2+ pools). Nolinium bromide (50-200 microM) was a reversible, insurmountable inhibitor of contractions induced by Ca2+ (in 40 mM KC1 depolarizing medium) and norepinephrine, with IC50 values of 96 and 118 microM, respectively, for suppression of maximum contractile force. Contractions in response to Asn1Val5-angiotensin II in both 2.5 mM Ca2+ and 0 mM Ca2+ medium were also inhibited (IC50 value = 110 microM under both conditions). Initial contraction rates for all these conditions were depressed by nolinium bromide. Nolinium bromide inhibited equally the phasic (internal Ca2+-dependent) and tonic (external Ca2+-dependent) components of norepinephrine-induced contractions. These results extend the muscle relaxant profile of nolinium bromide to include, albeit with low potency, vascular smooth muscle, and show that its potency is similar in inhibiting the contractile response to three different stimuli: angiotensin II, Ca2+, and norepinephrine.

Angiotensin II↗
PubMed1983

Inhibition of guinea pig gastric microsomal potassium-stimulated ATPase by nolinium bromide.

Although nolinium bromide (NB) [2-(3,4-dichlorophenylamino)-quinolizinium bromide] inhibited histamine-stimulated acid secretion in vivo in the pylorus-ligated guinea pig, no inhibition of basal or histamine-stimulated acid secretion from the isolated guinea pig gastric fundic disk was observed at serosal or mucosal concentrations from 0.1 to 200 microM. NB did not inhibit carbonic anhydrase in whole stomach homogenates of guinea pig, but did inhibit the potassium-stimulated gastric microsomal ATPase. The IC50 value (compound concentration giving 50% inhibition of the rate of ATP hydrolysis) for the net stimulated reaction (activity with KCl minus activity without KCl) was 65 microM (95% confidence limits = 42-101 microM). The basal reaction (no added KCl) was not inhibited. Inhibition of ATPase by NB was not due to its bromide ion, since NaBr did not, while the chloride analog of NB did, inhibit the enzyme. It was concluded that NB has no direct histamine-H2 receptor blocking activity. Whether ATPase inhibition contributes to its gastric acid antisecretory property is uncertain because of the lack of inhibitory activity in the isolated gastric disk assay.

Adenosine Triphosphatases↗
PubMed1979

Inhibition of bacteriophage-Q beta ribonucleic acid polymerase by guanosine triphosphate analogues.

Sixteen compounds related to GTP were evaluated as inhibitors of bacteriophage-Q beta poly(C)-dependent poly(G) polymerase. Non-phosphorylated compounds, including guanine, guanosine and deoxyguanosine, were inactive. Phosphorylated compounds gave significant inhibition at millimolar concentrations. For nucleotides the feature important for inhibition was the 5'-phosphate chain. Four triphosphates, XTP, ITP, 7-methyl-GTP and 2'-O-methyl-GTP, gave 50% inhibition of both the poly(C)- and poly(U2,C)-dependent reactions at concentrations from 0.1 to 5 mM. XTP was 10-fold more potent an inhibitor of the reaction with poly(U2,C) as template. None of these four compounds was able to substitute for GTP as substrate to a significant extent. The most active compound, 2'-O-methyl-GTP, was a competitive inhibitor (Ki = 0.4 mM) of GTP in the poly(C)-dependent reaction.

Coliphages↗
PubMed1979

Nickel uptake by Flacourtiaceae of New Caledonia.

Herbarium and field specimens (over 300) of all of the Flacourtiaceae of New Caledonia were analysed for nickel in order to identify hyperaccumulators (greater than 1000 microgram/g dry mass) and to assess nickel accumulation in relation to the evolutionary status of 'nickel plants' of New Caledonia. One hyperaccumulator was identified in the genus Lasiochlamys, ten among Xylosoma, one among Casearia and seven among Homalium. Although these Homalium nickel plants had previously been recorded, fresh data for these and other Homalium are presented. The remarkable tolerance of Flacourticeae to ultrabasic rocks is shown by the fact that 75% of the species are found on such substrates. The number of hyperaccumulators was greatest in the genera Xylosoma and Homalium. The Flacourtiaceae are among the most primitive of all angiosperms and in common with other primitive hyperaccumulators, contain nickel as a complex with citric acid. The only advanced New Caledonian nickel plant (Psychotria douarrei) has most of its nickel bound with ligands other than citric acid, a feature of other advanced hyperaccumulators. It is postulated that nickel complexing with citric acid may be a primitive character. Most of the New Caledonian nickel plants belong to the order Violales of subclass Dilleniidae. It is suggested that hyperaccumulation of nickel is an evolutionary character which occurs in long-indisturbed floras such as that of New Caledonia.

Biological Transport↗
PubMed1979

Hyperaccumulation of nickel by Alyssum Linnaeus (Cruciferae).

Herbarium specimens of all except one of the 168 recognized species of Alyssum Linnaeus have been analysed for their nickel content in order to identify hyperaccumulators (greater than 1000 microgram per g dry mass) of nickel. A further 31 hyperaccumulators (all in section Odontarrhena) were discovered in addition to the 14 European species reported earlier. Pot trials on the non-accumulator A. serpyllifolium Desfontaines and the hyperaccumulator A. pintodasilvae Dudley in ed. involving addition of nickel to the medium in which the plants were growing, showed that not all species of of section Odontarrhena were able to act as hyperaccumulators of nickel. Hyperaccumulation occurred almost exclusively in the eastern Mediterranean area and Turkey. There appeared to be a definite correlation between species diversity, proliferation and endemism on the one hand, and extremely high nickel concentrations (greater than 1%) on the other. The data have been used to assess the evidence for promoting section Odontarrhena to generic rank.

Biological Transport↗
PubMed1978

Substrate, metal and template effects on inhibition of bacteriophage-qbeta ribonucleic acid polymerase by ortho- and pyro-phosphate.

Two reactions of bacteriophage-Qbeta RNA polymerase with synthetic templates were characterized and used to study the effects of substrate, metal and template on inhibition by Pi and PPi. Analysis of the poly(C)-dependent reaction yielded results on kinetics, GTP-dependence, preference for Mn2+ over Mg2+, and Michaelis constants for template similar to those in the literature. New data are provided for the poly(U2,C)-dependent reaction. Our results suggest that GTP and Mn2+ can form relatively stable complexes with the polymerase and that such complexes change the interaction of the enzyme with the inhibitors, Pi and PPi.

Coliphages↗
PubMed1978

Blood lead levels in sheep exposed to automotive emissions.

The lead content of whole blood of 62 sheep grazed continuously for 6 months near a major highway was compared with 38 sheep from a nearby uncontaminated area. Mean values of 0.90 and 0.20 microgram/ml were obtained. Four sheep from the contaminated area were placed in an uncontaminated paddock and the lead content of the blood decreased rapidly during the first 10 days and thereafter more slowly. After 185 days, blood lead levels had still not quite reached normal levels. Animal from an uncontaminated area showed an immediate rise in the blood lead levels when placed near a major highway. Sheep placed in a concrete pen away from motor vehicle exhaust emissions showed a rise in lead levels when fed with forage cut from the verges of a busy highway. Sheep placed near a highway and fed with forage from an uncontaminated area showed an increase of lead levels in the blood, comparable to that of the previous experiment. It was concluded that lead uptake by ingestion of polluted forage and by inhalation of airborne particulates are both mechanisms responsible for enhanced lead levels in ovine blood.

Animals↗
PubMed1976

Digestion of fish samples for mercury determination by flameless atomic absorption spectrophotometry.

Methods of digestion of fish samples for mercury determination by flameless atomic absorption spectrophotometry have been investigated. Digestion in Teflon bombs, Kjeldahl flasks, or borosilicate test tubes gives comparable precisions and mercury recoveries. Because of their cost and effect in limiting productivity, Teflon bombs were considered unnecessary for analysis of fish samples. Experiments with cooked and uncooked fish samples have confirmed that no appreciable loss of mercury occurs during baking 30 min at 170 degrees C.

Fish Products↗