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Biomedical subjects

A J Lewis

Publications and source records attributed to A J Lewis.

At least 109 records · Page 6Linked to original sources
PubMed1987

Leukotriene D4 antagonists and 5-lipoxygenase inhibitors. Synthesis of benzoheterocyclic [(methoxyphenyl)amino]oxoalkanoic acid esters.

A series of novel benzoheterocyclic [(methoxyphenyl)amino]oxoalkanoic acid esters has been prepared. These compounds were tested as inhibitors of rat polymorphonuclear leukocyte 5-lipoxgenase (LO) in vitro and as inhibitors of leukotriene D4 (LTD4) and ovalbumin (OA) induced bronchospasm in the guinea pig (GP) in vivo. In general, inhibitory activity against 5-LO, LTD4, and OA was broadest for benzthiazole-containing analogues (benzthiazole greater than benzimidazole much greater than benzoxazole, benzofuran). The most potent 5-LO inhibitor, 4-[[3-(2-benzthiazolylmethoxy)-phenyl]hydroxyamino]-4-oxobutanoic acid methyl ester (7), had an IC50 of 0.36 microM. Compound 7, however, was inactive vs. OA. The most potent compound in vivo, 4-[[3-[(1-methyl-2-benzimidazolyl)methoxy]phenyl]-amino] -4-oxobutanoic acid methyl ester 4, inhibited both LTD4- and OA-induced bronchospasm by 83% and 60%, respectively, at 50 mg/kg intraduodenally. Compound 4 was studied in the Ames assay employing five strains of bacteria (TA1535, TA1537, TA1538, TA98, and TA100) with and without S-9 rat liver enzyme metabolic activation, and there was no significant number of reversions noted.

Animals↗
PubMed1987

Phenylephrine derivatives as leukotriene D4 antagonists.

Two series of phenylephrine derivatives were prepared and tested as inhibitors of leukotriene D4 (LTD4) induced and ovalbumin-induced bronchospasm in the guinea pig. The most potent compound of the urea series, (R)-N,N-diethyl-N-[2-hydroxy-2-[3-(2-quinolinylmethoxy)phenyl]ethyl]-N- methylurea (3, Wy-47,120), was orally active with ED50's of 56 mg/kg vs. LTD4 and 55 mg/kg vs. ovalbumin. When tested as an antagonist of LTD4-induced contraction of isolated guinea pig tracheal strips, 3 was a competitive inhibitor with a p kappa B value of 5.22. In the second series, (R)-3-methyl-5-[3-(2-quinolinylmethoxy)phenyl]-2-oxazolidinone (26, Wy-47,674) had oral ED50's of 36 mg/kg against LTD4 and 95 mg/kg against ovalbumin. Compound 26 selectively antagonized contractile responses of guinea pig trachea evoked by LTD4 (p kappa B = 6.09). In the cat coronary artery, 3 dilated the preparation and blocked the coronary constrictor effect of LTD4. Compound 3 (0.13 mg/kg, iv) also preserved myocardial integrity in rats 48 h after coronary artery ligation. When tested in the rat alcohol-induced gastric lesion model, 3 and 26 manifested a dose-dependent mucosal protection against ethanol.

Animals↗
PubMed1987

Effect of zinc source and picolinic acid on 65Zn uptake in an in vitro continuous-flow perfusion system for pig and poultry intestinal segments.

Twenty weanling pigs and fourteen 9-wk-old broiler chickens were used in three continuous-flow in vitro perfusion experiments using noneverted intestinal sacs to 1) determine differences in 65Zn absorption due to location within the intestinal tract, 2) evaluate 65Zn uptake from ZnCl2 and Zn-methionine (ZnMet) with or without added picolinic acid (PA) in pig intestinal sacs and 3) evaluate 65Zn uptake from ZnCl2 and ZnMet in chicken intestinal sacs. No differences in 65Zn uptake due to gut segment position were observed in the pigs. A Zn source x PA interaction was observed for 65Zn uptake into the pig gut tissue and for 65Zn uptake to the serosal side of the gut sacs. Total 65Zn absorption in the pig gut sacs from the two Zn sources was not different, but the addition of a 5 M ratio of PA to Zn depressed 65Zn absorption. No differences were observed in total 65Zn absorption or 65Zn uptake in poultry gut sac tissue. There was, however, greater uptake of 65Zn from ZnCl2 to the serosal side of the sacs than from ZnMet. The data indicate that 65Zn from ZnCl2 and ZnMet is similar in total absorption and that the addition of PA depresses Zn uptake.

Animals↗
PubMed1987

Effect of protein and energy intake by primiparous sows during lactation on sow and litter performance and sow serum thyroxine and urea concentrations.

The effects of protein and energy intakes by primiparous sows during a 28-d lactation on thyroxine (T4) and urea concentrations in blood serum of sows, and sow and litter performance were examined in two experiments. Dietary treatments were protein intakes of 380 (LP) and 760 (HP) g of crude protein X sow-1 X d-1 and energy intakes of 8 (LE) and 16 (HE) Mcal of metabolizable energy (ME) X sow-1 X d-1 in a 2 X 2 factorial arrangement. In Exp. 1 (34 sows), neither protein nor energy intake affected serum T4 concentrations. In both experiments, serum urea concentrations during lactation were influenced by both protein (P less than .001) and energy (P less than .001) intakes. In Exp. 2 (221 sows), sows fed LP or LE lost more weight (P less than .001) during lactation than sows fed either HP or HE. Backfat loss was greater (P less than .001) in sows fed diets of LE than HE, whereas sows fed HP lost more backfat (P = .016) than sows fed LP. Pig weights on d 28 were influenced by both protein (P less than .001) and energy (P = .038), with sows that were provided high intakes of either protein or energy having heavier pigs. Litter weight at weaning was heavier (P less than .005) for sows consuming HP. Sows fed LP had larger litters at d 14 (P = .051) and 28 (P = .046) than sows fed HP. Sow energy intake had no effect on litter size or weight. Percentages of sows in estrus by 7, 14 and 35 d postweaning were higher (P less than .004, P less than .030 and P less than .060, respectively) for sows fed HP than LP, whereas sow energy intakes had no effect on the interval from weaning to first estrus.

Animals↗
PubMed1987

Influence of picolinic acid on the uptake of 65zinc-amino acid complexes by the everted rat gut.

Three hundred fifty rats were used in three experiments to: 1) validate the everted gut procedure as an in vitro technique for estimating Zn absorption, 2) determine the effect of increasing ratios of picolinic acid (PA) to Zn on Zn absorption and 3) determine the effect of PA on absorption of Zn and amino acid complexes at pH 6, 7 and 8. In the first experiment the time delay between tissue collection with subsequent storage in ice-cold saline and start of tissue incubation was 0, 10, 20 or 30 min. A linear decrease was observed for 65Zn uptake with increasing delay time. Lysine absorption was not affected by delay time. In the second experiment, molar ratios of PA:Zn of 0, .5, 1.0, 1.5, 2.0 and 2.5 with Zn held constant were evaluated. A linear decrease in 65Zn absorption from 65ZnCl2 occurred as the molar ratio of PA to Zn increased. In the third experiment, 0 and 5 molar ratios of PA to a constant Zn level were evaluated using 65ZnCl2, 65Zn-14C-methionine (ZnMet) and 65Zn-3H-lysine (ZnLys) at pH 6, 7 and 8. The addition of PA decreased Zn absorption regardless of Zn source. The data suggest that the Zn sources used were of similar biological value. The data do not support the theory that PA facilitates Zn absorption.

Animals↗
PubMed1986

Interleukin 1 activates phospholipase A2 in rabbit chondrocytes: a possible signal for IL 1 action.

We examined the effects of Interleukin 1 (IL 1) on rabbit articular chondrocytes with particular emphasis on arachidonic acid metabolism in these cells. Articular chondrocytes were isolated from the knee joints of normal New Zealand white rabbits and were cultured in vitro until confluent. Addition of 5 U/ml of purified IL 1 to chondrocytes led to an early increase in cell-associated phospholipase A2 (PLA2; measured by hydrolysis of [14C]arachidonic acid-labeled E. coli). Within 1 hr after IL 1 addition, cell-associated PLA2 activity was increased by more than threefold relative to basal PLA2 activity, and further increases in cellular enzyme activity were observed up to 48 hr of IL 1 treatment. IL 1 stimulation also led to a time- and dose-related release of extracellular PLA2 and PGE2, but IL 1-induced PLA2 and PGE2 secretion occurred after the initial burst of intracellular PLA2 activity. Similar PLA2 and PGE2 responses were also observed when purified human IL 1 or IL 1-containing conditioned medium from LPS-stimulated human monocytes were used, but recombinant IL 2 or IL 3 were inactive. IL 1-induced chondrocyte PLA2 did not release radiolabeled free fatty acid from phosphatidylethanolamine labeled at the C-1 position with [14C]stearic acid, confirming the identity of this enzyme as PLA2. These data, therefore, provide the first direct evidence that IL 1 activates cellular PLA2, and we propose that PLA2 activation may be an early signal that initiates the inflammatory actions of IL 1.

Animals↗
PubMed1986

Correlation between mouse skin inflammation induced by arachidonic acid and eicosanoid synthesis.

We and others have shown that arachidonic acid (AA), when applied topically to ear surfaces, causes an intense acute inflammatory reaction within minutes (as measured by ear thickness). In this study, we have investigated the cellular and biochemical changes associated with this phenomenon and have attempted to correlate these changes with the induction of inflammation. Measurement of vascular permeability by the accumulation of [125I]albumin showed that significant plasma exudation was observed at 15 min in AA-treated ears. Furthermore, the increase in [125I]albumin was time related and was nearly 10-fold greater than control at 1 h. No time-related change in plasma exudation was observed with control ears. Measurement of LTC4 by radioimmunoassay showed that there was a significant increase in LTC4 synthesis at 15 min after AA treatment. Maximal LTC4 synthesis occurred at 15 min and subsequently decreased to 30% of peak level at 30 min. Histological examination and myeloperoxidase measurement indicated that few neutrophils were present at these early time points and suggested that cells other than neutrophils are contributing to LTC4 synthesis. Ear thickness, [125I]albumin accumulation and leukotriene C4 (LTC4) synthesis in AA-treated ears were reduced significantly by topically administered mixed lipoxygenase (LO) and cyclooxygenase inhibitors such as BW755C and phenidone. Therefore, we suggest that AA-induced ear inflammation is a suitable screen for detecting LO inhibitors in vivo.

Animals↗
PubMed1986

New developments concerning leukotriene antagonists: a review.

The numbers and subtypes of leukotriene (LT) receptors have only recently been investigated and more work is needed to evaluate the distribution of receptors on tissues and cells in both normal and pathological states. Classification of the heterogeneity of LT receptors may assist in the discovery of new antiallergy and antiinflammatory drugs much in the same way as the study of different adrenergic receptors has benefited cardiovascular drug discovery. The clinical evaluation of the currently available LT antagonists is awaited with interest; however, their therapeutic role in the treatment of asthma, a primary goal for the majority of these agents, will require painstaking clinical appraisal. They seem unlikely to supplant the currently used bronchodilators but may provide a valuable prophylactic adjunct that may suppress some of the inflammatory events that occur in obstructive lung disease. Whether the LT antagonists modify the hyperreactive state that prevails in asthma is also the subject of much speculation.

Animals↗
PubMed1986

Questionable role of leukotriene B4 in monosodium urate (MSU)-induced synovitis in the dog.

Monosodium urate (MSU)-induced synovitis in the dog's stifle (knee joint) is similar to an acute gouty attack in man in which a loss of function of the joint correlates with massive influx of neutrophils and the release of an assortment of inflammatory mediators (e.g. histamine, bradykinin, lysosomal enzymes, complement and eicosanoids) into the synovial space. We found in the urate-induced inflammatory exudates 3 hr post MSU the following: 88 million leukocytes/ml (approximately 95% neutrophils) and eicosanoid concentrations of LTB4, LTC4, and PGE2 of less than 0.1, 1.4 and 20 ng/ml, respectively. Isotonic saline injected knee joints at 3 hr contained 5 million leukocytes/ml (approximately 95% neutrophils) and concentrations of LTB4, LTC4, and PGE2 of less than 0.1, 0.7 and 0.2 ng/ml, respectively. Intrasynovial injections of 1 microgram LTB4, 10 micrograms PGE2 or the combination of LTB4 and PGE2 produced no reduction of paw pressure for up to 3 hr. Leukocyte concentrations measured at 3 hr in joints injected with these arachidonic acids metabolites were similar to saline controls. These results question the role of LTB4 as a chemotactic and inflammatory mediator in urate-induced synovitis in the dog but confirm the importance of PGE2 and possibly LTC4 in this model.

Animals↗
PubMed1986

Novel 1,3-bis(aryloxy)propanes as leukotriene D4 antagonists.

The synthesis and structure-activity relationships of a number of 1,3-bis(aryloxy)propanes, which are in vivo antagonists of LTD4 in the guinea pig, are described. One of these compounds, 4 (Wy-44,329), was not only approximately equipotent with the standard 1 (FPL 55712) in the LTC4 (ID50 = 0.17 and 0.23 mg/kg iv, respectively) and LTD4 (ID50 = 0.11 and 0.15 mg/kg iv, respectively) challenge models but also possessed greater potency in the ovalbumin challenge model (ID50 = 0.47 mg/kg and 4.1 mg/kg iv, respectively) and a longer duration of action. This compound was a competitive LTD4 antagonist on guinea pig ileum (pA2 = 9.4) and possessed mediator release (rat PCA, ID50 = 0.26 mg/kg iv) and 5-lipoxygenase (IC50 = 32 microM vs. 5-HETE) inhibitory activities.

Animals↗
PubMed1986

Synthesis of [[(naphthalenylmethoxy)- and [[(quinolinylmethoxy)phenyl]amino]oxoalkanoic acid esters. A novel series of leukotriene D4 antagonists and 5-lipoxygenase inhibitors.

A series of novel [[(naphthalenylmethoxy)- and [[(quinolinylmethoxy)phenyl]amino]oxoalkanoic acid esters have been prepared. These compounds were tested as inhibitors of rat polymorphonuclear leukocyte (PMN) 5-lipoxygenase (LO) in vitro and as inhibitors of ovalbumin (OA) and leukotriene D4 (LTD4) induced bronchospasm in the guinea pig (GP) in vivo. Many naphthalenyl compounds were potent inhibitors of 5-LO, and several quinolinyl compounds were potent inhibitors of LTD4-mediated bronchospasms in the GP. The most potent naphthalenyl compound, 4-[[3-(2-naphthalenylmethoxy)phenyl]hydroxyamino]-4-oxobutanoic acid, methyl ester (6v), had an IC50 of 0.6 microM in the 5-LO assay. The most potent compound in vivo, 4-[[3-(2-quinolinylmethoxy)phenyl]hydroxyamino]-4-oxobutanoic acid, methyl ester (6e), had ED50's of 3.3 mg/kg and 27.4 mg/kg (intraduodenally) against LTD4- and OA-induced bronchospasm, respectively. When tested as an antagonist of LTD4-induced contraction of isolated GP tracheal spiral strips, 6e was shown to be a competitive inhibitor with a pKB value of 5.33.

Animals↗
PubMed1986

Synthesis and antiallergic activity of a novel series of 5-lipoxygenase inhibitors.

A series of novel substituted [[(phenoxymethyl)phenyl]amino]oxoalkanoic acid esters have been synthesized. These compounds were tested in vitro for their ability to inhibit the synthesis of 5-hydroxyeicosatetraenoic acid and leukotriene (LT) B4 from rat polymorphonuclear leukocytes (PMN) and in vivo as inhibitors ovalbumin- (OA) and LTD4-induced bronchospasm in the guinea pig. Compounds 5-12 and 25 had IC50's between 1 and 5.6 microM in the rat PMN 5-lipoxygenase assay. Compounds 1, 3, and 16 inhibited OA-induced bronchoconstriction (61%, 64%, and 57%, respectively), but only 1 showed activity against LTD4-induced bronchoconstriction. When tested against LTD4-induced contraction of isolated guinea pig tracheal spiral strips, 1 was a competitive inhibitor with a pKB of 4.94.

Animals↗
PubMed1986

Antagonism of antigen-induced contraction of isolated guinea-pig trachea by 5-lipoxygenase inhibitors.

Tracheal strips were obtained from guinea pigs actively sensitized to chicken ovalbumin (OA). OA-induced contractile responses, obtained by cumulative log addition, were found to be comparable both temporally and in magnitude with responses obtained by single addition of OA. The concentration-response curve obtained by cumulative addition of OA was partially inhibited by pretreatment of tissues with chlorpheniramine. On tracheal spirals treated with chlorpheniramine, indomethacin enhanced OA-induced contractile responses. In the presence of chlorpheniramine and indomethacin, pretreatment with one of the reference 5-lipoxygenase inhibitors (ETYA, NDGA, phenidone or BW-755C) both reduced the maximum contractile response and produced a rightward shift of the OA concentration-response curve. The data suggest that cumulative log addition of OA, on the indomethacin- and chlorpheniramine-treated guinea-pig trachea, is a useful model for evaluating compounds active as either inhibitors of 5-lipoxygenase or antagonists of the products of this pathway.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1986

Effects of thiazinamium chloride on histamine release from rat peritoneal mast cells and on phosphodiesterase activity in guinea pig lung.

The effect of thiazinamium Cl (TCl) on histamine release from rat peritoneal mast cells (RPMC) was investigated. Although TCl inhibited compound 48/80-induced histamine release moderately (IC50 value 40 microM), the drug was a weaker inhibitor of ovalbumin-induced histamine release (100 microM, -21%). In contrast, promethazine HCl (PHCl) was more effective against antigen-induced histamine release (IC50 value 13 microM) than against compound 48/80-induced histamine release (100 microM, -53%). Disodium cromoglycate (DSCG) was effective against both antigen and compound 48/80-induced release of histamine with IC50 values of 7 and 1 microM, respectively. Neither TCl nor DSCG at 1 mM increased spontaneous release of histamine from RPMC, whereas PHCl induced spontaneous release by over 50% at 1 mM. TCl did not inhibit phosphodiesterase (PDE) activity in guinea pig lung at 1 mM, whereas theophylline and DSCG inhibited PDE with IC50 values of 1.1 and 0.32 mM, respectively. These data suggest that high local concentrations of TCl may reduce histamine release during an asthmatic attack and improve its effectiveness as a bronchoprotectant.

3',5'-Cyclic-AMP Phosphodiesterases↗