The Effects of a Novel Series of Selective Inhibitors of Arachidonate 5‐Lipoxygenase on Anaphylactic and Inflammatory Responses

Bhattacherjee, P.; Boughton‐Smith, N. K.; Follenfant, R.L.; Garland, L.G.; Higgs, G. A.; Hodson, H. F.; Islip, P. J.; Jackson, W. P. U.; Moncada, Salvador; Payne, A.N.; Randall, Roger; Reynolds, Charles H.; Salmon, John A.; Tateson, J.E.; Whittle, Brendan J.R.

doi:10.1111/j.1749-6632.1988.tb38554.x

Cited by 26 publications

(12 citation statements)

References 51 publications

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“…Since these compounds are rela tively selective inhibitors of 5-lipoxygenase and capable of inhibiting LTB4 production (14), one of the chemo tactic factors involved in the model is likely to be LTB4. It has been reported that 5-lipoxygenase inhibitors of the redox type, such as NDGA, were inactive when ad ministered orally (19). However, in our evaluation by oral treatment with AA-861, BW-755C (20) and the 4-acyl aminophenol derivatives, all of which are of the redox type, the latter two, but not AA-861, were effective (Figs.…”

Section: Discussioncontrasting

confidence: 44%

Inhibitory Effect of 4-Acylaminophenol Derivatives (T-0799 and T-0757), Novel Lipoxygenase Inhibitors, on Arachidonic Acid-Induced Infiltration of Polymorphonuclear Leukocytes in Rat Skin

Kikuchi

Ishikawa

Tsuzurahara

1994

Japanese Journal of Pharmacology

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ABSTRACT-Effects of 4-acylaminophenol derivatives, novel 5-lipoxygenase inhibitors, on the neutrophil infiltration in arachidonic acid (AA) (10 mg/site)-induced skin inflammation in rats were examined. Myeloperoxidase (MPO) activity in the skin lesion, used as an indicator of neutrophil infiltration, was significantly increased after intradermal injection of AA. Dual inhibitors of cyclooxygenase and 5-lipox ygenase, phenidone (100 mg/kg x 2, i.p. and p.o.) and BW-755C (50 mg/kg x 2, p.o.), and 5-lipoxygenase inhibitors, AA-861 (100 mg/kg x 2, i.p.) and the 4-acylaminophenol derivatives T-0799 and T-0757 (10-100 mg/kg x 2, p.o.), inhibited the increase in MPO activity 5 hr after AA-injection, but the cycloox ygenase inhibitor indomethacin (5 mg/kg, i.p.) showed no effect. These results suggest that products of lipoxygenase, but not of cyclooxygenase, are involved in the MPO activity increase (i.e., neutrophil infiltra tion), and that this model is useful for in vivo evaluation of 5-lipoxygenase inhibitors. It is suggested that the 4-acylaminophenol derivatives may be useful as orally active drugs for treatment of some leukotriene mediated diseases.

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Section: Discussioncontrasting

confidence: 44%

Inhibitory Effect of 4-Acylaminophenol Derivatives (T-0799 and T-0757), Novel Lipoxygenase Inhibitors, on Arachidonic Acid-Induced Infiltration of Polymorphonuclear Leukocytes in Rat Skin

Kikuchi

Ishikawa

Tsuzurahara

1994

Japanese Journal of Pharmacology

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“…However, the reduced mucosal synthesis of LTC4 may occur in part as a consequence of a reduction in ethanol-induced damage. Although NDGA is a potent inhibitor of lipoxygenase enzymes in vitro (Hamberg, 1986;Bhattacherjee et al, 1988) we have been unable to demonstrate inhibition of lipoxygenase by NDGA in rat whole blood ex vivo . A further possibility is that BW 755C may act by inhibiting 12-or 15-lipoxygenase (Randall et al, 1980) and that products from these enzyme pathways, such as hydroperoxy metabolites, are involved in ethanol-induced damage.…”

Section: Discussionmentioning

confidence: 99%

Failure of the inhibition of rat gastric mucosal 5‐lipoxygenase by novel acetohydroxamic acids to prevent ethanol‐induced damage

Boughton‐Smith

Whittle

1988

British J Pharmacology

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The role of leukotriene B4 (LTB4) and LTC4 as mediators of gastric mucosal damage following ethanol challenge in vivo has been investigated using two selective 5‐lipoxygenase inhibitors, BW A4C and BW A137C. Oral administration of ethanol to rats in vivo, induced macroscopic damage to the gastric mucosa and markedly increased the formation of the 5‐lipoxygenase products, LTB4 and LTC4, from the mucosa ex vivo. Pretreatment with the acetohydroxamic acids BW A4C and BW A137C (5–50 mg kg−1 p.o.) dose‐dependently reduced ethanol‐stimulated LTB4 and LTC4 formation by the gastric mucosa, with an ID50 of approximately 5 mg kg−1 p.o. A single oral dose of BW A4C (20 mg kg−1) induced near‐maximal inhibition of mucosal LTB4 formation within 30 min, which was well maintained for 5h, whereas BW A137C (20 mg kg−1 p.o.) induced maximal inhibition between 30 and 60 min after administration, which then diminished over the subsequent 5 h. The mucosal formation of the cyclo‐oxygenase product, 6‐keto‐prostaglandin F1α, which was unaltered following ethanol challenge, was not inhibited by the acetohydroxamic acids. Likewise, the small increase in mucosal thromboxane B2 formation following challenge was not inhibited by BW A4C. Neither BW A4C nor BW A137C, at doses that almost completely inhibited the mucosal synthesis of LTB4 or LTC4, reduced the macroscopic gastric mucosal damage induced by ethanol. Pretreatment with the lipoxygenase inhibitor BW 755C (5–50 mg kg−1 p.o.) did reduce mucosal damage, but there was a dissociation between the degree of protection and the inhibition of leukotriene biosynthesis. Oral administration of high doses of either BW A4C or BW A137C (300 mg kg−1) did not induce macroscopic gastric damage over a 3 h period. These findings suggest that the leukotrienes, LTB4 and LTC4 are not the primary mediators of ethanol‐induced acute mucosal damage, but do not exclude their role in more chronic gastric damage and inflammation.

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“…3e). With this in mind specific cyclo-oxygenase and lipoxygenase inhibitors, (ibuprofen and BWA 137c respectively [3]) were tested for activity in the in vitro virus growth assay; neither of these compounds enhanced HSV-1 growth, or CPE, in L929 cells (data not shown). 3g).…”

Section: Bha Reverses Virus-induced Cpe and Enhances Hsv-1 9rowth In mentioning

confidence: 99%

The antiviral activity of tumour necrosis factor on herpes simplex virus type 1: role for a butylated hydroxyanisole sensitive factor

Lidbury

Ramshaw

Rolph

et al. 1995

Archives of Virology

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We have previously shown that specific antibodies (Mab 32/Ab 301) against tumour necrosis factor (TNF) enhance its antiviral activity in vaccinia virus-infected mice. In the present study, TNF alone was found to have antiviral activity against herpes simplex virus-1 (HSV-1). Antibody enhancement was found, both in vivo and in vitro, at lower TNF doses. The magnitude of the TNF-induced antiviral response was dependent upon the genetic background of the mouse. C57BL/6 mice were very sensitive to the antiviral activity of TNF, which was inhibited by the free radical scavenger butylated hydroxyanisole (BHA). TNF plus Mab 32 induced a significant antiviral effect in L929 cells which was associated with pronounced CPE. The CPE was largely reversed in the presence of BHA, and furthermore, TNF antiviral activity was significantly reversed in the presence of BHA. Specific inhibitors of nitric oxide synthetase, lipoxygenase or cyclo-oxygenase did not influence either the CPE or growth kinetics of HSV-1, suggesting that neither reactive nitrogen intermediates nor arachidonic acid metabolites were involved in the antiviral mechanism of TNF. This, together with observed increases in Cu/Zn SOD levels in virus infected cells, suggests that reactive oxygen intermediates may have a role in the direct control of HSV-1 growth and that free radicals may play a part in the antiviral activity induced by TNF.

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The Effects of a Novel Series of Selective Inhibitors of Arachidonate 5‐Lipoxygenase on Anaphylactic and Inflammatory Responses

Cited by 26 publications

References 51 publications

Inhibitory Effect of 4-Acylaminophenol Derivatives (T-0799 and T-0757), Novel Lipoxygenase Inhibitors, on Arachidonic Acid-Induced Infiltration of Polymorphonuclear Leukocytes in Rat Skin

Inhibitory Effect of 4-Acylaminophenol Derivatives (T-0799 and T-0757), Novel Lipoxygenase Inhibitors, on Arachidonic Acid-Induced Infiltration of Polymorphonuclear Leukocytes in Rat Skin

Failure of the inhibition of rat gastric mucosal 5‐lipoxygenase by novel acetohydroxamic acids to prevent ethanol‐induced damage

The antiviral activity of tumour necrosis factor on herpes simplex virus type 1: role for a butylated hydroxyanisole sensitive factor

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