Inhibitory effect of SK&amp;F 86002 on monocyte IL-1 production

Lee, J. C.; Votta, Bart; Griswold, Don E.; Hanna, Nabil

doi:10.1007/bf01972797

Cited by 9 publications

(2 citation statements)

References 7 publications

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“…Most of the literature on anti-inflammatory drugs in PTB has focussed on non-steroidal anti-inflammatory drugs (NSAIDs) -prostaglandin synthesis inhibitors that have widespread applications but which have been associated with significant fetal side effects (Kaplan et al 1994, Nakhai-Pour et al 2011. On the other hand, cytokinesuppressive anti-inflammatory drugs (CSAIDs) work by interfering with inflammatory signalling cascades and are therefore able to specifically block infection-mediated inflammation without some of the deleterious side effects of NSAIDs (Lee et al 1989, Keelan 2011. CSAIDs have been shown to block inflammation in a variety of animal models of chronic inflammation (Underwood et al 2000, Ward et al 2001, Buhimschi et al 2003, Jimi et al 2004, di Meglio et al 2005 as well as in human fetal membranes (Lappas et al 2003, De Silva et al 2010.…”

Section: Introductionmentioning

confidence: 99%

Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes

Stinson¹,

Ireland²,

Kemp³

et al. 2014

Reproduction

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Intrauterine infection and inflammation are responsible for the majority of early (!32 weeks) spontaneous preterm births (PTBs). Anti-inflammatory agents, delivered intra-amniotically together with antibiotics, may be an effective strategy for preventing PTB. In this study, the effects of four cytokine-suppressive anti-inflammatory drugs (CSAIDs: N-acetyl cysteine (NAC), SB239063, TPCA-1 and NEMO binding domain inhibitor (NBDI)) were assessed on human and ovine gestational membrane inflammation. Full-thickness membranes were collected from healthy, term, human placentas delivered by Caesarean section (nZ5). Using a Transwell model, they were stimulated ex vivo with g-irradiation-killed Escherichia coli applied to the amniotic face. Membranes from near-term, ovine placentas were stimulated in utero with lipopolysaccharide, Ureaplasma parvum or saline control and subjected to explant culture. The effects of treatment with CSAIDs or vehicle (1% DMSO) on accumulation of PGE 2 and cytokines (human interleukin 6 (IL6), IL10 and TNFa; ovine IL8 (oIL8)) were assessed in conditioned media at various time points (3-20 h). In human membranes, the IKKb inhibitor TPCA-1 (7 mM) and p38 MAPK inhibitor SB239063 (20 mM) administered to the amniotic compartment were the most effective in inhibiting accumulation of cytokines and PGE 2 in the fetal compartment. NAC (10 mM) inhibited accumulation of PGE 2 and IL10 only; NBDI (10 mM) had no significant effect. In addition to the fetal compartment, SB239063 also exerted consistent and significant inhibitory effects in the maternal compartment. TPCA-1 and SB239063 suppressed oIL8 production, while all CSAIDs tested suppressed ovine PGE 2 production. These results support the further investigation of intra-amniotically delivered CSAIDs for the prevention of inflammation-mediated PTB.

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Section: Introductionmentioning

confidence: 99%

Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes

Stinson¹,

Ireland²,

Kemp³

et al. 2014

Reproduction

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“…Standard compounds that inhibit cyclooxygenase and 5-lipoxygenase did not inhibit IL-1 production at non-toxic concentrations [11]. Finally, analysis of SKF86002 analogs showed no clear correlation between 5-lipoxygenase inhibition and the IL-1 inhibitory activity of these compounds [12].…”

Section: The Initial P38 Discoverymentioning

confidence: 94%

The Discovery of Novel Chemotypes of p38 Kinase Inhibitors

Diller¹,

Lin²,

Metzger³

2005

CTMC

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In the late 1970s and the early 1980s the initial p38 chemotype, the triaryl imidazoles, was discovered as an off-target effect during the development of cyclooxygenase and 5-lipoxygenase inhibitors long before the identity of the p38 kinase was known. During the last 10 years a number of novel p38 chemotypes were discovered via high throughput screening. More recently, the first series of p38 inhibitors discovered by xray crystallographic and virtual screening was announced. Finally, throughout the life span of p38 drug discovery programs significant medicinal chemistry effort has continually been placed on the design of new inhibitors from known chemotypes using molecular modeling, protein crystallography, hybrid design and simply sound intuition. Indeed, the search for p38 kinase inhibitors offers an excellent historical perspective as to how technological changes that have taken place in the pharmaceutical industry over the last decade, have affected the ways in which new leads are discovered and advanced. It is the intent of this review to highlight the discoveries of novel p38 chemotypes, emphasizing where possible the key technologies used in the discoveries and the knowledge gained from each discovery.

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