Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vesnarinone (3,4-Dihydro-6-[4(3,4-dimethoxybenzoyl)-1-piperanizyl]-2(1H)-quino linone), a recently synthesized quinolinone derivative with positive inotropic properties, has been reported the survival of patients with chronic congestive heart failure. However, the mechanisms that contribute to this improvement are not yet well understood. There is increasing evidence that vesnarinone has novel immunosuppressive properties related to its inhibition of cytokine production. Cytokines have been shown to play a pivotal role in the pathophysiologic consequences of fatal bacteremic shock. In this study, we investigated the effects of vesnarinone in a murine model of lethal endotoxemia induced by lipopolysaccharide (LPS). Eight-week-old female BALB/c mice were given 300 or 400 micrograms of LPS, and 50 or 100 mg/kg of vesnarinone was administered by oral gavage and/or 10 or 30 micrograms of vesnarinone was given intra peritoneally. Vesnarinone prolonged the median survival time and reduced lethality when given at the same time as the LPS injection. However, vesnarinone did not have a beneficial effect when administered 2 hours after LPS treatment. Plasma TNF-alpha reached a maximum level 1 hour after LPS challenge, and vesnarinone reduced the plasma level of TNF-alpha, when administered at the same time as LPS injection. Vesnarinone had protective effects against lethal endotoxemia; these effects were considered to be due to the suppression of TNF-alpha production. These findings suggest that vesnarinone may be a promising agent for the treatment of bacterial sepsis and shock.
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PMID:Vesnarinone prolongs survival and reduces lethality in a murine model of lethal endotoxemia. 796 53

We investigated the effects of inotropic agents with phosphodiesterase III inhibitory properties, amrinone, pimobendan and vesnarinone, and cell permeable cyclic nucleotide analogue, 8-bromo adenosine 3'5'-cyclic monophosphate (8 Br-cAMP) on the induction of nitric oxide synthase (NOS) by lipopolysaccharide in J774A.1 macrophages in vitro. Although all three inotropic agents inhibited nitrite accumulation, the degree of inhibition was different, with pimobendan being the most potent inhibitor and amrinone the least. Vesnarinone inhibited nitrite formation biphasically. 8 Br-cAMP increased nitrite production at high concentrations, suggesting that the inhibitory effects of inotropic agents could not be explained by an increase in cAMP. Although differential inhibition of inducible NOS by inotropic agents may explain the different effects of these drugs in patients with heart failure, further study is necessary to reach this conclusion.
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PMID:Inotropic agents differentially inhibit the induction of nitric oxide synthase by endotoxin in cultured macrophages. 876 21

We studied the effects of various phosphodiesterase (PDE) III inhibitors: amrinone, pimobendan and vesnarinone: a PDE IV inhibitor (Ro 20-1724) and a PDE V inhibitor (E-4021) on the production of cytokines which have been shown to depress myocardial function. Recently developed inotropic agents which inhibit PDE III activity have produced short-term hemodynamic benefits in patients with advanced heart failure, but long-term treatment with these agents has an adverse effect on survival. However, vesnarinone, which has been shown to improve survival dramatically, has an immunomodulating effect and inhibits the production of cytokines. Peripheral blood mononuclear cells obtained from healthy human subjects were stimulated with lipopolysaccharide and each PDE inhibitor was added. After 24 h of incubation, tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) and IL-6 in the culture supernatants were measured by an enzyme-linked immunosorbent assay. All three PDE III inhibitors, amrinone, pimobendan and vesnarinone, inhibited TNF-alpha production, but vesnarinone's inhibitory effect was the most prominent. Amrinone and pimobendan enhanced IL-1 beta production, whereas vesnarinone had no effect. Vesnarinone inhibited IL-6 production and pimobendan slightly decreased IL-6 production, whereas amrinone had no significant effect on IL-6 production. The PDE IV inhibitor, Ro 20-1724, decreased the production of IL-1 beta and TNF-alpha and also tended to inhibit IL-6 production; its modulation of cytokine production was similar to the effects of vesnarinone. Because 8Br-cAMP or 8Br-cGMP did not suppress cytokine production, the modulating effects were not considered to result from an increase in cAMP or cGMP. Differential modulation of cytokine production may play a role in the therapeutic effect in heart failure patients who are treated with drugs that have PDE-inhibitory actions. It may be important to study whether the use of dual inhibitors of PDE III and PDE IV is therapeutically more useful for the treatment of heart failure due to their immunomodulating properties.
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PMID:Differential modulation of cytokine production by drugs: implications for therapy in heart failure. 900 65

Vesnarinone (OPC-8212) is a synthetic quinolinone derivative with inotropic and immunomodulatory effects. Vesnarinone has been shown to inhibit tumor necrosis factor-alpha (TNF alpha) produced by mitogen stimulated macrophages, and to inhibit phosphodiesterase (PDE) type III in cardiac muscle. TNF alpha and interferon-gamma (IFNgamma) have been implicated in the pathogenesis of autoimmune diseases, and both cytokines are targets for therapeutic intervention. IFNgamma can enhance autoimmune disease through direct effects, and indirectly by priming macrophages to produce TNF alpha. In this study, we demonstrate that while vesnarinone enhances basal TNF alpha levels, it inhibits TNF alpha production in peripheral blood mononuclear cells from multiple sclerosis (MS) patients and healthy donors stimulated with lipopolysaccharide (LPS) or primed with IFNgamma and stimulated with suboptimal doses of LPS. In addition, vesnarinone inhibited TNF alpha production in primary adult human microglial cultures. However, in contrast to rolipram, another TNF alpha inhibiting agent, vesnarinone failed to inhibit TNF alpha production by myelin basic protein specific T-cell lines. As oral TNF inhibitors are currently being considered in the USA for clinical application in MS, the implications of our findings on the development of vesnarinone for treatment of MS are discussed.
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PMID:The effect of vesnarinone on TNF alpha production in human peripheral blood mononuclear cells and microglia: a preclinical study for the treatment of multiple sclerosis. 1040 67