Of endotoxin-induced

K10. Klabunde, R. E., and Calvello, C., Inhibition of endotoxin-induced microvascular leakage by a platelet-activating factor antagonist and 5-lipoxygenase inhibitor. Shock 4, 368-372 (1995). 

Behar-Cohen, F.F., et al. 1997. Iontophoresis of dexamethasone in the treatment of endotoxin-induced-uveitis in rats. Exp Eye Res 65 533. 

Gonzalez PK et al (1996) Role of oxidant stress in the adult respiratory distress syndrome Evaluation of a novel antioxidant strategy in a porcine model of endotoxin-induced acute lung injury. Shock 6 S23-S26... 

We had sought to address two questions (a) what is the elimination half-life of DS-96 in the murine model, and does the tV2 correspond to pharmacodynamic data shown in Fig. 12.19 (b) what is the therapeutic plasma concentration of DS-96 that corresponds to full protection against endotoxemic challenge in mice. DS-96 at a dose of 200 (xg/mouse (8 mg/kg) was administered to CF1 mice via i.p. and i.v. routes. Plasma concentrations of DS-96 were determined by LC-MS/MS using a deuterated DS-96 internal standard (Nguyen et al., 2008 Shrestha et al., 2008). The elimination tV2 in mice is about 400 min (Fig. 12.22), which is consistent with the observed pharmacodynamic (in vivo efficacy) data shown in Fig. 12.19. The observed concentration-versus-time profile of DS-96 in the mouse i.p. model suggests that a plasma concentration of 0.5-1.5 txg/mL corresponds to complete protection by a dose of 200 ng/animal of LPS in the D-galactosamine-primed model of endotoxin-induced lethality. 

Scherer RU.GieblerRM, Schmidt U et al. (1995) Short-time rabbit model of endotoxin-induced hypercoagulability. Lab Anim Sci 45 538-546... 

Single u-PA deficiency viable, fertile, normal life span occasionally spontaneous fibrin deposits in normal and inflamed tissue higher incidence of endotoxin-induced thrombosis. Combined t-PA and u-PA deficiency mice survive embryonic development retarded growth, reduced fertility, shortened life span spontaneous fibrin deposits more extensively and in more organs (Carmeliet et al. 1994 Heckel et al. 1990). 

Jarvis GE, Evans RJ. PAF and not TXA, is an important mediator of endotoxin induced platelet aggregation in equine heparinised whole Mood in vitro. Blood Coagulation and Fibrinolysis 1996 7 194-198... 

Endotoxin induces horse platelet aggreption, however, the effect of endotoxin is indirect requiring the presence of neutrophils (Jarvis et al. 1994). The leukocyte-dependent initiator of endotoxin-induced platelet aggreption is PAF (Jarvis et al. 1996). 

Richman AV, Gerber LI, Balls JU Peritubular capillaries. A major target site of endotoxin-induced vascular injury in the primate kidney. Lab Invest 43 327-332,1980... 

King J N, Gerring E L 1989 Antagonism of endotoxin-induced disruption of equine bowel motility by flunixin meglumine and phenylbutazone. Equine Veterinary Journal Supplement 7 38-42... 

Because of its multiple effects on immunoinflammatory response, recombinant IL-12 has been shown to have therapeutic activity in a variety of mouse tumor and infectious disease models and is being evaluated in clinical trials in human cancer patients. IL-12 also appears to play a role in the genesis of some forms of immunopathology, including endotoxin-induced shock and some autoimmune diseases associated with aberrant Thl activity. Therefore IL-12 antagonists may also have therapeutic potential in the treatment of autoimmune disorders. In addition, intraocular injection of IL-12 significantly inhibited the development of endotoxin-induced intraocular inflammation, suggesting that IL-... 

Hartmarm, G., Vassileva, V.. and Piquette-Miller, M. (2005) Impact of endotoxin-induced changes in P-glycoprotein expression on disposition of doxorubicin in mice. Drug Metabolism and Disposition, 33 (6), 820-828. 

Levosimendan is a novel inotropic calcium-sensitizing drug. In advanced congestive heart failure, it improves cardiac contractility by sensitizing troponin C to calcium. It has been used recently in a porcine model of endotoxin-induced septic shock, in which pretreatment with levosimendan improved cardiac output and systemic and gut oxygen delivery." There are currently two ongoing clinical trials of levosimendan in septic shock. The role of levosimendan in the supportive management of circulatory failure in sepsis remains to be determined. 

PAF-induced shock (Chen et al., 1994). The knockout mice fail to show PAF-induced bronchoconstriction, vasoconstriction, or the release of peptidyl leuko-trienes (Table 5). This suggests that leukotrienes are important mediators of PAF-, but not of endotoxin-induced shock. 

A diet supplemented with GLA and eicosapentaenoic acids improved oxygen delivery by decreasing vascular resistance and increasing cardiac index in endotoxin-induced lung injury in pigs. This mechanism is thought to involve attenuation of endotoxin-induced thromboxane B2 synthesis (Murray et al., 1995). A study (Mancuso et al., 1997) in endotoxic rats demonstrated that in addition to attenuation of thromboxane B2 production, production of leukotriene B4, leukotriene C/D4, and PGFla,... 

The other broad category of MSP actions on macrophages relates to mediator production. Endotoxin, or combinations of proinflammatory cytokines, causes expression of murine macrophage-inducible nitric oxide synthase, an effect that can be detected by Northern blots for the mRNA or by measurement of nitrate in the culture fluid. MSP prevents induction of NO-synthase by any of the above stimuli (Wang et al., 1994d). The inhibitory action of MSP is confined to this specific mediator. MSP did not inhibit endotoxin-induced expression of mRNA for monocyte chemoattractant protein-1. Furthermore, MSP caused secretion of IL-6 (but not IL-1 or TNFa) within 6 hr, and did not inhibit endotoxin-induced secretion of IL-1, IL-6, or TNFa (A. Skeel and E. J. Leonard, unpublished data). The in vitro modulation by MSP of endotoxin-induced NO production now has an in vivo counterpart. Concentrations of nitrate in serum of Stk / mice that received endotoxin intravenously were higher than in serum of comparably treated normal mice and at a critical endotoxin dose, only 20% of the Stk / mice survived, compared to 80% survival for normal mice (Correll et al., 1997). If MSP plays a role in the host response to endotoxemia, pro-MSP must be cleaved to biologically active MSP. Within 4 hr after i.v. administration of... 

M57. Myers, A. K Robey, J. W and Price, R. M. Relationships between tumour necrosis factor, eicosanoids and platelet-activating factor as mediators of endotoxin-induced shock in mice. Br. J. Pharmacol 99, 499-502 (1990). 

Evans, T., Carpenter, A., and Cohen, J. (1992). Purification of a distinctive form of endotoxin-induced nitric oxide synthase from rat liver. Proc. Natl. Acad. Sci. U.S.A. 89,5361-5365. 

Schott, C. A., Gray, G. A., and Stoclet, J. C. (1993a). Dependence of endotoxin-induced vascular hyporeactivity on extracellular L-arginine. Br. J. Pharmacol. 108, 38-43. 

At this time, it is difficult to reconcile the results from all the studies in the literature regarding the role of specific eicosanoids or PAF in the development of endotoxin-induced lung injury. The differences in results may be due to the use of inadequate or ineffective inhibitors, different doses and preparation of endotoxin, variable sensitivity of different species of animals to endotoxin effect and differences in eicosanoid metabolism in different species . A final possibility is that perhaps none of the metabolites alone is adequate to cause injury, but mediator chain reactions and synergistic actions of several mediators are important. This might explain why interventions targeting a single mediator (thromboxane or leukotrienes) have so far met with limited success. 

The macrophage is both a major site of endotoxin sequestration in vivo and a major source of endotoxin-induced mediators. A potential role of macrophage-derived arachidonic acid metabolites in the sequelae of endotoxic shock is supported by studies demonstrating direct in vitro endotoxin... 

Broaddus VC, Boylan AM, Hoeffel JM, et al. Neutralization of IL-8 inhibits neutrophil influx in a rabbit model of endotoxin-induced pleurisy. J Itrununol 1994 152 2960-2967. 

Kuhnle S, Nicotera P, Wendel A et al. Prevention of endotoxin-induced lethality, but not of liver apoptosis in poly (ADP-ribose) polymerase-deficient mice. Biochem Biophys Res Common 1999 263 433-8. 

N. Tirkey, S. Bharrhan and K. Chopra, Inhibition of oxidative stress and cytokine activity by circumin in amelioration of endotoxin induced experimental hepatotoxicity in rodents. Clin. Exp. Immunol., 145(2), 313-321 (2006). 

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