Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock

Reinhart, Konrad; Wiegand-Löhnert, C; Grimminger, Friedrich; Kaul, Martin; Withington, Stuart; Treacher, David; Eckart, J.; Willatts, Sheila M.; Bouza, Carmen; Krausch, Dietmar; Stockenhuber, Felix; Eiselstein, Jurgen; Daum, Lothar; Kempeni, Joachim

doi:10.1097/00003246-199605000-00003

Cited by 343 publications

(126 citation statements)

References 38 publications

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“…Nevertheless, the heterogeneous and dynamic nature of sepsis requires an adequate risk stratification in terms of not only research, but also therapeutic strategies (49). For example, a phase II trial by Reinhart et al found beneficial effects of treatment with the anti-TNF antibody fragment MAK 195F only in septic patients with IL-6 blood levels above 1,000 pg/mL (50).…”

Section: Anti-inflammatory Therapies In Sepsis: a Hopeless Case?mentioning

confidence: 99%

Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient

et al. 2016

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Sepsis and septic shock are associated with high mortality rates and remain a serious menace for the critically ill patient. Concurrent activation of pro-and anti-inflammatory pathways and an excessive cytokine release represent initial key features in the deregulation of the humoral and cellular antimicrobial defense. Research of the last decades addressed both the ebullient inflammation as well as the resulting longterm failure of the host immunity. While the reestablishment of an adequate immune-competence is still under investigation, many promising experimental trials to limit the inflammatory response during sepsis were challenged by missing beneficial effects in clinical studies. Nevertheless, due to advanced knowledge about the complex regulation of inflammatory mediators and their overlapping involvement in other potentially life-threatening diseases, further evaluation of these approaches in relevant subgroups could help to identify critically ill patients with potential benefit from anti-inflammatory therapies.

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Section: Anti-inflammatory Therapies In Sepsis: a Hopeless Case?mentioning

confidence: 99%

Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient

et al. 2016

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“…The pathophysiologic relevance of such TNF ␣ -related mechanisms to tissue injury is supported by observations that inhibition of TNF ␣ processing to the active form, passive immunization with neutralizing anti-TNF ␣ antibodies, or gene deletion of the 55-kD TNF ␣ receptor increase survival in animal models of endotoxemia (16)(17)(18)(19)(20)(21)(22)(23). However, clinical studies using TNF ␣ -neutralizing antibodies in the treatment of sepsis failed to show clear physiological or survival benefits in the overall study population (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Role of NFkappaB in the mortality of sepsis.

Böhrer¹,

Qiu²,

Zimmermann³

et al. 1997

J. Clin. Invest.

449

277

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“…This inflammatory cascade can become self-sustaining when cytokines produced early in the infectious process (e.g., tumor necrosis factor alpha [TNF-␣] and interleukin-1 [IL-1]) induce further production of these and other proinflammatory cytokines (20,44) Agents directed at common triggers for the sepsis syndrome (e.g., lipopolysaccharide [LPS]) or cytokines (e.g., TNF-␣ and IL-1) associated with systemic inflammation would, at least conceptually, be attractive therapeutic targets (1,14). Regrettably, most of these potentially novel therapeutic approaches have failed to significantly affect the overall mortality of sepsis patients despite their success in many experimental animal models of sepsis (1,2,9,16,29,38). One potential explanation for these repeated clinical failures is that sepsis, in fact, represents a heterogeneous collection of clinically related diseases whose pathogenesis may vary substantially, depending upon the microbe responsible for inducing the systemic proinflammatory cascade (e.g., gram-negative versus gram-positive organisms) (6,34,43).…”

mentioning

confidence: 99%

Anomalous Role of Tumor Necrosis Factor Alpha in Experimental Enterococcal Infection

Papasian¹,

Silverstein

Gao³

et al. 2002

Infect Immun

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The murine D-galactosamine (D-gal) model of tumor necrosis factor alpha (TNF-␣) hypersensitization was used as an initial tool to investigate the potential contribution of TNF-␣ to lethal intraperitoneal (i.p.) infection with Enterococcus faecalis. D-gal sensitized mice to lethal E. faecalis infection, whereas dexamethasone and neutralizing anti-TNF-␣ antibody protected D-gal-treated, E. faecalis-infected mice, implicating TNF-␣ in the lethal response to E. faecalis infection in D-gal-treated mice. Circulating TNF-␣ was undetectable for at least 8 h following i.p. E. faecalis infection, although low peritoneal levels of TNF-␣ were detected within 3 h, suggesting that localized TNF-␣ production contributed to the lethal response to E. faecalis infection in D-gal-treated mice. Although i.p. E. faecalis infection failed to induce a detectable systemic TNF-␣ response, circulating Interleukin-6 (IL-6) was detected within 3 h of infection. IL-6 was also detected in the peritoneum within an hour of infection, prior to the appearance of peritoneal TNF-␣. In striking contrast to in vivo results, E. faecalis induced a potent and rapid TNF-␣ response from both mouse peritoneal macrophages and the RAW 264.7 cell line in vitro. This led us to hypothesize that TNF-␣ production in response to E. faecalis infection is suppressed by IL-6 in vivo. In vitro experiments demonstrated a statistically significant, but modest, inhibitory effect of IL-6 on TNF-␣ production by RAW cells stimulated with E. faecalis. Collectively, these data indicate that acute, lethal E. faecalis infection appears to induce an unusual cytokine response that differs in character from that previously described for most other gram-positive and gram-negative bacteria.

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Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock

Cited by 343 publications

References 38 publications

Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient

Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient

Role of NFkappaB in the mortality of sepsis.

Anomalous Role of Tumor Necrosis Factor Alpha in Experimental Enterococcal Infection

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