{"id":1140,"date":"2014-11-17T13:48:42","date_gmt":"2014-11-17T18:48:42","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1140"},"modified":"2014-11-24T01:40:58","modified_gmt":"2014-11-24T06:40:58","slug":"two-new-approaches-for-dealing-with-sepsis-toxemia","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2014\/11\/17\/1140\/two-new-approaches-for-dealing-with-sepsis-toxemia\/","title":{"rendered":"Two New Approaches For Dealing with Sepsis \/ Toxemia"},"content":{"rendered":"

There is hardly an indication which has accumulated more failed clinical trials than the sepsis area.\u00a0 Called first bacteremia, later sepsis, sepsis syndrome or septic shock, there have been numerous attempts to influence the cascade of events that eventually lead to MSOF and death.\u00a0 While it is convenient to think of a bacterial origin for this syndrome, there are non-bacterial causes for \u2018toxemia\u2019 as well which present in a similar fashion.\"Pacman\"<\/a><\/p>\n

If bacteria and their toxins are the root problem, the condition should be manageable with antibiotics, antitoxins, and immunomodulators.\u00a0 However, while the role of antibiotics is undisputed, additional interventions have not improved outcomes.<\/p>\n

After the early but unwarranted euphoria for the HA1A antibody to LPS, the endotoxin released by Gram-negative bacteria, it failed in a confirmatory trial [1]<\/a>.\u00a0 So did the E5 anti-endotoxin [2]<\/a>.\u00a0 TNF-alpha, an immune product revved up in sepsis, seemed an attractive target but treatment with an anti-TNF alpha mAb did not benefit patients [3]<\/a>.\u00a0 For Lilly\u2019s roller coaster drotrecogin alpha program, an activated protein C inhibitor, a separate blog would be in order but suffice it to say it failed in every single repeat study after gaining approval and was eventually mercifully taken off the market [4]<\/a>. Then there was the large and ill-conceived tifacogin trial in CAP (Community-acquired pneumonia) and severe sepsis which showed that this TFPI did not reduce mortality [5]<\/a>.\u00a0 Despite the industry\u2019s disillusion with sepsis trials which consumed so much effort, time and money, Eisai embarked on a 5-yr Phase 3 trial with Eritoran, a lipid A mimetic and TLR4 inhibitor only to fail yet again [6]<\/a>.

Unfortunately, the Bone definition of sepsis and sepsis syndrome has not served us well in the clinical trials arena<\/p>\n<\/div><\/p>\n

Unfortunately, the \u00a0definition of sepsis and sepsis syndrome introduced by R. Bone et al. has not served us well in the clinical trials arena. \u00a0Because of these frustrating setbacks, treatment of sepsis has actually changed very little in the last 30 years.\u00a0 Antibiotics and supportive ICU care to manage organ failure are still the mainstay of therapy.\u00a0 There is a die-hard group of folks that believe in steroids despite overwhelming data that they don\u2019t work, and also some stake holders that decry the demise of drotrecogin (Xigris).\u00a0 The fact remains that neither drug has stood the test of time or shown benefit in any consistent fashion.<\/p>\n

Two innovative approaches were recently described to deal with bacteremia \/ toxemia:<\/p>\n

Henry et al. [7]<\/a> developed liposomes composed of sphingomyelin alone or in combination with cholesterol to trap microbial toxins.\u00a0 Unlike the use of liposomes as delivery vehicles, the underlying idea was to provide a toxin \u2018sink\u2018 thus competitively preventing toxin binding to their mammalian cell target.\u00a0 In-vitro testing showed binding and inactivation of many toxins, including pneumolysin, alpha-hemolysin, streptolycin O, and phospholipase C, i.e., membrane lysing toxins and virulence factors in staphylococci, streptococci, pneumococci and clostridia.\u00a0 In animal experiments these liposomes were able to prevent mortality in staphylococcal and streptococcal mouse models.<\/p>\n

A somewhat similar approach was taken by a group from Boston.\u00a0 Kang and colleagues[8]<\/a> used a dialysis system to clear blood of pathogens and toxins with the help of magnetic nanospheres coated with mannose-binding lectin (MBL), a universal bacteria- and toxin-binding substance which is part of our innate immune system.\u00a0 The researchers were able to show in a rat sepsis model that circulating pathogen levels declined by 90% and that sepsis-related inflammatory response markers and LPS levels were much reduced.<\/p>\n

Both approaches are innovative and could be put to test in clinical trials. \u00a0Nonetheless\u00a0I am skeptical that either\u00a0interventions will prove successful at reducing 28-day mortality reproducibly.\u00a0 Animal models have misled us too often in the past; they are just not reflecting the breadth and complexity of what we call sepsis syndrome.\u00a0 Among friends, the next sepsis program will cost at least $100 million, a major high-risk investment even for Big Pharma.<\/p>\n

But who knows:\u00a0 Glory goes to the brave who dares to execute the next severe sepsis mega-trial even if he fails.\u00a0 Just as we all like a\u00a0good old Greek tragedy\u2026<\/p>\n

References:<\/strong><\/p>\n

[1]<\/a> E. Ziegler.\u00a0 NEJM 324, 1991: 429
\n[2]<\/a> D. Angus.\u00a0 JAMA. 2000 Apr 5;283(13):1723
\n[3]<\/a> E. Abraham.\u00a0 Lancet. 1998;351(9107):929
\n[4]<\/a> http:\/\/www.fda.gov\/Drugs\/DrugSafety\/ucm277114.htm
\n[5]<\/a> R. Wunderink.\u00a0 Am J Respir Critical Care Medicine, Vol. 183, (2011), pp. 1561
\n[6]<\/a> S. Opal.\u00a0 JAMA.\u00a0<\/em>2013;309:1154
\n[7]<\/a> B. Henry.\u00a0 Nature Biotechnology: advance online publication\u00a0 published online 2 November 2014; doi:10.1038\/nbt.3037
\n[8]<\/a> J Kang.\u00a0 Nature Medicine 20; 2014: 1211<\/p>\n","protected":false},"excerpt":{"rendered":"

There is hardly an indication which has accumulated more failed clinical trials than the sepsis area.\u00a0 Called first bacteremia, later sepsis, sepsis syndrome or septic shock, there have been numerous attempts to influence the cascade of events that eventually lead to MSOF and death.\u00a0 While it is convenient to think Continue reading Two New Approaches For Dealing with Sepsis \/ Toxemia<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1142,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[227,18],"tags":[403,691,698,697,220,695,682,684,689,687,690,688,93,699,686,694,693,701,702,700,677,262,679,680,692,703,681,685,678,696,683],"class_list":["post-1140","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-recent_literature","category-the_viewpoint","tag-antibiotic-blog","tag-bacteremia","tag-bacterial-dialysis","tag-bacterial-trapping","tag-bayer","tag-dialysis","tag-drotrecogin","tag-e5-mab","tag-eisai","tag-endotoxin","tag-eritoran","tag-ha1a","tag-lilly","tag-liposomes","tag-lps","tag-mannose-binding-protein","tag-mbp","tag-msof","tag-multi-system-organ-failure","tag-nanoparticles","tag-roger-bone","tag-sepsis","tag-sepsis-syndrome","tag-septic-shock","tag-steroids","tag-tfpi","tag-tifacogin","tag-tnf-alpha-inhibitor","tag-toxemia","tag-toxin-binding","tag-xigris"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/11\/sepsis-slider.jpg?fit=640%2C200&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-io","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":2344,"url":"https:\/\/allphasepharma.com\/dir\/2016\/03\/07\/2344\/recent-sepsis-literature\/","url_meta":{"origin":1140,"position":0},"title":"Recent Sepsis Literature","author":"Harald","date":"March 7, 2016","format":false,"excerpt":"SIRS, sepsis, severe sepsis, septic shock is a continuum, a crescendo of signs and symptoms associated with an infection uncontrolled by host responses. 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