Prevention and Treatment of Botulism

Adler, Michaël; Gul, Nizamettin; Eitzen, Edward M.; Oyler, George A.; Molles, Brian E.

doi:10.1007/978-1-4614-9454-6_13

Cited by 2 publications

(3 citation statements)

References 256 publications

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“…Subjective impressions and elusive early symptoms make it difficult to establish a meaningful model for symptomatic animals. For these reasons, reliable data to establish postsymptom antitoxin efficacy, such as dosage and timing, still need further elucidation (14,17,43); hence, the prognosis for successful antitoxin treatment for symptomatic patients with botulism is unclear.…”

Section: Discussionmentioning

confidence: 99%

A Novel Rabbit Spirometry Model of Type E Botulism and Its Use for the Evaluation of Postsymptom Antitoxin Efficacy

Diamant

Pass

Rosen

et al. 2018

Antimicrob Agents Chemother

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Botulinum neurotoxins (BoNTs), the most poisonous substances known in nature, pose significant concern to health authorities. The only approved therapeutic for botulism is antitoxin. While administered to patients only after symptom onset, antitoxin efficacy is evaluated in animals mostly in relation to time postintoxication regardless of symptoms. This is most likely due to the difficulty in measuring early symptoms of botulism in animals. In this study, a rabbit spirometry model was developed to quantify early respiratory symptoms of type E botulism that were further used as a trigger for treatment. Impaired respiration, in the form of a reduced minute volume, was detected as early as 18.1 ± 2.9 h after intramuscular exposure to 2 rabbit 50% lethal doses (LD) of BoNT serotype E (BoNT/E), preceding any visible symptoms. All rabbits treated with antitoxin immediately following symptom onset survived. Postsymptom antitoxin efficacy was further evaluated in relation to toxin and antitoxin dosages as well as delayed antitoxin administration. Our system enabled us to demonstrate, for the first time, full antitoxin protection of animals treated with antitoxin after the onset of objective and quantitative type E botulism symptoms. This model may be utilized to evaluate the efficacy of antitoxins for additional serotypes of BoNT as well as that of next-generation anti-BoNT drugs that enter affected cells and act when antitoxin is no longer effective.

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Section: Discussionmentioning

confidence: 99%

A Novel Rabbit Spirometry Model of Type E Botulism and Its Use for the Evaluation of Postsymptom Antitoxin Efficacy

Diamant

Pass

Rosen

et al. 2018

Antimicrob Agents Chemother

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“…The unusually high potency and long duration of action of BoNT/A, coupled with the intracellular localization of LC/A impose severe constraints on the discovery of effective inhibitors of BoNT/A intoxication (Adler et al, 2014). The above may account for the finding that no SMIs examined to date have been able to provide robust protection from BoNT/A-induced lethality.…”

Section: Discussionmentioning

confidence: 99%

“…Therapy for botulism relies on antitoxins to neutralize BoNT in circulation, and severe cases require intensive care with artificial ventilation (Cheng et al, 2009; Trott et al, 2009; Yu et al, 2009; Adler et al, 2014). Currently, only one formulation of antitoxin is licensed for clinical use: a despeciated equine-derived heptavalent botulism antitoxin (BAT®) that received FDA approval in 2013 (Hill et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

Jacobson¹,

Adler²,

Silvaggi

et al. 2017

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Botulinum neurotoxins (BoNTs) are the most toxic substances known to mankind and are the causative agents of the neuroparalytic disease botulism. Their ease of production and extreme toxicity have caused these neurotoxins to be classified as Tier 1 bioterrorist threat agents and have led to a sustained effort to develop countermeasures to treat intoxication in case of a bioterrorist attack. While timely administration of an approved antitoxin is effective in reducing the severity of botulism, reversing intoxication requires different strategies. In the present study, we evaluated ABS 252 and other mercaptoacetamide small molecule active-site inhibitors of BoNT/A light chain using an integrated multi-assay approach. ABS 252 showed inhibitory activity in enzymatic, cell-based and muscle activity assays, and importantly, produced a marked delay in time-to-death in mice. The results suggest that a multi-assay approach is an effective strategy for discovery of potential BoNT therapeutic candidates.

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Prevention and Treatment of Botulism

Cited by 2 publications

References 256 publications

A Novel Rabbit Spirometry Model of Type E Botulism and Its Use for the Evaluation of Postsymptom Antitoxin Efficacy

A Novel Rabbit Spirometry Model of Type E Botulism and Its Use for the Evaluation of Postsymptom Antitoxin Efficacy

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

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