The Role of the Interchain Disulfide Bond in Governing the Pharmacological Actions of Botulinum Toxin

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Therapeutic antibodies are one of the major classes of medical countermeasures that can provide protection against potential bioweapons such as botulinum toxin. Although a broad array of antibodies are being evaluated for their ability to neutralize the toxin, there is little information that defines the circumstances under which these antibodies can be used. In the present study, an effort was made to quantify the temporal factors that govern therapeutic antibody use in a postchallenge scenario. Experiments were done involving inhalation administration of toxin to mice, intravenous administration to mice, and direct application to murine phrenic nerve-hemidiaphragm preparations. As part of this study, several pharmacokinetic characteristics of botulinum toxin and neutralizing antibodies were measured. The core observation that emerged from the work was that the window of opportunity within which postchallenge administration of antibodies exerted a beneficial effect increased as the challenge dose of toxin decreased. The critical factor in establishing the window of opportunity was the amount of time needed for fractional redistribution of a neuroparalytic quantum of toxin from the extraneuronal space to the intraneuronal space. This redistribution event was a dose-dependent phenomenon. It is likely that the approach used to identify the factors that govern postchallenge efficacy of antibodies against botulinum toxin can be used to assess the factors that govern postchallenge efficacy of medical countermeasures against any agent of bioterrorism or biological warfare.

Section: Methodsmentioning

confidence: 99%

Identification of the Factors That Govern the Ability of Therapeutic Antibodies to Provide Postchallenge Protection Against Botulinum Toxin: A Model for Assessing Postchallenge Efficacy of Medical Countermeasures against Agents of Bioterrorism and Biological Warfare

Al-Saleem¹,

Nasser²,

Olson³

et al. 2011

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“…Murine phrenic nerve hemidiaphragm preparations were used to bioassay the residual toxicity of BoNT in biological specimens Simpson et al, 2004). Tissues were excised and suspended in physiological buffer that was aerated with 95% O 2 and 5% CO 2 and maintained at 35°C.…”

Section: Methodsmentioning

confidence: 99%

The Role of Systemic Handling in the Pathophysiologic Actions of Botulinum Toxin

Al-Saleem

Ancharski²,

Ravichandran³

et al. 2008

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“…Murine phrenic nerve-hemidiaphragm preparations were used to bioassay the residual toxicity of botulinum toxin in biological specimens Simpson et al, 2004). Tissues were excised and suspended in physiological buffer that was aerated with 95% O 2 , 5% CO 2 , and maintained at 35°C.…”

Section: Methodsmentioning

confidence: 99%

An Initial Assessment of the Systemic Pharmacokinetics of Botulinum Toxin

Ravichandran¹,

Gong²,

Saleem³

et al. 2006

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Botulinum toxin is an extraordinarily potent molecule that has an unusually long duration of action. Despite this, there is little information available on natural mechanisms for metabolism or elimination and virtually no information on pharmacologically induced mechanisms for metabolism and elimination. Therefore, a number of experiments were performed on laboratory animals that addressed two major issues: 1) the effect of blood on the structure, function, and biologic half-life of the toxin, and 2) the effect of neutralizing antibodies on half-life and elimination of circulating toxin. In the first series of studies, the metabolic transformation of toxin was assessed by incubating it in blood for varying lengths of time. At each time point, aliquots were examined to determine the amount of toxin, the structure of toxin, the catalytic activity of toxin, and the neuromuscular blocking activity of toxin. This work demonstrated that blood did not alter any characteristic of the toxin molecule. Experiments were also done in which toxin was administered to mice and rats at doses that produced clinical poisoning. The results demonstrated that the elimination half-life for native (nonmetabolized) toxin in blood and serum was 230 to 260 min. During the second series of studies, the rate of elimination of circulating toxin was studied in the presence of antibodies directed against the carboxyl-terminal half of the toxin molecule. This work demonstrated that neutralizing antibodies 1) enhanced clearance of toxin from the circulation and 2) enhanced tissue accumulation of toxin, particularly in liver and spleen.