title: Improved bioassays using a local effect, such as muscle paralysis, as an endpoint.
abstract: Drug potency testing consumes many animals, botulinum neurotoxin (BoNT) testing being perhaps the most notorious example. To avoid 50% lethal dose determination, the so-called digital abduction score (DAS) and other BoNT induced local paralysis assays were developed. This paper reveals that a simple mathematical expression - the Bateman's equation used in many pharmacokinetic data analyses - can describe in full detail the time dependence of the BoNT induced local paralysis; the equation hence allows robust interpolation and extrapolation, as well as integral effect (AUC), and its dose dependence, evaluation. The equation is moreover a convenient tool for experimental planning and for extracting, from experimental data, the parameters that characterise BoNT potency. Most important, one can generally reduce the number of animals needed to gain reliable results at least 20-33% (and possibly 50% or even 75%) by analysing and modelling the time course of a local effect (such as muscle paralysis) with the equation, rather than just by averaging the maximum observed effect size at one point in time.
authors: The Advanced Treatments Institute, Tassilostr. 3, D-82131 Gauting, Germany. Electronic address: Cevc@Advanced-Treatments.org.
authors: Gregor
authors: G
authors: Cevc
mesh_terms: D000465:Algorithms; D023401:Animal Use Alternatives; D000818:Animals; D001681:Biological Assay / Q000379:methods*; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage / Q000032:analysis* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007273:Injections, Intramuscular; D051379:Mice; D008954:Models, Biological; D018908:Muscle Weakness / Q000139:chemically induced* / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000187:drug effects*; D009498:Neurotoxins / Q000008:administration & dosage / Q000032:analysis* / Q000633:toxicity; D010243:Paralysis / Q000209:etiology*; D015203:Reproducibility of Results; D066007:Toxicokinetics
chemical_list: D009498:Neurotoxins; D019274:Botulinum Toxins, Type A
keywords: Animal experiment; Botulinum toxin (BoNT); Digital abduction score (DAS); Dose dependence; Local effect; Mathematical modelling