Botulinum toxin pretreatment augments the weakening effect of injection with ricin-mAb35 in rabbit extraocular muscle

Abstract

Purpose-To examine force generation and duration of effect of botulinum toxin pretreatment, followed by injection of ricin-mAb35 in extraocular muscle (EOM).Methods-In normal adult rabbits, one superior rectus muscle was injected with either 5 units botulinum toxin or 1/50 maximally tolerated dose for rats (rMTD) of ricin-mAb35. Additional rabbits were first injected with 5 units botulinum toxin, and after one, two, or four weeks the same muscle was injected with either 1/10 or 1/50 rMTD ricin-mAb35. In each treatment group, the contralateral muscle was injected with an equal volume of saline. After 12 weeks (1/50 rMTD) or 6 months (1/10 rMTD), the rabbits were euthanized. Both superior rectus muscles were removed and assayed physiologically, using an in vitro apparatus.Results-Twelve weeks after treatment with either botulinum toxin or immunotoxin alone, only ricin-mAb35 treated muscles were weaker than control muscles at tetanic stimulation frequencies. Pretreatment with botulinum toxin prior to injection with immunotoxin, especially at shorter intervals between injections, resulted in significant decreases in twitch and tetanic force generation compared to controls and muscles treated with ricin-mAb35 only or botulinum toxin only. At 6 months, force generation was decreased from control only in muscles treated with the higher dose of ricin-mAb35. Botulinum toxin pretreatment did not augment this effect at 6 months.Conclusions-Upregulation of postsynaptic nicotinic acetylcholine receptors caused by botulinum toxin pretreatment amplifies the reduction of force generation in EOM following secondary injection of the immunotoxin ricin-mAb35 within three months of treatment.

Modulating Neuromuscular Junction Density Changes in Botulinum Toxin–Treated Orbicularis Oculi Muscle

“…13 Some animal studies examining co-treatment strategies have been performed, including studies from our laboratory. These include co-treatment with the immunotoxin ricinmAb35, 14 insulin growth factor binding proteins, 15 and bupivacaine. 16 The goal of our research is to test agents that have the potential to enhance the duration of paralysis, which would potentially decrease the number of "lifetime" injections of botulinum toxin needed by patients.…”

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“…The best results were reported in hematological malignancies, where the efficacy of these hybrid molecules was particularly promising in controlling unwanted immune response [18,19]. Among the various possible uses, immunotoxins were also proposed for the locoregional treatment of strabismus, both alone [20,21] and in combination with BTX [22].…”

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