Immunity and inflammation are forms of physiologic processes defined as the body's response against foreign substances such as antigens or, in some cases, itself, autoantigens, or some form of damaging biologic or mechanical insult. The process often involves the production of antibodies by type B lymphocytes which interact with foreign substances and subsequently destroy or inactivate the antigen using a number of cellular and chemical amplification systems and regulation systems such as complement, arachadonic acid metabolites such as prostaglandin and leukotriennes, cytokines, preformed mediators such as serotonin and histamine, and enzymes. Inflammatory responses occur in conjunction and as a result of the immune recognition process and functions to provide the basic tissue insult.
Unfortunately, inflammatory reactions intrinsically may have destructive effects on tissue and organ structure and function, and may lead to painful or subjectively adverse sensory experiences. A specific form of inflammation defined herein deals with an organism's ability to produce a rapid regional inflammatory response over a several second to 12 hour period.
While various anti-inflammatory agents have existed in the past, none have been associated with the mechanism of regional chemodenervation such as achievable with botulinum toxin. Regional chemodenervation refers to the practice of injecting or otherwise providing the chemodenervation agent to a particular-region or site with diffusion of that agent from that site over a fixed distance. Dosages associated with regional chemodenervation range from 20-600 units per region for the treatment of movement disease.
Regional chemodenervation is accomplished for therapeutic purposes for the treatment of a number of movement disorders of the body, involving excessive tone, involuntary movement and abnormal postures often associated with abnormal sensations. Examples of such movement disorders include essential blepharospasm, hemifacial spasm, adult onset spasmodic torticollis, regional occupation limb and hand dystonia, spasmodic dysphonia, aberrant facial nerve region with facial muscle synkinesis, and bruxism and jaw dystonia as described by Borodic, G. E., Pearce, L. B., Johnson, E., Schantz, E., Clinical and Scientific Aspects of Therapeutic Botulinum toxin Administrations, Opthalmology Clinics of N. America, September, Vol. 4, No. 3, 1991.
Chemodenervation is accomplished by injecting a biologically quantized amount of botulinum toxin into the regional muscles involved with the involuntary movement, effecting a block in neuromuscular transmission leading over a period of several weeks to neurogenic muscular atrophy, decreased muscular resting tone and decreased muscular contractility over a defined region determined by the quantity of chemodenervating agent used in the injection site. The preferred agent is botulinum toxin, generally quantized using the LD 50 bioassays which may be refined by regional denervation bioassays as described by Borodic, G. E., Alderson, K., Pearce, L. B., Ferrante, R., Histologic changes in muscle and clinicopathologic correlations after therapeutic botulinum toxin administration, Textbook of Botulinum toxin Therapy Eds, J. Jankovic, M. Hallet, M. Dekker, New York, Hong Kong, Chapter 10, Pages 119-158, 1994.
The botulinum unit is defined as that quantity of botulinum toxin capable of killing 50% of a population of Swiss Webster mice. The quantity is an activity unit, and specifically not a unit of mass. Depending on the quality of the botulinum toxin used, the mass necessary to produce this activity may vary.
The dosage associated with such regional movement diseases is on the order of 25-600 units, with the duration of the chemodenervative effect being generally 12-16 weeks, with complete reversibility for most therapeutic preparations of botulinum toxin. Botulinum is known to exist as immunotypes A-G which affect different cytoplasmic acceptor proteins after being internalized at the presynaptic motor axon terminal. Each immunotype has been associated with varying durations of action and chemodenervating potency per LD 50 unit, as described by Borodic, G. E., Pearce, L. B., New Concepts in Botulinum toxin Therapy, Drug Safety 11(3): 145-152, 1994.
Despite the known tissue effects from regional injections of botulinum toxin, certain medical observations regarding the use of chemodenervating agents can not be easily explained by such denervating tissue effects. For instance, when chemodenervation is used to treat patients with benign essential blepharospasm, photophobia or sensitivity of the eye to light is often markedly decreased. Botulinum toxin in the dosages associated with the blocking in neuromuscular transmissions has also been shown to occasionally be helpful for the treatment of regional pain syndromes such as myofascial pain syndromes, headaches, and migraine headaches which can not easily be explained by the traditional chemodenervation model that has been evoked for the efficacy in regional movement diseases.