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KASHIF NAWAZ Presentation

Botulinum Toxin: Pharmacology, chemistry, and Immunology

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KASHIF NAWAZ Presentation

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  1. Botulinum Toxin: Chemistry, Pharmacology, Toxicity, and Immunology

  2. What is Botulinum? Botulinum is a powerful neurotoxin produced by the bacteria Clostridium botulinum. Known for its ability to cause a condition called botulism. lead to muscle paralysis and potentially be life-threatening.

  3. Clostridium botulinum • Gram-positive, rod-shaped, anaerobic, spore-forming, motile bacterium with the ability to produce the neurotoxin botulinum.  • Scientific name: Clostridium botulinum • Class: Clostridia • Domain: Bacteria • Family: Lachnospiraceae • Genus: Clostridium • Order: Eubacteriales • Phylum: Bacillota

  4. Types Of Botulinum • There are seven known types of botulinum toxins • labeled as type A to type G • Each type has slightly different characteristics and effects • The most commonly used types in medical and cosmetic applications are type A and type B. • Type A includes products like Botox and Dysport, while type B includes products like Myobloc. • . These different types of botulinum toxins have varying potencies and durations of action.

  5. Introduction • The first use of local intramuscular injection of minute doses of botulinum toxin A (BTXA) was in the treatment of strabismus. • BTX-A injections have several advantages over surgical therapy in the management of intractable disease. • BTX-A is marketed worldwide under the name BOTOX® (Allergan) and in Europe as Dysport® (Speywood)

  6. Approved for “the treatment of strabismus, blepharospasm, and focal spasms including hemifacial spasm.” • Approved for cervical dystonia in 23 countries throughout the world. • Acceptance of BTX-A for treatment of spasticity is growing, with approvals pending in many European countries

  7. Pharmacology of BTX • Botulinum toxin blocks the release of acetylcholine from nerve endings to paralyze muscles and to decrease the pain response. • Botulinum toxin acts by binding presynaptically to high-affinity recognition sites on the cholinergic nerve terminals and decreasing the release of acetylcholine. • causing a neuromuscular blocking effect. • There are three steps involved in toxin mediated paralysis • That are; • Binding • 2) Internalization • 3) Blockade (see Figure).

  8. Preparation of Crystalline BTX • Pharmaceuticals must be manufactured in a standard fashion that guarantees quality, safety, and efficacy • To prepare BTX, cultures of Clostridium botulinum are established in a fermenter, grown, and then harvested by centrifugation after acidification. • The precipitated crude toxin is solubilized and purified,

  9. A Note on Units and Nomenclature • Under the trade name BOTOX, botulinum toxin type ‘A’ has been successfully used inworldwideclinical trials for over a decade. • The European preparation of botulinum toxin type A has the trade name Dysportdistributed by SpeywoodPharmaceuticals in England.

  10. Toxicity Studies • • The lethal parenteral dose of BTX-A in humans is not known. • It has been estimated to be nearly 3000 U • • The maximum recommendeddose per treatment session is 300-400 U • • Antitoxin antibodies are presumedresponsible for most cases of resistance

  11. Immunoresistance and Antibody Detection • Development of resistance to BTX-A therapy is an important clinical issue • Several types of assays are available to detect the presence of antibody in serum • The most widely used is the in vivo mouse neutralization assay, available through Northview Pacific Labs (Berkeley, Calif.) • Binding of antibodies with toxin protects the mice from the toxin’s lethal effects. • Death of the mice indicates no antibodies (or insufficient antibodies) are present.

  12. • The mouse assayprobablyunderestimatesthe prevalence ofantibody mediated resistance. • The prevalence ofneutralizingantibodies amongpatients receivingchronic treatmentat the higherdoses for spasticity isprobably at least3%. • Patients withBTX-A resistancemay benefit frominjections withother serotypes,including BTX-B,-C, and -F.Differences induration of effectmay be significant.

  13. Cautions and Contraindications • In 1994, American Academy of Neurology(TTAC) released Training Guidelines on the use of BTX-A. • Before using BTX in clinical practice, the treating physician should be knowledgeable about the diagnosis and medical management of disorders characterized by inappropriate muscle spasms. • Knowledge of the relevant anatomy and basic skills in using EMG equipment is also desirable • BTX is generally contraindicated inpregnancy, lactation, and neuromusculardisease, though there are cases of uncomplicatedtherapy in some of these conditions. • Efficacy in children parallels that in adults, but long-term safety has not been studied in great detail. Preliminary studies in children have not revealed a more extensive adverse effect profile.

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