Introduction and History of Botulinum Toxin

INTRODUCTION

Botulinum toxin (abbreviated either as BTX or BoNT) is produced by Clostridium botulinum, a gram-positive anaerobic bacterium. The clinical syndrome of botulism can occur following ingestion of contaminated food, from colonization of the infant gastrointestinal tract, or from a wound infection.

BoNT is broken into 7 neurotoxins (labeled as types A, B, C [C1, C2], D, E, F, and G), which are antigenically and serologically distinct but structurally similar. Human botulism is caused mainly by types A, B, E, and (rarely) F. Types C and D cause toxicity only in animals.

The BoNT molecule is synthesized as a single chain (150 kD) and then cleaved to form the dichain molecule with a disulfide bridge. The light chain (~50 kD - amino acids 1-448) acts as a zinc (Zn2+) endopeptidase similar to tetanus toxin with proteolytic activity located at the N-terminal end.

 The heavy chain (~100 kD - amino acids 449-1280) provides cholinergic specificity and is responsible for binding the toxin to presynaptic receptors; it also promotes light-chain translocation across the endosomal membrane.


HISTORY:-

The German physician and poet Justinus Kerner (1786-1862) first developed the idea of a possible therapeutic use of botulinum toxin, which he called "sausage poison."

-In 1870, Muller (another German physician) coined the name botulism. The Latin form is botulus, which means sausage.
-In 1895, Professor Emile Van Ermengem, of Belgium, first isolated the bacterium Clostridium botulinum.
-In 1928, Dr. Herman Sommer, at the University of California, San Francisco, first isolated in purified form botulinum toxin type A (BoNT-A) 
  as a stable acid precipitate.
-In 1946, Dr. Edward J Schantz succeeded in purifying BoNT-A in crystalline form–cultured Clostridium botulinum and isolated the toxin.
-In 1949, Dr. Burgen's ASV group discovered that botulinum toxin blocks neuromuscular transmission.
-In the 1950s, Dr. Vernon Brooks discovered that when BoNT-A is injected into a hyperactive muscle, it blocks the release of acetylcholine ]   from motor nerve endings.
-In 1973, Dr. Alan B. Scott, of Smith-Kettlewell Eye Research Institute, used BoNT-A in monkey experiments; in 1980, he used BoNT-A for
  the first time in humans to treat strabismus.
-In December 1989, BoNT-A (BOTOX®) was approved by the US Food and Drug Administration (FDA) for the treatment of strabismus, 
  blepharospasm, and hemifacial spasm in patients aged younger than 12 years.
-On December 21, 2000, BoNT-A received FDA approval for treatment of cervical dystonia.
-In 2001, the United Kingdom approved BOTOX®, synthesized by Allergan, for axillary hyperhidrosis (excessive sweating). Canada approved
  BOTOX® for axillary hyperhidrosis, focal muscle spasticity, and cosmetic treatment of wrinkles at the brow line.
-On April 15, 2002, the FDA announced the approval of BOTOX® Cosmetic to temporarily improve the appearance of moderate-to-severe
  frown lines between the eyebrows (glabellar lines).
-In July 2004, the FDA approved BOTOX® to treat severe underarm sweating, known as primary axillary hyperhidrosis, that cannot be
  managed by topical agents, such as prescription antiperspirants.
-Although it has not been approved by the FDA for any other indications, the acceptance of BoNT-A use for the treatment of spasticity and
  muscle pain disorders is growing, with approvals pending in many European countries.
-The clinical use of BoNT-B has been studied, and several products currently are available commercially (eg, MyoBloc, in the United States;
  NeuroBloc, in Europe). MyoBloc was approved by the FDA on December 8, 2000, for treatment of cervical dystonia, to reduce the severity
  of abnormal head position and neck pain.