BOTOX and Botulinum Neurotoxin Timeline

• 1822: Justinus Kerner develops the idea of a possible therapeutic use of botulinum toxin, which he calls “sausage poison.”
• 1870: Muller coins the name “botulism” from the Latin word (botulus) for sausage.
• 1895: Emile Van Ermengem identifies the bacterium Clostridium botulinum as the causative agent of botulism.
• 1919: G.S. Burke conducts the first toxicity test on botulinum toxin—a test for the Minimum Lethal Dose, or the minimum amount of toxin that kills guinea pigs within 48 hours following subcutaneous injection.
• 1928 Herman Sommer isolates botulinum neurotoxin in purified form.
• 1946: Carl Lamanna is the first to use the LD50 Test as a measure of the activity of botulinum neurotoxins.

Edward Schantz and colleagues purify botulinum toxin type A (the active ingredient in BOTOX®) in crystalline form.

• 1949: Arnold Burgen and colleagues discover that botulinum toxin blocks neuromuscular transmission.
• 1950s: Vernon Brooks discovers that botulinum toxin type A (BTA) blocks the release of acetylcholine from motor nerve endings when injected into hyperactive muscles.
• 1960s: Schantz and Alan Scott use botulinum toxin type A in monkey experiments to assess its effectiveness in treating crossed eyes (strabismus).
• 1980: Scott uses botulinum toxin type A for the first time in humans to treat crossed eyes.
• 1984: FDA designates∗ BOTOX® for the treatment of crossed eyes and spasmodic winking caused by the involuntary contraction of an eyelid muscle (blepharospasm) in adults.
• 1986: FDA designates BOTOX for the treatment of involuntary contraction of neck muscles (cervical dystonia).
• 1987: A patient in Canada being treated for blepharospasm notices that the product eases her brow furrow – the first noted cosmetic benefit for the drug.

∗Technically speaking, FDA uses the term “designate” instead of “approval” when referring to orphan drugs, or those drugs that treat diseases/conditions that affect less than 200,000 Americans (Office of Rare Diseases: http://rarediseases.info.nih.gov/html/resources/about_ord.html and FDA: http://www.fda.gov/orphan/designat/index.htm).

• 1988: Allergan acquires the rights to distribute Scott’s botulinum toxin type A product, Oculinum, and the responsibilities to conduct clinical trials of the drug’s effectiveness for other indications.
• 1989: Oculinum receives FDA approval to market botulinum toxin type A as an orphan drug to treat strabismus, blepharospasm, and hemifacial spasm associated with dystonia.
• 1990: The American Academy of Neurology and the National Institutes of Health endorse botulinum toxin therapy for cervical dystonia.
• 1991: FDA designates BOTOX for the treatment of dynamic muscle contracture in pediatric cerebral palsy patients. Allergan buys Oculinum, Inc. and renames their BTA product BOTOX (from botulinum toxin).
• 1992: FDA designates botulinum toxin type A (Botulinum Toxin Research Associates, Inc.) for the treatment of synkinetic closure of the eyelid associated with VII cranial nerve aberrant regeneration.
• 1993 SNAP-25 is identified as the molecular target of botulinum toxin type A.
• 2000: FDA approves BOTOX to treat cervical dystonia.
• 2001: BOTOX®Cosmetic gets its first approval for cosmetic procedures in Canada and New Zealand.
• 2002: FDA approves BOTOX Cosmetic to “temporarily improve the appearance of moderate to severe frown lines between the eyebrows (glabellar lines), a medical condition that is not serious.”10 BOTOX Cosmetic also receives approval in Australia, Switzerland, Taiwan and Singapore.
• 2003: BOTOX Cosmetic receives cosmetic approval as VISTABEL® in France.
• 2004: FDA approves BOTOX for primary axillary hyperhidrosis (severe underarm sweating).