Dr. Patrick Treacy discusses the origins of Dysport BTX-A. Used in the Europe/UK since 1991, Dysport is used in 76 other countries as well for both therapeutic use (such as movement disorders) and in 27 countries for aesthetic use, similar to Botox Cosmetic. In the United States, the safety of Dysport for the treatment of glabellar lines (frown lines) was studied in more than 2,400 patients. It is estimated that more than 600,000 patients in Europe have been treated over many years.
Dr. Patrick Treacy discusses the origins of Dysport BTX-A
1. INTRODUCTION TO THE COSMETIC
USES OF DYSPORT
by Dr. Patrick Treacy
Medical Director
Ailesbury Clinic
Dublin Ireland
3. COSMETIC USES OF BOTULINUM-A
TOXIN AS DYSPORT
1. Short history of the development of BTX-A
2. Uses of BTX-A in conventional medicine
3. Mechanism of action of BTX-A at the NMJ
5. Botulinum neurotoxin
Botulinum toxin (BTX) is produced by a gram-positive
anaerobic bacterium Clostridium botulinum,
The clinical syndrome of botulism can occur following
ingestion of contaminated food, from colonisation of
the infant gastrointestinal tract, or from a wound
infection.
Botulinum toxin is broken into 7 neurotoxins
(types A, B, C [C1, C2], D, E, F, and G),
which are antigenically and serologically distinct but
structurally similar.
Human botulism is mainly due to types A, B, E,
and, rarely, F,G. Types C and D cause toxicity only in
animals.
6. Botulinum Toxin Molecule
The botulinum toxin molecule is
synthesized as a single chain (150 kDa)
It is cleaved to form a dichain molecule
with a disulfide bridge.
The light chain (~50 kDa) acts as a zinc
(Zn2+) endopeptidase similar to tetanus
toxin
The heavy chain (~100 kDa) provides
cholinergic specificity and binding of the
toxin to presynaptic receptors,
7. 19th
Century History of BTX-A toxin
•1822 The German physician and poet Justinus Kerner
published in a medical journal clinical symptoms of
"sausage poison" in about 200 cases of gastroenteritis
in Stuttgart
•1822 Kerner noted the neurological symptoms and
suggested the idea of a possible therapeutic use of
“sausage poison“ in St. Vitus dance
•1870, Muller (German physician) coined the name
botulism for the symptoms. The Latin form is botulus,
which means sausage.
1895, Microbiologist Emile Van Ermengem investigated
three deaths after food poisoning outbreak in Ellezelles
and isolated the bacterium Clostridium botulinum.
16. 1953 US built Fort Detrick
Experiments by Edward Schantz gave rise to Botox
17. 20th
century History of BTX-A toxin
•1944, Edward Schantz cultured Clostridium botulinum
and isolated the toxin (BTX-A) .
•1949, Burgen et al discovered that botulinum toxin
blocks neuromuscular transmission.
.
18. 20th
century History of BTX-A toxin
•1973, Alan B Scott, MD, of Smith-Kettlewell Eye
Research Institute used (BTX-A) in monkey
experiments
•1980, Scott suggested and used BTX-A for the first
time in humans to treat strabismus.
•I989, BTX-A approved by the FDA for treatment of
strabismus, blepharospasm, and hemifacial spasm in
patients aged younger than 12 years.
19. Late 20th
century History of BTX-A toxin
•1987, Canadian ophthalmologist Jean Carruthers
noted that vertical glabellar creases (frown lines)
disappeared following the use of Botox to treat
patients for blepharospasm. She informed her
dermatologist husband Alastair Carruthers
1990, The Carruthers presented their findings in a
seminal paper entitled ’ The treatment of glabellar
furrows with botulinum A exotoxin’
Carruthers JDA, Carruthers JA. J Dermatol Surg
Oncol. 1990;
THE ROLE OF THE CARRUTHERS
20. Late 20th
century History of BTX-A toxin
•1991, The Carruthers resented their findings at the
annual meeting of the American Society for
Dermatologic Surgery, Orlando, Florida on March 13-
17, 1991.
•1992 The doctors continued research into the
cosmetic effect of botulism toxin. It was their
article in J Dermatol Surg Oncol.1992;18:17-21
that set the stage for the FDA to finally approve
botulinum toxin A for use in cosmetic medicine.
24. ‘Extralabel’ use of BTX-A
•Focal dystonias - Involuntary, sustained, or spasmodic
patterned muscle activity
•Cervical dystonia (spasmodic torticollis)
•Blepharospasm (eyelid closure)
•Laryngeal dystonia (spasmodic dysphonia)
•Limb dystonia (writer's cramp)
•Oromandibular dystonia
•Orolingual dystonia
•Truncal dystonia
•Sweating disorders
•Axillary and palmar hyperhidrosis
•Frey syndrome, also known as
auriculotemporal syndrome
25. ‘Extralabel’ use of BTX-A
•Disorders of localized muscle spasms and pain
•Chronic low back pain
•Myofascial pain syndrome
•Temporomandibular joint disorders associated with
increased muscle activity
•Tension headache
•Migraine headache
•Cervicogenic headache
A Smooth muscle hyperactive disorders
• Detrusor-sphincter dyssynergia
• Achalasia cardia
• Hirschsprung disease
• Sphincter of Oddi dysfunctions
• Chronic anal fissures
26. ‘Extralabel’ use of BTX-A
•Spasticity - Velocity-dependent increase in muscle tone
•Stroke
•Traumatic brain injury
•Cerebral palsy
•Multiple sclerosis
•Spinal cord injury
A Achalasia (oesophageal)
Ø Chronic anal fissures
Ø Migraine and tension headaches
Ø Hyperhidrosis
Ø Cerebral Palsy
Ø Low back pain
Ø Myofascial pain syndrome
Ø Tics
Ø Spastic bladder and urinary sphincters
27. How muscles contract
At a normal neuromuscular
junction, a nerve impulse
triggers the release of
acetylcholine, which
causes the muscles to
contract. Excessive release
of acetylcholine at the
neuromuscular junction
causes overactive
contraction of corrugator
and procerus muscle,
which over time can cause
wrinkles to form.
28. Mechanism of action of BTX-A
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.
This mechanism laid the
foundation for the development
of the toxin as a therapeutic
tool.
30. BINDING, INTERNALISATION,
TRANSLOCATION and BLOCKING
•Binding of BTX-A to receptors
on presynaptic cell membrane.
•Internalisation of Receptor/
BTA-X complex as toxin vesicle
by membrane into nerve cell
•Translocation S-S cleaved and
50Ka released to cytoplasm
•Blocking 50Ka chain cleaves
SynNptosome-Associated
Protein (SNAP-25), required for
docking of neurotransmitter-
containing vesicles.
31. Mechanism of BLOCKING of BTX-A
The 50-kDa light chain of
BTX-A inhibits acetylcholine
release by cleaving SNAP-2
(a cytoplasmic protein)
SNAP-2 is required for the
docking of acetylcholine
vesicles on the inner side of
the nerve terminal plasma
membrane.
34. Mechanism of unBLOCKING of BTX-A
The clinical effect
of botulinum
toxin injections
lasts 2-6 months
and then resolves
After several months, the
inactivated terminals
slowly recover function,
and the new sprouts
and end plates regress
35. RESOLUTION of the CLINCIAL EFFECT
of BTX-A
Clinical effect lasts about
2-6 months and then
resolves
Recovery occurs through
proximal axonal sprouting
and muscle reinnervation
by formation of new
neuromuscular junction.
A recent study by De Paiva
suggests that, eventually,
regeneration of the original
neuromuscular junction
takes place.
36. BOTULINUM-A TOXIN formulations
Dysport ® is another formulation
of BTX-A made in England and
available in Europe.
It is distributed in 500-unit vials
that can be stored at room
temperature
Dysport ® is produced by Speywood Pharmaceuticals in
England (Dysport)
DYSPORT ®
The relative potency of Botox® units
to Dysport ® units is approximately 1:4.
37. Contraindications to Dysport injections
Treat patients with
diseases of the
neuromuscular junction
(eg, myasthenia gravis)
cautiously because
underlying generalized
weakness can be
exacerbated, and local
weakness at injection sites
can occur more than
otherwise expected