Dr. Patrick Treacy discusses the origins of Dysport BTX-A

INTRODUCTION TO THE COSMETIC USES OF DYSPORT

by Dr. Patrick Treacy

Medical DirectorAilesbury ClinicDublin Ireland

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

Cosmetic Use of Dysport

1.Horizontal forehead lines

2. Glabellar frown lines

3. Lateral canthal lines

4. Temporal brow lift

5. Upper lips

6. Nasolabial folds

7. Horizontal neck lines

8. Vertical neck lines

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.

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,

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.

New Century 1900 New Century 1900

Chemical warfare brought new means of killing people

Ypres April 22nd 1915 Ypres April 22nd 1915

5,000 died on the first day and another 5,000 on the second

1916 British chemical warfare complex

1916 British chemical warfare complex

7000 acres of scrubland in Porton Down Wiltshire

Dublin 1916 Dublin 1916

Porton Down Research Centre

Porton Down Research Centre

Research experiments on Botulinum by Dr. Paul Fides gave rise to DysPORT

Porton Down is still active today

Porton Down is still active today

First victim of experimentsFirst victim of experiments

Aircraftman Ronald Madison died in May 1953

Reinhard Heydrich Reinhard Heydrich

Assassinated by Czech agents in Prague on 27th May 1942

1953 US built Fort Detrick 1953 US built Fort Detrick

Experiments by Edward Schantz gave rise to Botox

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.

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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.

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

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.

USE OF DYSPORT COSMETICALLY

PATIENT FIVE DAYS LATER

FDA approved uses of BTX-A

1. Cervical dystonia2. Blepharospasm3. Cranial nerve 11 disorders4. Facial spasm5. Glabellar frown lines

‘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

‘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

‘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 fissuresØ     Migraine and tension headachesØ     HyperhidrosisØ     Cerebral PalsyØ     Low back painØ     Myofascial pain syndromeØ     TicsØ     Spastic bladder and urinary sphincters

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.

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.

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.

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.

How muscles contract

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

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.

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.

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