HOW DOES IT WORK? › sites › default › files › pdf › How-Does-it-Work.pdf• Neuronox®...
Transcript of HOW DOES IT WORK? › sites › default › files › pdf › How-Does-it-Work.pdf• Neuronox®...
-
HOW DOES IT WORK? Chemical denervation, Dermal
fillers
Constantinos Laskarides DMD, DDS, PharmD, FICD ORAL & MAXILLOFACIAL SURGERY
Assoc i a te Professor , TUFTS UNIVERSITY
At tend i ng Surgeon, TUFTS MEDICAL CENTER
D i p l omate , Amer i can Board of Ora l & Max i l l o fac ia l Surgery
Fe l l ow, Amer i can Assoc i a t i on of Ora l & Max i l l o fac ia l Surgeons
Fe l l ow, Amer i can Co l l ege of Ora l & Max i l l o fac ia l Surgeons
-
Clostridium botulinum
• Anaerobic, Gram+ spore forming bacterium, commonly found in soil, that under certain conditions can germinate and create a toxin.
• First recognized and isolated in 1895 by Emile van Ermengem from home cured ham implicated in a botulism outbreak. Named Bacillus botulinus (botulus = sausage in Latin)
• Symptoms: double vision, blurred vision, drooping eyelids, slurred speech, difficulty swallowing, dry mouth, and muscle weakness. Progress to paralysis of the respiratory muscles, arms, legs, and trunk.
-
Botulinum Toxin A
• Exotoxin. Total of 7 subtypes of botulinum toxin: A, B, C1, D, E, F, G
• Types A, B, and E are most commonly associated with botulism in human
• Only A & B available for clinical use. Type A for cosmetic use.
• Type B has been studied for cosmetic use, it generally
elicits more pain upon injection. Faster onset but shorter
duration of action than type A
-
• Definition: one unit of toxin is the calculated median intraperitoneal LD50 for a group of female Swiss Webster mice, weighting 18-20 g.
• Activity: 20 Units/nanogram
• The estimated LD50 for humans is 40 U/kg or 2,500-3,000 U (25-30 vials) for a 70 kg man.
• The potency Units of BOTOX are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products
• Duration of effect: 3-4 months
Botulinum Toxin A
-
History of the Cosmetic Use of Botulinum A Exotoxin
• 1973
– Dr. Alan Scott (Ophthamologist) treated for the first time strabismus. Smith Kettlewell Research
Institute in San Francisco.
• 1979
– First preparation of Botulinum toxin-A. Limited FDA-approval to use of BTX-A for strabismus.
• 1985
– FDA-approval for blepharospasm.
• 1987
– Dr. Jean Carruthers. One patient with blepharospasm pointed out the smooth, relaxed
appearance she had after treatment of the glabellar area
• 1989
– Oculinum Inc. (Dr. Scott’s company) acquired by Allergan, Inc. Product named Botox. FDA-
approval for hemifacial spasm.
• 1992 – Carruthers JDA, Carruthers JA. Treatment of glabellar frown lines with C. botulinum-A exotoxin.
J Dermatol Surg Oncol. 1992;18(1):17–21
• 2003 – FDA-approval for treatment of glabellar rhytides.
-
Mechanism of action
• BTA is a dichain molecule with a
heavy and light chain
• The heavy chain is responsible for
selective binding of the neurotoxin
to cholinergic nerve terminals, and
the light chain acts intracellular to
prevent acetylcholine release
• BTA blocks neuromuscular
transmission by binding to acceptor
sites on motor or sympathetic nerve
terminals, entering the nerve
terminals, and inhibiting the release
of acetylcholine.
The action of botulinum toxin on the neuro-muscular junction. A. S. V. Burgen et al.
J Physiol. 1949 August 1; 109(1-2): 10–24
-
Hathaway. In: Hauschild AHW, ed. Clostridium Botulinum: Ecology and Control in Foods New York, NY: Marcel Dekker, Inc.;1993;54:pp 3-20.
Inoue et al. Infect Immun 1996;64:1589-1594. Lacy et al. Nat Struct Biol 1998;5:898-902
Non-toxic,
non-hemagglutinin (NTNH)
Hemagglutinin (HA)
-
Motor end plate
-
BTA blocks neuromuscular transmission by binding to acceptor
sites on motor or sympathetic nerve terminals, entering the
nerve terminals, and inhibiting the release of acetylcholine.
-
BTA cleaves synaptosomal membrane-associated protein 25 kDa SNAP-
25, a protein integral to the successful docking and release of
acetylcholine from vesicles situated within nerve endings.
Muscle atrophies - axonal sprouting may occur - extrajunctional
acetylcholine receptors may develop - reinnervation of the muscle
-
BOTOX® BOTOX®
Cosmetic/
Vistabel®/
Vistabex®
Dysport®/
Reloxin®
Dysport®
Cosmetic
Myobloc®/
NeuroBloc
®
NT-201/
XEOMIN®
PurTox®
Company Allergan Inc.
85% of
market
Allergan Inc. Ipsen Inc./
Medicis Inc.
Ipsen Inc./
Medicis Inc.
Solstice
Neuroscience
s Inc.
Merz
Pharmaceutic
al
Mentor
Corporation
Type Type A-Hall
strain
Type A-Hall
strain
Type A Type A Type B Type A-Hall
strain
Type A-Hall
strain
Approvals In over 75
countries
worldwide,
including US
and Canada
In over 16
countries,
including US,
Canada, Italy,
France
In over 65
countries;
approved in
US
Germany,
other
European
countries
Some
European
countries,
US, Canada
Germany,
other
European
countries,
Mexico,
Argentina,
US
None (clinical
trial phase)
-
BOTOX® BOTOX®
Cosmetic/
Vistabel®/
Vistabex®
Dysport®/
Reloxin®
Dysport®
Cosmetic
Myobloc®/
NeuroBloc
®
NT-201/
XEOMIN®
PurTox®
Active
Substance
(molecular
weight)
Botulinum
toxin type A
complex
(900kD)
Botulinum
toxin type A
complex
(900kD)
Botulinum
toxin type A
complex
(900kD)*
Botulinum
toxin type A
complex
(900kD)*
Botulinum
toxin type B
complex
(700kD)
Botulinum
toxin type A,
free from
complexing
proteins
(150kD)
Botulinum
toxin type A,
free from
complexing
proteins
(150kD)
Strength of
Action
(BTX-
A:Product)
1:1 1:1 1:2 - 1:4
(approximate)
1:2 - 1:4
(approximate)
1:50 - 1:100 1:1 1:1.5?
* The formulation contains complexes of variable size between
500kD-900kD
-
BOTOX® BOTOX®
Cosmetic/
Vistabel®/
Vistabex®
Dysport®/
Reloxin®
Dysport®
Cosmetic
Myobloc®/
NeuroBloc
®
NT-201/
XEOMIN®
PurTox®
Indications Blepharospas
m; cervical
dystonia;
glabellar
lines;
hyperhidrosis
Glabellar
lines Crow’s
feet
Blepharospas
m; cervical
dystonia
Glabellar
lines
Cervical
dystonia
Blepharospas
m; cervical
dystonia;
glabellar lines
in Argentina
Phase 3 for
glabellar
lines; Phase
1 for
spasmodic
torticollis/cerv
ical dystonia
Mode of
Action
SNAP-25
SNAP-25 SNAP-25 SNAP-25 VAMP SNAP-25 SNAP-25
Pharmaceuti
cal
Form
Powder
dissolved in
solution for
injection
Powder
dissolved in
solution for
injection
Powder
dissolved in
solution for
injection
Powder
dissolved in
solution for
injection
Solution Powder
dissolved in
solution for
injection
?
• SNAP-25 (synaptosomal associated protein with the molecular mass of 25kD) = An intracellular protein that is essential for synaptic vesicle transmission; it has been identified as the molecular target of BTX-A.
• VAMP (synaptobrevin) = A protein involved in synaptic vesicle movement that has been identified as the molecular target of BTX-B.
• ? = Data unavailable or unconfirmed
-
BOTOX® BOTOX®
Cosmetic/
Vistabel®/
Vistabex®
Dysport®/
Reloxin®
Dysport®
Cosmetic
Myobloc®/
NeuroBloc
®
NT-201/
XEOMIN®
PurTox®
Units/vial 100 100, 50 500 300 or 500 2,500; 5,000;
10,000
100 ?
Volume 10mL
maximum
1.25mL or
2.5mL
recommend
2.5mL
recommend
5mL
maximum
0.5mL; 1mL;
2mL
8mL
maximum
?
Re-
constitution
0.9% NaCl
solution
0.9% NaCl
solution
0.9% NaCl
solution
0.9% NaCl
solution
Prepared
solution,
dilutable
0.9% NaCl
solution
0.9% NaCl
solution
Storage 2-8°C or < -5°C
2-8°C or < -5°C
2-8°C 2-8°C 2-8°C do not freeze
Up to 25°C ?
-
Other BTX Products Under Global Development
• CBTX-A (Lanzhou Institute of Biological Products)
People’s Republic of China; marketed in Brazil as Prosigne®; bovine gelatin protein is added; potential to induce allergic reactions, or possibly bovine spongiform encephalopathy
• CNBTX-A (Nanfeng Medical Science and Technology Development Co., Ltd.)
neither licensed nor approved in any country, Shijiazhuang Hebei China
• Neuronox® (Medy-Tox Inc.)
South Korea; worldwide licensing of its cosmetic use has been acquired by Q-Med Inc. (Sweden)
• Topical • RT001 (Revance Therapeutics, CA) BTA Topical Gel. In Phase 3.
Has developed a proprietary platform that enables transcutaneous flux of large medicinal payloads
• Linurase (Prollenium Medical Technologies, Canada) topical BTA serum
-
New Generic Names FDA acknowledge that toxins are produced by different biological manufacturing
processes, obtained by different isolation and purification techniques, and
derived from different Clostridium batches
active neurotoxin is 150 kDa. formulations differ because of
presence or absence of complexing proteins.
-
Dilution and Storage of Botulinum Toxin
• Each vial of Botox is freeze-dried, has approx. 100 U (5 ng protein) of
toxin, 0.5 mg of human albumin, and 0.9 mg of sodium chloride (or 50
Units, 0.25 mg, and 0.45 mg) in a sterile, vacuum-dried form without a
preservative.
• Diluent: normal saline with no preservatives
• Technique: thoroughly evaporate the alcohol applied to the cap,
introduce the saline into the vial by vacuum and not by squirting, avoid
bubbles/foaming by not agitating the solution during dilution and filling
of the syringe, and do not shake the vial.
-
Dilution:
• 5cc of NS / vial, 1cc syringe with 30-gauge needle (2units
/ 0.1cc)
• This amount is more that recommended but permits even
distribution. Greater dilution decrease potency of Botox,
greater chance of toxin migration.
B O T O X (100u)
DILUENT
(NS)
CONCENTRATION U per
0.1ml
1ml 100 U/ml 10
2ml 50 U/ml 5
2.5ml 40 U/ml 4
4ml 25 U/ml 2.5
5ml 20 U/ml 2
8ml 12.5 U/ml 1.25
D Y S P O R T (300u)
DILUENT
(NS)
CONCENTRATION U per
0.1ml
1ml 300 U/ml 30
2ml 150 U/ml 15
2.5ml 120 U/ml 12
4ml 75 U/ml 7.5
5ml 60 U/ml 6
8ml 37.5 U/ml 3.75
Dilution and Storage of Botulinum Toxin
-
Dilution and Storage of Botulinum Toxin
• Un-reconstituted BTA can be stored up to 36 months (indefinitely) in a
conventional freezer
• Storage: once reconstituted, should be stored at 2-8 ºC (refrigeration).
The length of viability of reconstituted product is subject to debate.
Most clinicians (46%) store it for up to 1 week, 23% for 24 hours, 15%
for 2 weeks, 8% for 10 days, and 8% for 4 days. (Allergan: 24h)
Allergan: BOTOX Cosmetic vials are for single-use only. Discard any remaining solution.
• Up to 6 weeks at 4 ºC without loosing efficacy
Hexsel et al. Dermatol Surg. 2009;35(6):993
-
Tray for neurotoxin treatment
• Neurotoxin vial
• Normal Saline (0.9% NaCl), single use, injectable,10cc vial
• Alcohol pads
• 2 x 2 gauzes
• 5cc syringe
• 1cc syringes
• 30G or 31G needles
• Disposable ice-packs
• EMLA or Lidocaine 4% cream (optional)
• Skin marker (optional)
• Gloves, mask
-
• Autologous fat transfer was first described by Neuber in 1893
• Medical-grade liquid silicone was used successfully in thousands of
patients in the United States and elsewhere since the 1960s for off-label
cosmetic purposes
• 1981: FDA approval of bovine collagen
• Medically useful hyaluronic acid was first isolated and purified in 1962. In
the 1980s, cross-linking was perfected to support the stability and
viscoelastic properties.
• Hylaform (Inamed Corporation), the first hyaluronic acid skin filler; this
product was released in Europe 1996.
Dermal Fillers Historical overview
-
• Resorbable materials (collagen, hyaluronic acid,
hydroxyethyl methacrylate, dextran, and polylactic
acid) enzymatically metabolized or phagocytized
slowly, with minimal histologic reaction.
• Permanent and semipermanent fillers (last longer
than 1 to 2 years) such as silicone, Teflon and
PMMA. Some particles may have an irregular surface that cannot be phagocytosed and may eventually form foreign body
granulomas.
Particles
-
Fillers
-
Hyaluronic acid
• In humans, HA serves as the ground substance of
dermis, fascia, and most fluid mediums because of its
viscoelastic properties. A 70kg man has 15gr dry HA.
• Natural HA has a half-life in tissue of only 1 to 2 days
before undergoing aqueous dilution and enzyme
degradation.
• There is no antigenic specificity for species or
tissues; and thus, it has a low potential for allergic or
immunogenic reaction
• Cross-linking native HA forms larger, more stable
molecules with longer residue time in tissues.
-
• Consists of polyanionic di-saccharide units of glucuronic acid and
N-acetyl-glucosamine connected by alternating β 1–3 and β 1–4 bonds
• Cross-linking agents: butanediol-diglycidyl-ether (BDDE)
divinyl sulfone
bis-epoxides
Trace amounts may be found in the final product
• Biphasic gels:
Selectively sized particles of cross-linked HA suspended within non-cross-linked HA used
as a carrier
• Monophasic gels:
Varied degree of high-molecular weight HA and low-molecular weight HA.
Varied degree of cross-linking
Adjusted hardness, size, hydration
Hyaluronic acid
-
Hyaluronic acid
Elastic modulus (G’) of HA fillers
-
• Animal derived (Hylaform)
• Non-animal derived (streptococcus species biofermentation) (Restylane,
Juvederm)
• Total HA concentration in filler: ~24mg/ml
• Percentage of uncross-linked: HA ~10%
• Formulation: smooth cohesive viscoelastic gel
• Needle: 27 or 30G
• Highly hydrophilic. Swelling until equilibrium for bound water is reached.
Depends on concentration, cross-link density, gel hydration
Hyaluronic acid
-
• No single parameter defines the use of a HA filler
• Results are also depended on implantation technique and the response of
the biological host
Hyaluronic acid
-
Genzyme
Biosurgery
Captique Hyaluronic
Acid
FDA approved
Anika
Therapeutics
Hydrelle – Elevess
Hyaluronic
Acid with
Lidocaine
FDA approved
-
Fibrocell
Science
Laviv azficel-T autologous fibroblast cellular product FDA approved
Aesthetic
Factors
Selphyl
Platelet Rich
Plasma
Matrix
“Vampire facelift”
CE mark
-
Tray for dermal filler (HA) treatment
• Dermal filler package
• Alcohol pads
• 2 x 2 gauzes
• Disposable ice-packs
• EMLA or Lidocaine 4% cream (optional)
• Skin marker (optional)
• Dental syringe for local anesthesia, disposable needles
• Local anesthetic ampules (lidocaine, etc)
• Topical anesthesia gel swabs for mucosa (optional)
• Gloves, mask
-
Non-animal Stabilized Hyaluronic Acid (NASHA)
-
Calcium Hydroxylapatite Facial Filler (Radiesse)
• Ca-HA microspheres (25-45 μm) suspended in a gel
carrier.
• Gel is dissipated in vivo and replaced with collagen,
whereas Ca-HA remains at the site.
• Average longevity: 18 – 24 mo.
• FDA approved (12-06)
-
Calcium Hydroxylapatite Facial Filler (Radiesse)
Radiographic appearance
-
• Non-animal, non-bacterial, not chemically cross-linked
absorbable polymers
• Protein-free, reduced immunogenic potential
• Ultra-smooth, non-particulate gel
• Better rheologic properties in higher concentrations
• Currently available to practitioners in the European
Union
Carboxymethylcellulose (CMC) and polyethylene oxide (PEO) (Laresse)
-
• Approved for the treatment of of HIV-associated facial lipoatrophy
• Sculptra Aesthetic approved by FDA for nasolabial folds and other facial wrinkles .
• Elicit the stimulation of fibroblasts, which in turn produce collagen, adding volume to the skin gradually.
• 3 injection sessions over a few months.
• Results can last up to 2 years.
• Reconstituted at room temperature with 3 to 5mL of sterile water for injection, 2 to 72 hours before administration
Poly-L-lactic acid (PLLA) (Sculptra)
-
• PMMA microspheres (20% by volume), 30–50 μm in diameter, suspended in 3.5% bovine collagen solution (80% by volume) and 0.3% lidocaine.
• collagen carrier is absorbed within 1 month after injection and completely replaced by the patient’s own connective tissue within 3 months. “PERMANENT” FILLER
• Bovine collagen allergy testing is required, 4 months prior.
Polymethylmethacrylate (PMMA) (ArteFill)
http://rds.yahoo.com/_ylt=A0WTefZXCddL4yYAj9KjzbkF/SIG=13aiie004/EXP=1272470231/**http://www.realself.com/files/imagecache/full/Artefill-Syringe-01-wcopyright-26358.jpg
-
Growth of dermal fillers
-
Growth of dermal fillers
-
Growth of dermal fillers
-
Growth of dermal fillers
-
Growth of dermal fillers