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Review Article
New Neurotoxins on the Horizon
Scott R. Freeman, MD; and Joel L. Cohen, MD
Toxins isolated from lethal bacteria allow for safe, versatile, and minimally invasive interventions that have revolutionized the field of cosmetic and therapeutic treatments. Botulinum toxins are high–molecular weight proteins produced by Gram-positive, spore-forming Clostridial bacteria. The toxins of 5 distinct strains (A, B, E, F,
and G) affect humans. Currently, type A and B toxins are available for the treatment of human diseases in the
United States, with type A being the only agent approved for cosmetic use by the U.S. Food and Drug
Administration. This article reviews the history of botulinum toxin as a cosmetic intervention, discusses its current role in cosmetic treatment, and provides an update of other neurotoxins on the horizon for therapeutic
and cosmetic use. (Aesthetic Surg J 2008;28:325–330.)
ntramuscular injection of botulinum toxin (BTX) to
improve facial wrinkles is the most common cosmetic
procedure currently performed in the United States,
with more than 2.75 million procedures performed in
2007.1,2 Only one botulinum neurotoxin (Botox; Allergan
Inc, Irvine, CA) is approved by the U.S. Food and Drug
Administration (FDA) for cosmetic use in the United
States.1 Other agents on the horizon include
Dysport/Reloxin (Ipsen Limited, Slough, England),
Xeomin (NT-201; Merz Pharmaceuticals GmBH,
Frankfurt am Main, Germany), Prosigne (Lanzhou
Biological Products Institute, Lanzhou, China), PurTox
(Mentor Corp, Santa Barbara, CA), Myobloc/Neurobloc
(Solstice Pharmaceuticals, South San Francisco, CA),
and topical type A toxin.
I
BOTULINUM TOXINS
Botulism exists as 3 distinct clinical entities (food-borne,
infantile, and wound), all caused by toxins produced by
the Gram-positive, spore-forming anaerobe Clostridium
botulinum.3 Seven different strains of Clostridium have
been described (designated A, B, C, D, E, F, and G), and
each produces a distinct toxin identified by the corresponding letter of the bacterial strain producing it (BTX-A
through -G).3,4 Humans can be affected by the toxins of 5
strains (A, B, E, F, and G) and are not affected by the toxins of strains C and D.3,5 Toxins produced by Clostridial
bacteria are high–molecular weight protein complexes
that include 3 key proteins: a 150-kDa toxin, a non-toxin
hemagglutinin protein, and a non-toxin non-hemagglutinin protein. The non-toxin proteins may provide the
toxin complex protection against temperature or enzyDr. Freeman is from the Department of Dermatology, University
of Colorado at Denver and Health Sciences Center, Aurora, CO.
Dr. Cohen is Assistant Clinical Professor, Department of
Dermatology, University of Colorado, Englewood, CO.
Aesthetic Surgery Journal
matic denaturation.6 The 150-kDa toxin is composed of a
100-kDa heavy chain and a 50-kDa light chain. Disulfide
and noncovalent bonds link the heavy and light chains,
and both chains are required for neurotoxicity.3
The process of chemical denervation requires that the
neurotoxin-heavy chain binds a specific receptor on the
presynaptic nerve terminal, which leads to toxin–receptor complex endocytosis and then toxin-light chain
release through vesicle lysis.7 While binding sites for
each toxin have not been clearly defined, all toxins
cause chemical denervation by suppressing the release
of acetylcholine from the axon terminals of peripheral
nerves (Table 1). After vesicle lysis occurs within the
axon terminus, toxin-light chains ultimately prevent neurotransmission by cleaving specific protein isoforms necessary for the docking, fusion, and release of
acetylcholine from this nerve terminus. Toxins A, C, and
E cleave synaptosomal associated protein (SNAP-25),
and toxins B, D, F, and G cleave vesicle associated membrane protein (VAMP, also known as synaptobrevin).3
Muscle paralysis occurs within approximately 3 to 7
days, and synaptic regeneration reverses its paralytic
effect within 3 to 6 months.7
During World War II, the United States created laboratories focused on purifying BTX for use in biological
weapons, including the National Academy of Sciences
laboratory at Fort Detrick, Maryland. President Richard
Nixon terminated all research related to biological
weaponry in 1972 by signing the Biological and Toxin
Weapons Convention, but purification practices with BTX
for medical use continued in the laboratories of scientists
like Edward Schantz at the University of Wisconsin.4
Botulinum Toxin Type A
BTX-A (originally called “Oculinum”) was first used in
humans in 1968 by Alan Scott in San Francisco to treat
strabismus. By 1989, clinical data from thousands of
Volume 28 • Number 3 • May/June 2008 • 325
Table 1. Botulinum toxins
Toxins
Target
Cosmetic indications approved by the FDA
Botulinum toxin type A
Botoxa
Dysportb
Xeominc
Prosigned
PurToxe
Synaptosomal associated protein (SNAP-25)
Glabellar rhytides and axillary hyperhidrosis (Botox)
Vesicle-associated membrane protein
(VAMP; synaptobrevin)
Not approved for cosmetic use in United States
Botulinum toxin type B
Myoblocf
FDA, U.S. Food and Drug Administration.
aAllergan, Inc, Irvine, CA.
bIpsen Ltd, Slough, UK. (This product will be marketed as Reloxin [Medicis, Scottsdale, AZ] in the United States.)
cMerz Pharmaceuticals GmBH, Frankfurt am Main, Germany.
dLanzhou Biological Products Institute, Lanzhou, China.
eMentor Corp, Santa Barbara, CA.
fSolstice Pharmaceuticals, South San Francisco, CA. (This product is marketed in Europe as Neurobloc.)
patients showed efficacy without evidence of systemic
adverse effects, which led to FDA approval for the treatment of strabismus as well as blepharospasm.4,8 In 1991,
Allergan Inc purchased several batches of this purified
BTX-A, and the agent was given the name Botox.4
The complex size of Botox is approximately 900 kDa,
and one vial contains 5 ng (100 units) of toxin, with one
unit (U) equal to the median amount necessary to kill
50% of female Swiss-Webster mice after intraperitoneal
injection (LD50).4,7,9 Botox is a vacuum-dried product,
and in addition to 100 U of toxin, each vial contains 500
μg of albumin and 900 μg of sodium chloride.9 The
Botox 150-kDa toxin is activated (enzymatically cleaved)
by the bacterial strain that produces it before collection
and purification, and the complex also includes both
non-toxin hemagglutinin and non-toxin nonhemagglutinin proteins.6
In the United States, Botox is currently the only available BTX product approved for cosmetic use. Botox is
specifically approved by the FDA for the therapeutic
treatment of strabismus, blepharospasm, cervical dystonia, and axillary hyperhidrosis. For cosmetic use, it has
FDA approval only for the cosmetic treatment of glabellar rhytides. But Botox has been shown to be very effective in treating many regions of facial wrinkles as well as
various locations of hyperhidrosis.10 In addition, there
have been reports of Botox specifically improving patient
self-perception.11–18 Typical cosmetic and therapeutic
doses range from 30 to 300 units, depending on the
number of areas treated in one session.
Botox is an agent with a large margin of safety (LD50
in humans approximately 3000 U),4 and a recent study
compared the adverse events reported to the FDA in
patients treated with therapeutic and cosmetic Botox
procedures since the licensure of Botox (13.5 years).8 Of
the 1437 Botox-associated events reported to the FDA,
there were 253 FDA-defined “serious” events (217 in
therapeutic group vs. 36 in cosmetic group) and 1184
326 • Volume 28 • Number 3 • May/June 2008
“nonserious” events (189 in therapeutic group vs. 995 in
cosmetic group). There were 28 deaths among the 1437
events reviewed, all of which occurred in patients treated for therapeutic reasons.8 Significant comorbidities
existed in most (26 of 28) patients that died, and no link
between Botox and the deaths was established. Most
“nonserious” adverse events reported in patients treated
for cosmetic reasons were previously described in published studies and included lack of effect (63%), injection site reaction (19%), and eyelid ptosis (11%). It
should be noted that adverse events described in this
study were reported on a voluntary basis (therefore, all
adverse events may not have been captured) and comparison of the total numbers of injections that took place
in therapeutic and cosmetic groups is not possible.
Once a vial of Botox is reconstituted, the package
insert indicates viability for 4 hours (refrigerated), but
recent studies suggest that this product is viable for
much longer when properly handled. A double-blind randomized study of 30 patients showed no significant difference in the treatment of canthal lines among those
treated with Botox reconstituted with sterile, nonpreserved saline immediately before injection compared
with toxin reconstituted 1 week before injection.19
Further, product reconstitution at times ranging from 1 to
6 weeks before injection produced statistically similar
results in patients treated for glabellar rhytides compared
with product reconstitution 1 day before injection.20
Contraindications to BTX-A are few and include Eaton
Lambert syndrome, amyotrophic lateral sclerosis, myasthenia gravis, hypersensitivity to BTX or one of its ingredients, and pregnancy.3
Dysport (Ipsen Limited) is also a BTX-A product, and
is currently marketed and sold in more than 60 countries
worldwide (not including the United States) and is
approved for cosmetic use in some European countries
as well as Russia, New Zealand, Mexico, Brazil,
Argentina, and Vietnam.21 The complex size of this
Aesthetic Surgery Journal
product is approximately 500 kDa, and one vial contains
12.5 ng (500 U) of air-dried toxin, 125 μg of albumin,
and 2.5 mg of lactose.9 Like Botox, the Dsyport 150-kDa
toxin is activated (enzymatically cleaved) by the bacterial strain that produces it, and the complex also includes
both non-toxin hemagglutinin and non-toxin nonhemagglutinin proteins.6 Dysport comes from a different type A
strain of bacteria than Botox and therefore dosages are
not equivalent. Because the units are different, direct
comparisons of Botox and Dysport in animal studies
suggest that the equivalence doses are one U Botox to
2.5 to 5 U Dysport, though in humans, this conversion is
largely an estimate.9
In the cosmetic arena, 2 randomized, double-blind,
and placebo-controlled dose-finding safety and efficacy
studies suggested that 50 U of Dysport is the optimal
dose when used for glabellar injection.22,23 Botox (20 U)
and Dysport (50 U) were compared in a randomized,
double-blind comparison study for the treatment of
glabellar lines.12,13 Both agents produced similar efficacies at weeks 8 and 12, but Botox offered a significant
treatment prolongation effect at 16 weeks (P = .04);
however, this was a small study of 62 subjects.13 A randomized, double-blind, 20-week smaller trial of 26 subjects comparing Botox (12 U) to Dysport (36 U) for the
treatment of forehead wrinkles found that Dysport had
statistically significantly longer lasting effects as measured by electromyogram at weeks 10 through 20.24
For hyperhidrosis, a double-blind, randomized comparative study of only 8 patients found Dysport to have
similar efficacy to Botox in the treatment of primary palmar hyperhidrosis at a Botox to Dysport ratio of 1:4.25 A
similar study found comparable efficacies between Botox
and Dysport (ratio 1:3) in treating axillary hyperhidrosis,
with mean sweat rates being reduced by more than 95%
for both groups.26 A recently published pilot study comparing diffusion characteristics between Botox and
Dysport reported an increased area of diffusion for
Dysport when injected into patients with forehead
hyperhidrosis at identical injection volumes to Botox.27
One of the conclusions of this particular study was that
diffusion characteristics of specific products should be
considered carefully, especially when the precise localization of treatment effect is important and undesired
migration of toxin could have unwanted effects.
Medicis (Scottsdale, AZ) has purchased the rights from
Ipsen to distribute Dysport in the United States under the
name Reloxin and has recently submitted data and filed
for approval with the FDA.28 Submitted data include 3250
patients treated at 83 sites, and the product could be
available for use in the United States in late 2008.29
One concern regarding the long-term use of BTX is the
risk of immunogenicity. Neutralizing antibodies to BTX-A
toxins that can lead to loss of treatment effect have been
reported in the neurologic literature, usually associated
with toxins used at high doses (currently at higher risk
for doses ⱖ400 U of Botox).9,30,31 Botox underwent a formulation change in 1997 that decreased the complexing
New Neurotoxins on the Horizon
protein load from 25 ng/100 U to 5 ng/100 U; this change
was associated with a marked decrease in neutralizing
antibody formation.30 Data reporting antibody formation
should be reviewed with the formulation change in mind
(as being before or after the 1997 formulation change)
and it should be noted that high single doses and short
intertreatment intervals are associated with increased
neutralizing antibody formation.32
Neutralizing antibodies associated with BTX-A in typical cosmetic doses is mostly anecdotal and considered
very rare but, nonetheless, has been reported and should
be suspected in patients who fail to respond to previously effective doses.32 Interestingly, serologic analysis of
patients enrolled in 3 trials published after the 1997 formulation change (treatment range, 12 to 42 wks) for the
treatment of post-stroke spasticity found neutralizing
antibodies in only 1 of 191 patients.30 In this study, the
mean dose of BTX-A was 241 U (range, 100 to 400 U)
and the median number of treatments was 2 (range, 1 to
4). With respect to Dysport, a retrospective study of 4103
injection cycles in 945 individuals treated with this other
BTX-A product over a 6-year period failed to find evidence of tolerance to Dysport.33
Xeomin (NT-201; Merz Pharmaceuticals GmBH,
Frankfurt am Main, Germany), packaged as a freezedried powder, is a purified BTX-A which is free of the
accessory complexing proteins (hemagglutinin and nonhemagglutinin) found in the other BTX-A products.34
The lower protein load of this purified agent is purported
to be less immunogenic than other BTX-A products.35
Animal studies support this notion, but reliable human
immunogenicity data are not yet available.35
Two phase III noninferiority studies, including more
than 700 patients, compared Xeomin with Botox for the
treatment of blepharospasm36 and cervical dystonia.37
Similar efficacy and safety profiles were observed for
Xeomin and Botox in the treatment of blepharospasm at
3 weeks and cervical dystonia at 16 weeks. In addition,
diffusion of Xeomin into adjacent muscle groups was not
observed.36 Median doses used in each treatment session were similar for both toxins in the cervical dystonia
study (120 U of Xeomin vs 122.5 U of Botox), suggesting
similar toxin potencies.37 A recent randomized doubleblind study (N = 32) compared Xeomin with Botox at a
1:1 dose ratio by measuring action potentials before and
after toxin injection was performed in the extensor digitorum brevis muscle.34 Both agents were well tolerated,
had similar dose-dependent paralytic effects, and had
minimal diffusion effects on surrounding musculature.
The protein profile of Xeomin may prove to be useful in
decreasing the risk of immunogenicity, especially in
patients with neurologic problems who require large
amounts of toxin for extended periods of time.
Prosigne (Lanzhou Biological Products Institute,
Lanzhou, China) is a Chinese type A toxin that has been
available for clinical use (not in the United States) since
October 1993 after its approval by the Ministry of Health
in China.38 Reliable data are lacking to properly assess
Volume 28 • Number 3 • May/June 2008 • 327
efficacy, but some preliminary studies suggest that
Prosigne may have therapeutic actions comparable with
Botox for the treatment of conditions such as focal dystonia, hemifacial spasm, and blepharospasm.38,39 Trials
specifically examining the use of Prosigne in the cosmetic arena are lacking at this point.
PurTox (Mentor Corp, Santa Barbara, CA) is a purified
type A toxin that began phase IIIa study in June 2007 for
the treatment of glabellar rhytides. The company is also
involved in phase I study of PurTox for the treatment of
pain associated with adult onset cervical dystonia.
The lower pH (5.6) of Myobloc is thought to cause
the increased amount of pain associated with injection
when compared with the more physiologically buffered
type A agents (pH 6 to 7.3).5,9,40 Despite the pain, shorter action, and seemingly less predictable diffusion pattern, BTX-B could potentially be useful in situations in
which rapid onset is desirable (such as asymmetry or an
imminent event) or situations in which there are concerns about antibody production to BTX-A toxins.
Botulinum Toxin Type B
Because intradermal BTX injection has been so successful in treating focal hyperhidrosis of the palms, soles,
and axillae, as well as facial areas, investigators have
considered the potential for a topical formulation. As
with other injectable medications and devices, there has
been a long controversy debating whether topical formulations could achieve the appropriate penetration and
necessary concentration to deliver an effective product.
Topical application of BTX-A was tested against vehicle
in a randomized study of 12 patients with primary axillary hyperhidrosis.48 Patients included had baseline
sweat productions of 50 mg or more over a 5-minute
time span (as determined by gravimetric analysis), and
patients served as their own controls. Exclusion criteria
included any patients that had received BTX treatment
within 6 months of trial initiation and/or more than
25% asymmetrical sweating between axillae. BTX-A
(dissolved in 1.5 mL of sterile, preservative-free saline
and complexed with a proprietary delivery peptide
reported to successfully transport insulin and other
macromolecules across intact skin), was applied to one
axilla and allowed to stay on the skin for 60 minutes,
and vehicle was applied to the other for comparison.
Primary efficacy was sweat production and baseline and
follow-up sweat production was determined by gravimetric analysis using 90-mm filter paper (Whatman,
Middlesex, UK). Ten patients (2 were excluded from the
analysis because of >25% asymmetrical sweating) were
assessed at 4 weeks. Results were also substantiated
qualitatively with Minor’s iodine starch testing. The
ratios (baseline to follow-up) of mean sweat production
were 0.35 ± 0.22 for topical BTX-A–treated axillae and
0.75 ± 0.66 for vehicle-treated axillae. These results
were statistically significant (P < .05). Interestingly,
decreased sweating was observed in the vehicle-treated
side, and this finding has been observed in other
patients treated for axillary hyperhidrosis with injected
BTX-A.49 The reason decreased sweat production occurs
in non-treated axillae is unknown, but proposed mechanisms include systemic absorption of BTX-A and downregulation of the autonomic nervous system.
Concern surrounding the potential for type A toxin antigenicity/tolerance and the fact that toxin serotypes do
not cross-neutralize has heightened interest in enhancing
neurotoxin variety.9 BTX-B is available in the United
States as Myobloc (Solstice Pharmaceuticals, South San
Francisco, CA) and is marketed as Neurobloc outside of
the United States.9 Myobloc has shown efficacy in clinical trials for the treatment of various movement disorders since 1995 and was approved by the FDA for the
treatment of cervical dystonia and hemifacial spasm in
2001.40 Though Myobloc has not yet received cosmetic
approval in any country, there are reports of Myobloc
efficacy in the treatment of lateral canthal, glabellar, and
forehead rhytides; Myobloc also appears to offer versatility in cosmetic neuroblockade by exhibiting action in
patients resistant to BTX-A products.7,9,40–46
Instead of being packaged as a powder, Myobloc
comes preconstituted in vials containing 25 ng (2500
U)/0.5 cc, 50 ng (5000 U)/1.0 cc, and 100 ng (10,000
U)/2.0 cc of product in solution with 0.05% albumin.
The size of this product complex is 700 kDa, which falls
between that of Dysport (500 kDa) and Botox (900
kDa).9 Serotype B toxins are secreted as both active
(enzymatically cleaved) and inactive (not cleaved) complexes, depending on the specific Clostridial strain that is
used. Myobloc consists of the 150-kDa type B active toxin and both hemagglutinin and non-hemagglutinin proteins.6 Treatment of patients with cervical dystonia with
Botox and Myobloc led to attempts at equivalency doses
used in many cosmetic studies (1 U Botox = approximately 50 to 100 U Myobloc), although the optimal ratio
is not yet established.
Studies comparing the cosmetic efficacies of BTX-A
with BTX-B report interesting findings in several
respects. The rate of onset (usually within 72 hrs) of
Myobloc seems to precede that of Botox by about 1 to 3
days, but seems to have a shorter duration of action and
a greater radius of diffusion compared with type A toxins.5,9,40,41,47 A double-blind randomized comparison
study found the mean duration of Myobloc and Botox to
be 6.4 and 12.7 weeks, respectively, when injected into
lateral canthal rhytides.9 The duration of effect is likely
dose-dependent, and further studies are needed to better
assess treatment duration once optimal dosages are
established.7,42,43
328 • Volume 28 • Number 3 • May/June 2008
FURTHER ON THE HORIZON: TOPICAL
FORMULATION
DISCUSSION
The use of several standardized BTXs under development appear to be safe and effective for various therapeutic and cosmetic applications, and some new agents
Aesthetic Surgery Journal
will likely be available in the United States in coming
years. Ongoing work with these neurotoxins focuses on
identifying potential benefits of each agent, and studies
continue to refine their dosage conversions with current
formulations. The market share associated with the
arrival of new products will likely foster a competitive
atmosphere.
The future of BTX will likely be marked by continued
exploration of its use in various combination therapies
(including fillers, intense pulsed light, laser modalities
and dermabrasion).50,51 It has been shown that attractive
people earn more money, and the aging of today’s population has heightened the focus on a youthful appearance.52 A large emphasis is now placed on minimally
invasive cosmetic procedures, and since 1997 there has
been a 754% increase in nonsurgical procedures and a
4159% increase in the number of Botox cosmetic procedures.53 Neurotoxin injection by experienced physicians
can create a quick, satisfying, youthful facial appearance.
However, the public demand for this procedure and
the profit profile associated with BTX injections have
created a provider boom that has opened avenues for
potential abuse and misuse. Despite a suspended
license, an osteopathic physician in Florida paralyzed
himself and 3 others with bogus BTX.54 He purchased
this unapproved and unlicensed product, a botulinum
neurotoxin that was 10 times as powerful as Botox, from
Toxin Research International in Tucson, Arizona. This
same product was purchased by at least 200 doctors in
the United States and more than 1000 unknowing
patients were injected with it.55 In California, a hairdresser who injected several women with cooking oil
that she claimed was Botox is being tried for one person’s death.56
Even with an approved agent, cosmetic neurotoxin
injections are not a trivial procedure and should not be
administered by those with little anatomic knowledge or
skill in managing complications.57,58 Educating patients
regarding the benefits of using experienced and reputable physicians properly trained in performing aesthetic procedures is of paramount importance. ◗
DISCLOSURES
Dr. Cohen is a consultant for Allergan, Medicis, and Merz. He is a
clinical trial participant for Allergan and Medicis.
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Accepted for publication February 25, 2008.
Reprint requests: Joel L. Cohen, MD, About Skin Dermatology, 499 E
Hampden Ave, Ste 450, Englewood, CO 80113. E-mail:
[email protected].
Copyright © 2008 by The American Society for Aesthetic Plastic Surgery, Inc.
1090-820X/$34.00
doi:10.1016/j.asj.2008.03.006
Aesthetic Surgery Journal