17
Click here to load reader
Click here to load reader
ORIGINAL ARTICLE
The Convergence of Medicine and Neurotoxins: A Focus onBotulinum Toxin Type A and Its Application in AestheticMedicine—A Global, Evidence-Based Botulinum ToxinConsensus Education InitiativePart I: Botulinum Toxin in Clinical and Cosmetic Practice
ALASTAIR CARRUTHERS, MA, BM, BCH, FRCPC, FRCP (LON),* MICHAEL A. C. KANE, MD,+
TIMOTHY C. FLYNN, MD,†‡ PETER HUANG, MD,§ SANG D. KIM, MD,¶ NOWELL SOLISH, MD, FRCP,**
AND GINA KAEUPER, MACC‡‡
BACKGROUND The U.S. Food and Drug Administration has approved four distinct formulations ofbotulinum toxin (BoNT) serotypes A and B (BoNTA and BoNTB) for medical use. These four products areindicated for many medical applications, but the three BoNTA formulations are the most widely usedworldwide and are the only products approved for aesthetic use. The latest approval of a BoNTA with nocomplexing proteins (incobotulinumtoxinA) necessitates a review and discussion of differences betweenavailable formulations and the effect that these differences may have on clinical practice.
OBJECTIVES To review the history, science, safety information, and current and emerging applications ofBoNT in clinical and cosmetic practice and to compare commercially available BoNTA formulations.
METHODS AND MATERIALS Publications, clinical trials, and author experience were used as a basis for anup-to-date review of BoNT and its use in human medicine. The similarities and differences betweenformulations are presented, and diffusion, spread, equivalency ratios, stability, and storage are discussed.
RESULTS Each commercial formulation has unique characteristics that may influence its use in aestheticmedicine. Familiarity with the similarities and differences between products will aid physicians in makingpatient care decisions.
CONCLUSION New formulations, emerging uses, and continued research into the science and uses ofBoNTA will lead to increasingly refined therapeutic approaches and applications. Continued education isimportant for physicians to optimize use of the agent according to the most current evidence and approaches.
This activity is supported by an educational grant from Merz Aesthetics. Alastair Carruthers, Michael Kane,Timothy Flynn, Peter Huang and Nowell Solish are consultants for Merz. Sang Duck Kim is a consultant forAmore Pacific. A. Carruthers and Michael Kane are consultants for Allergan. N. Solish is a consultant forAllergan, Revance, and Medicis.
Botulinum toxin (BoNT) is a fascinating com-
pound. This potent neurotoxin has proven to be
an effective therapeutic tool for a wealth of human
medical applications, and research is continually
generating exciting new possibilities for future use.
Few agents have demonstrated such promise across
diverse areas of medicine; BoNT is a foundational
tool in the treatment of eye disorders, pain, and
*Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada;+Manhattan Eye, Ear, and Throat Institute, New York, New York; †Department of Dermatology, University of NorthCarolina, Chapel Hill, North Carolina; ‡Cary Skin Center, Cary, North Carolina; §Rebecca Cosmetic Institute, Taipei,Taiwan; ¶Bright and Clear Dermatology Clinic, Seoul, Korea; **Department of Dermatology, University of Toronto,Toronto, Ontario, Canada; ‡‡Freelance Writer, Knoxville, Tennessee
© 2013 by the American Society for Dermatologic Surgery, Inc. � Published by Wiley Periodicals, Inc. �ISSN: 1076-0512 � Dermatol Surg 2013;39:493–509 � DOI: 10.1111/dsu.12147
493
neuromuscular disorders, to name a few. In certain
fields, BoNT has completely changed the standard of
care, with perhaps no use garnering more attention
than its applications in aesthetic medicine. From its
first published mention as an aesthetic treatment for
glabellar lines in 19921, the use of commercially
available BoNT type A (BoNTA) has captivated
healthcare professionals and lay people alike. Mul-
tispecialty statistics collected and reported annually
by the American Society for Aesthetic Plastic Surgery
demonstrate BoNTA’s exceptional popularity.
Injection of BoNTA is the most prevalent aesthetic
procedure in the United States; more than
2.6 million BoNTA procedures were reported
in 2011 alone.2
Recent expansion in the BoNT armamentarium
provides an opportunity to explore the use of this
powerful agent with a fresh perspective. Today’s
aesthetic physician now has several BoNT formula-
tions from which to choose, enhancing the possi-
bilities for increasingly refined and personalized
treatment approaches. Effective selection and use of
each specific formulation requires an understanding
of the basic science behind BoNT’s relevance to
human medicine, the clinical similarities and differ-
ences between available formulations, and the
unique qualities and practical characteristics inher-
ent to each. In this section, we present essential
background information about BoNT, review its
efficacy and safety records, and discuss the data and
experience behind available formulations to lay the
foundation for understanding the agent’s optimal
use in aesthetic medicine.
Historical Perspectives: From Toxic to
Therapeutic
Dr. Justinus Kerner hypothesized the existence of
BoNT in the early 1800s when he investigated a
deadly outbreak of food poisoning from improp-
erly prepared blood sausages. His extensive
experiments improved the medical community’s
understanding of the biologic basis for food
poisoning, as well as the neurologic effects and
potential therapeutic applications of the as-yet-
unnamed agent that caused paralysis and death. In
1895, Belgian scientist Emile Pierre van Ermengem
identified the causative bacterium for botulism,
which he named Bacterium botulinum. Its name
was subsequently changed to Clostridium botu-
linum. This discovery opened the doors to broader
research into the bacterium, its toxin, and its
effects on humans.
Dr. Herman Sommer first isolated BoNTA in
purified form at the University of California at San
Francisco. A pivotal point in BoNT research was
the purification of BoNTA in crystalline form in
1946 at Fort Detrick. Dr. Edward Schantz com-
monly receives credit for this accomplishment, but
Dr. Schantz credits Dr. Carl Lammana and col-
leagues with this milestone.3 Purification methods
were improved over the next decade, and
Dr. Schantz produced a batch of BoNTA at Fort
Detrick that was selectively provided to government
and educational researchers to contribute to the
growing understanding of the agent’s characteristics
and mechanism of action. During this same period,
Dr. Vernon Brooks’ discovery that BoNTA blocks
the release of acetylcholine from motor nerve
endings when injected into a hyperactive muscle
(thereby temporarily reducing the target muscle’s
activity) was a critical breakthrough that led to
increased focus on BoNT’s potential applications
in medicine.
In the early 1970s, using BoNTA supplied by Dr.
Schantz, Dr. Alan Scott, an eye surgeon at Smith-
Kettlewell Eye Research Institute in San Francisco,
California, studied the efficacy of chemical dener-
vation of hyperactive muscles as a possible treatment
for strabismus. His initial tests in monkeys were
successful,4 and Dr. Scott and Dr. Schantz began to
collaborate on the development of BoNT as a drug
for medical purposes. Dr. Scott obtained Food and
Drug Administration (FDA) approval for human
testing in the late 1970s, and in 1979, Dr. Schantz
(who had moved his research to the University of
Wisconsin) successfully produced a 150-mg batch of
THE CONVERGENCE OF MEDICINE AND NEUROTOXINS
DERMATOLOGIC SURGERY494
highly purified medical-grade toxin for use in
humans—the famous batch 79–11.
In the early 1980s, Dr. Scott led the first large
multicenter clinical trial of BoNT, involving more
than 7,000 subjects, establishing its safety and
efficacy as a treatment for strabismus. Research into
the agent’s efficacy as a treatment for muscle-related
eye disorders expanded, and in 1989, the FDA
approved BoNT (BoNTA; trade name Oculinum)
for the treatment of strabismus, blepharospasm, and
hemifacial spasm in adults. In 1990, Allergan
acquired Oculinum, marketing the product under a
new trade name: Botox (onabotulinumtoxinA;
BoNTA-ONA).
Dr. Scott’s work dramatically advanced our knowl-
edge of BoNT and coincidentally planted the seed
for its future cosmetic applications. Dr. Jean Car-
ruthers, who worked with Scott on his trials of the
ophthalmologic uses of BoNTA, noted an unex-
pected side effect in a patient with blepharospasm—
diminished wrinkles in the glabellar region. She
discussed her observations with her husband,
Dr. Alastair Carruthers, a dermatologist treating this
area with the earliest fillers, and their subsequent
studies are credited as the first experiments with
BoNTA for purely cosmetic purposes.1 Other
researchers who had been conducting their own
experiments for therapeutic purposes also noticed
unusual but desirable side effects. The Carruthers’
publication of their findings seemed to trigger an
explosion of interest in BoNTA’s cosmetic applica-
tions, prompting additional studies and considerable
off-label use. So much interest was generated, that
the original batch 79–11 finally ran out in 1997.
A new manufacturing process producing consistent
batches of BoNTA-ONA with reduced protein load
has been in use since.
BoNTA received its first aesthetic approval in
2001, when health regulators in Canada
Figure 1. A select history of BoNT for medical use.
CARRUTHERS ET AL
39 :3 PART I I : MARCH 2013 495
approved BoNTA-ONA’s use for treatment of
glabellar lines. U.S. approval for glabellar lines
followed in April 2002. BoNT’s dramatic
progress in reaching this approval seems to have
been only the beginning of the story. Today,
barely 10 years later, BoNT is used globally for a
broad range of therapeutic and aesthetic applica-
tions and is one of the most widely researched
agents in the world (Figure 1).
Much remains to be discovered about BoNT. New
agents with unique characteristics and proprietary
manufacturing and purification processes provide
valuable opportunities for increasingly refined
approaches to patient care in therapeutic and
aesthetic applications alike. We look forward
to continuing to explore the unique benefits of
BoNT.
The Science of BoNT
In preface to a discussion of commercial formula-
tions, an understanding of BoNT’s basic science is
useful for establishing a framework for evaluation of
the similarities and differences between them. BoNT
is a product of Clostridium botulinum, a species of
anaerobic, rod-shaped, spore-forming bacteria. The
various strains of C. botulinum produce at least
seven distinct neurotoxins, denoted as types A
through G. The human nervous system is susceptible
to only five of the seven serotypes; type A appears to
be the most naturally potent serotype to humans.5
All BoNT serotypes demonstrate the same basic
mechanism of action. Upon introduction into the
human system, BoNT travels to the neuromuscular
junction, where it binds to high-affinity presynaptic
receptors, is internalized, and then cleaves a mem-
brane protein responsible for acetylcholine exocy-
tosis. This functionally blocks acetylcholine release,
causing neuromuscular paralysis through chemical
denervation. The intracellular targets vary among
BoNT serotypes; BoNTA cleaves synaptosomal-
associated protein 25, whereas BoNT type B (BoN-
TB) cleaves a vesicle-associated membrane protein,
or synaptobrevin. The effects of BoNT intoxication
are not permanent in nature; similarly, the effects of
BoNT injections in medicine are not permanent,
with facial cosmetic treatment results typically
lasting at least 3 months and in some cases
6 months or longer.6 During that time, normal
muscle innervation and function are restored
through axonal sprouting at a new neuromuscular
junction. Evidence suggests that the original
Figure 2. BoNTA structure.
THE CONVERGENCE OF MEDICINE AND NEUROTOXINS
DERMATOLOGIC SURGERY496
neuromuscular junction is also restored in that
time.7
BoNT occurs naturally as a macromolecular protein
complex (900 kDa) composed of the core neuro-
toxin (150 kDa) noncovalently bound to various
hemagglutinins and a nontoxin nonhemagglutinin
protein (Figure 2). This structure appears to have a
protective function after ingestion, shielding the
neurotoxin from acidic stomach conditions and
thermal and pH stress.8–10 It has also been suggested
that the natural complex acts as a shield for the
antigenic epitopes on the 150-kD heavy chain11 and
facilitates BoNTA transfer across the intestinal
epithelium.12–15 In medicine, the effect and role of
the complex’s size and composition are not clear and
remain controversial. It is an interesting contempo-
rary consideration, because each commercially
available BoNTA formulation is unique. All com-
mercial formulations contain the 150-kDa core
neurotoxin, but the presence and amount of non-
toxin proteins vary, yielding products with molecu-
lar weights ranging from 900 kDa for BoNTA-ONA
to 150 kDa for incobotulinumtoxinA (BoNTA-
INCO), which is composed only of the core neuro-
toxin protein. AbobotulinumtoxinA (BoNTA-ABO)
falls somewhere in between; its estimated complex
size is a variable 500 to 900 kDa, reflecting the
presence of accessory proteins.16
It has been proposed that complexing proteins
enhance toxin activity, stabilize and protect the
neurotoxin, and limit diffusion, but recent research
has provided some insight into whether accessory
proteins really aid in clinical effectiveness and safety.
It has long been established that the neurotoxin must
be freed from its complex before it can act; there-
fore, all BoNTA formulations must dissociate. Fri-
day and colleagues evaluated the stability of three
commercial toxin preparations (BoNTA: Botox,
Dysport; BoNTB: Myobloc) under physiologic pH
and temperature conditions.17 They found that, in
all three formulations, the neurotoxin was released
from its complex as soon as the preparations were
exposed to physiologic conditions. Perhaps most
interesting is that all formulations showed paralytic
activity at zero incubation time. Eisele and col-
leagues found that BoNTA 900- and 500-kDa
neurotoxin complexes dissociated in <1 minute after
being exposed to a pH of 6.9 or greater.18 They also
found that other environmental factors, such as
dilution and changes in salt concentration, affect the
dissociation process. Their experiments revealed that
the dilution, drying, and reconstitution processes
associated with the normal preparation of commer-
cial toxins lead to complete dissociation of the 900-
kDa complex. An alternative view questions the pH
measurements in the Eisele experiments, suggesting
that the pH was much higher than physiologic and
therefore much more likely to induce decomplexing.
There appear to be differences between the toxins,
suggesting that complexing proteins have an effect
of some kind, but when reconstitution volume and
dose are adjusted, it seems possible to produce
similar effects with each of the commercially
available BoNTAs. Further exploration of the influ-
ence of complexing proteins is necessary to establish
their role clearly in clinical effect, but current
knowledge supports the idea that the clinical
effect of complexing proteins, if any, is likely to
be short-lived.
Is there any reason to be cautious about the presence
of complexing proteins? In general, the introduction
of any foreign proteins can activate the human
immune system and cause the formation of neutral-
izing antibodies. Neutralizing antibody formation
has potentially significant implications for therapy
and can diminish therapeutic response. Further
study is warranted to assess whether and to
what degree complexing proteins influence
antibody development and how this correlates to
clinical response.
Overview of Commercially Available BoNT
Formulations
As of 2012, four distinct BoNT formulations are
approved for human medical use in the United
CARRUTHERS ET AL
39 :3 PART I I : MARCH 2013 497
States. BoNTA is available as onabotulinumtoxinA
(BoNTA-ONA; Botox, Botox Cosmetic, Allergan,
Inc., Irvine, CA), abobotulinumtoxinA (BoNTA-
ABO; Dysport, Medicis Aesthetics Inc, Scottsdale,
AZ), and incobotulinumtoxinA (BoNTA-INCO;
Xeomin, Merz Aesthetics, Inc., San Mateo, CA).
BoNTB is available as rimabotulinumtoxinB
(BoNTB; Myobloc, Solstice Neurosciences LLC,
South San Francisco, CA). At present, BoNTA
formulations are the most widely used worldwide
and are the only products with an approved indica-
tion for aesthetic use. Table 1 lists the BoNTA
formulations currently approved worldwide and
their trade names.
Additional botulinum products are poised for
potential entry into the U.S. aesthetic market in the
coming years. PurTox (BoNTA; Mentor Corpora-
tion, Santa Barbara, CA) has completed three phase
III trials for treatment of glabellar lines.19 It may
enter the U.S. market as early as the end of 201220
and, if approved, will be the second BoNTA
formulation available with no complexing proteins.
A novel topically applied BoNTA (RT001; Revance
Therapeutics, Newark, CA) has completed phase II
trials for use in lateral canthal lines21; research has
been promising and indicates that this method of
delivering BoNTA may have clinical benefits.22
Although these future BoNTA products look
interesting, our discussions in this monograph will
focus on the formulations currently approved
for aesthetic indications in the United States:
onabotulinumtoxinA, abobotulinumtoxinA, and
incobotulinumtoxinA.
OnabotulinumtoxinA
BoNTA-ONA has been used for therapeutic and
aesthetic purposes for longer than 2 decades and is
one of the most widely researched medicines in the
world. It has been approved for more than 20
therapeutic indications in approximately 80 coun-
tries. In the United States, BoNTA-ONA is currently
approved for the treatment of strabismus, blepha-
rospasm, cervical dystonia, upper limb spasticity,
chronic migraine, axillary hyperhidrosis, urinary
incontinence, and glabellar lines. Although many
aesthetic physicians are familiar with the clinical
literature regarding this agent’s use in aesthetic
medicine, a brief review of BoNTA-ONA’s aesthetic
clinical program is helpful as preface to a discussion
of more recently released agents.
The U.S. clinical trial program for the use of
BoNTA-ONA in glabellar lines was conducted over
a 12-month period in two phases: a placebo-
controlled phase (Period 1) followed by an open-
label repeat-injection phase (Period 2). Period 1
consisted of two identical randomized, multicenter,
double-blind, placebo-controlled studies,23,24 in
which 405 subjects were randomly assigned to
receive a single fixed-dose treatment of BoNTA-
ONA. Responders were defined as subjects whose
TABLE 1. Botulinum Toxin Type A (BoNTA) Products Worldwide
Country OnabotulinumtoxinA AbobotulinumtoxinA IncobotulinumtoxinA Other BoNTA
United States Botox Cosmetic Dysport Xeomin
Canada Botox Cosmetic Dysport Xeomin
Mexico Botox Cosmetic Dysport Xeomin
United Kingdom Vistabel Azzalure Bocouture
France Vistabel Azzalure Bocouture
Spain Vistabel Azzalure Bocouture
Germany Vistabel Azzalure Bocouture
Italy Vistabel Bocouture
Brazil Dysport Bocouture Prosigne (CBTX-A)
China Esthetox (CBTX-A)
South Korea Botox Cosmetic Xeomin Neuronox/Meditoxin
Russia Lantox
Peru Redux
THE CONVERGENCE OF MEDICINE AND NEUROTOXINS
DERMATOLOGIC SURGERY498
glabellar line severity changed from moderate or
severe at baseline to none or mild at follow-up. At
day 30, approximately 80% of subjects had
responded to treatment (physician’s assessment).25
Adverse events were similar to those of placebo,
with the exception of blepharoptosis (3.2% in the
active group vs 0% in the placebo group in Period
1).25 Patients enrolled in Period 2 were given the
opportunity to receive two additional BoNTA-ONA
treatments at 4-month intervals. In patients enrolled
in both periods, the overall incidence of blepharop-
tosis decreased from 3.0% after the first treatment
(Period 1) to 2.2% after the second (Period 2) and
0.8% after the third (Period 2).25 Dosing did not
change between the treatments, and the lower
incidence of blepharoptosis was possibly due
to improvement in injector technique during the
study period.
Beyond these initial aesthetic clinical trials, BoNTA-
ONA has been the subject of numerous additional
clinical studies and literature reports of uses span-
ning a broad array of therapeutic and aesthetic
applications. It has a well-established presence in
clinical practice, and more recent BoNT formula-
tions are understandably subject to comparisons
with this first-generation neurotoxin.
AbobotulinumtoxinA
BoNTA-ABO has been used worldwide for thera-
peutic purposes since 1991 and is approved for
aesthetic use in more than 45 countries.26 It received
FDA approvals for treatment of cervical dystonia
and glabellar lines in 2009, becoming the second
BoNT formulation approved for aesthetic use in the
United States.
BoNTA-ABO’s U.S. aesthetic clinical trial program
consisted of three randomized, multicenter, pla-
cebo-controlled, double-blind studies27–29 and two
open-label, repeat-dose studies.30–32 Its efficacy was
studied through three treatment protocols: a single
fixed-dose treatment, repeat injections of a fixed
dose, and a single treatment of a variable dose
determined according to patient sex and muscle
assessment. The day 30 response rate to a single
fixed dose was approximately 90% (investigator’s
assessment).27 Subjects were considered responders
when their glabellar line severity grade changed
from moderate or severe (at maximum frown) at
baseline to none or mild at day 30. Day 30
response rate in the variable-dose protocol was
approximately 85% (blinded evaluator), with a
median duration of effect of 109 days.29 Study
results indicated a median time to onset of
3 days.27 Adverse events across the clinical studies
were similar to placebo, with the exception of
blepharoptosis (2% in the active group vs <1%
with placebo).33
IncobotulinumtoxinA
BoNTA-INCO was FDA-approved for the treatment
of cervical dystonia and blepharospasm in 2010,
followed by approval in 2011 for the treatment of
glabellar lines. It is a relative newcomer to the BoNT
armamentarium, first registered in Germany in
2005. Despite its short history, BoNTA-INCO’s
unique characteristics have made it the subject of
extensive research and interest, and its market
growth has been rapid, with more than 261,000
patients treated worldwide. BoNTA-INCO is
approved in more than 20 countries for therapeutic
indications (including cervical dystonia, blepharo-
spasm, and upper limb spasticity) and in 15 coun-
tries for the treatment of glabellar lines. BoNTA-
INCO is expected to become widely available in the
United States in spring 2013.
BoNTA-INCO’S U.S. aesthetic clinical trial program
consisted of two randomized, multicenter, placebo-
controlled studies (GL-1 and GL-2) of identical
design evaluating the safety and efficacy of a 20-U
fixed-dose treatment in the glabella; 547 subjects
with glabellar lines of at least moderate severity at
maximum frown were randomized (2:1) to receive
20 U of BoNTA-INCO administered in five intra-
muscular injections of 4 U each or placebo. Patients
were followed for 120 days and evaluated at days 7,
CARRUTHERS ET AL
39 :3 PART I I : MARCH 2013 499
30, 60, 90, and 120. The primary efficacy endpoint
was day 30 response rate. Efficacy was assessed
according to a 4-point Facial Wrinkle Scale (FWS);
responders were subjects who showed a minimum
2-point improvement from baseline on the FWS, as
assessed by the investigator and the patient. Sixty
percent of 184 subjects in GL-1 and 48% of 182
subjects in GL-2 met the responder criteria.34
Adverse events were similar to those with placebo.
After the placebo-controlled period, 105 eligible
subjects were enrolled in an open-label study eval-
uating the efficacy and safety of repeat treatments;
99% achieved at least a 1-point improvement on the
FWS (investigator assessment) at 4 weeks after
treatment (unpublished observations.) Adverse
events were mild.
Results from an international phase III active-
comparator study demonstrated that 24 U of
BoNTA-INCO was as effective as 24 U of BoNTA-
ONA in the treatment of glabellar frown lines.35
Response rates and patient satisfaction scores were
high in the BoNTA-ONA and BoNTA-INCO
treatment groups; adverse events were similar in
type and incidence in both groups. Comparative
studies of the two formulations in the treatment of
cervical dystonia and blepharospasm also demon-
strated that BoNTA-INCO and BoNTA-ONA were
equally effective.36,37
Similarities and Differences Between BoNTA
Formulations
Understanding the similarities and differences
between available BoNTA products enables more-
educated decisions about their usefulness in practice.
This section reviews current knowledge of the
commonalities and unique qualities of commercially
available BoNTA formulations. An overview of
basic information about the three formulations can
be found in Table 2.
Complex Structure
BoNTA-ONA, BoNTA-ABO, and BoNTA-INCO
are similar in fundamental ways. They are all BoNTA
TABLE 2. Commercially Available Botulinum Toxin Type A (BoNTA) Product Overview
OnabotulinumtoxinA AbobotulinumtoxinA IncobotulinumtoxinA
Brand Name BOTOX, BOTOX Cosmetic,
Vistabel, Vistabex
Dysport, Reloxin,
Azzalure
Xeomin, Bocouture
Manufacturer Allergan, Inc. Ipsen Merz Pharmaceuticals
Serotype & Strain A—Hall Strain A—Ipsen Strain A—Hall Strain
Complex molecular weight, kD 900 ~500–900 150
Unit activity in relation to
onabotulinumtoxinA
1:1 1:2–1:4 1:1
Stabilization Vacuum-dried Lyophilized Lyophilized
Storage before reconstitution Refrigerated (2–8°C) Refrigerated (2–8°C) Three storage options:
Room temperature
(20–25°C)Refrigerated (2–8°C)
Frozen (�20 to �10°C)
Shelf life before reconstitution 36 months Not specified 36 months
After reconstitution Store refrigerated for
up to 24 hours
Store refrigerated for
up to 4 hours
Store refrigerated for
up to 24 hours
Packaging (U/vial) 100 or 50 300 100 or 50
THE CONVERGENCE OF MEDICINE AND NEUROTOXINS
DERMATOLOGIC SURGERY500
and have the same basic mechanism of action. The
proprietary manufacturing process for each product
yields a unique formulation with intrinsic differ-
ences. Each formulation’s most basic difference is in
complex size and structure. BoNTA-ONA and
BoNTA-ABO are formulated as complexes, differing
from one another in size and composition. BoNTA-
INCO is unique in that it is the first BoNTA
formulated with no complexing proteins.
Diffusion and Spread
Much of the interest in the differences in complexes
between formulations is rooted in the premise that
the complex affects toxin movement from the site of
injection and thereby has a potential clinical effect.
This movement has been referred to as diffusion or
spread, and the availability of multiple BoNTA
products has created much discussion regarding these
terms and how different formulations compare.
To put it simply, all toxins diffuse upon injection,
because diffusion is a natural process to attain
equilibrium. Although a prevailing premise has been
that smaller complexes allow greater diffusion,
several studies have found no difference in diffusion
rate between formulations.38,39 During diffusion,
the toxin complex (if present) dissociates, and the
neurotoxin proteins begin to bind.
Spread is a clinical consideration distinct from
diffusion. Spread refers to the physical movement of
the injected product due in part to controllable
factors such as injection technique, choice of dilu-
tion volume, and needle length and gauge. Some
research has found that there are potential differ-
ences in the spread of various formulations,
regardless of controllable factors. A study of the
three commercially available formulations deter-
mined that BoNTA-ONA and BoNTA-INCO have
comparable spread (as determined by anhidrotic
halos) and that BoNTA-ABO has a greater spread.40
Other studies that compared the spread of BoNTA-
ABO and BoNTA-ONA have yielded varying
results, with some finding comparable spread
between the products41,42 and others finding that
BoNTA-ABO has greater spread than BoNTA-
ONA.43 Further research is necessary to clarify the
differences between study results and the nuances of
how formulations may differ in terms of spread.
Unit Potency
When it comes to comparing the different BoNTA
formulations, perhaps the most common practical
question has to do with units and dosages. Because
BoNT use in medicine originated with BoNTA-
ONA, the unit equivalencies of new formulations
are established in the context of BoNTA-ONA
potency, but simple conversions from one product to
the next are not evident with every formulation.
Because BoNTA formulations are unique products,
the injector must be clear on the appropriate dose
for the formulation being used.
Although regulatory agencies emphasize that the
units of different toxin preparations are not inter-
changeable because of proprietary manufacturing
processes and median lethal dose assays, evidence
from the literature clearly suggests that BoNTA-
ONA and BoNTA-INCO have a clinical equivalency
ratio of 1:1; that is, 1 U of BoNTA-INCO is
equivalent to 1 U of BoNTA-ONA. This equivalence
is convenient for injectors who are widely experi-
enced and comfortable with the use of BoNTA-
ONA in that it allows interchangeability of the two
formulations with less concern about inadvertent
overdosing.
Some research has called into question whether
BoNTA-INCO’s potency is truly equivalent to that
of BoNTA-ONA. A study by Moers-Carpi
compared results obtained from 30 U of BoNTA-
INCO with those from 20 U of BoNTA-ONA in the
glabellar region and found comparable clinical
results between the two treatments,44 but method-
ologic questions undermine the significance of this
finding. In an earlier study, Carruthers and Carru-
thers tested BoNTA-ONA in the glabella and were
unable to distinguish the results obtained from
CARRUTHERS ET AL
39 :3 PART I I : MARCH 2013 501
administration of 20, 30, and 40 U.45 This suggests
that the failure of the Moers-Carpi study to distin-
guish 20 U of BoNTA-ONA from 30 U of BoNTA-
INCO may not be due to a true difference between
the formulations’ potencies but rather to lack of
sensitivity of the method. Substantial other research
supports clinical equivalence at a 1:1 ratio between
these two formulations.35–37
BoNTA-ABO’s unit potency is difficult to compare
with those of other available formulations. The
equivalency ratio of BoNTA-ONA to BoNTA-ABO
is approximately 1:2 to 1:4,39,46,47 with expert
consensus publications recommending that injectors
unfamiliar with BoNTA-ABO apply a ratio of 1:2.5
to 1:3.48,49 The same ratio should be applied when
attempting conversions between BoNTA-INCO and
BoNTA-ABO. Regardless of formulation, optimal
outcomes depend on the injector’s understanding of
the product being used and the application of
professional judgment to the development of a
treatment plan that considers a range of product and
patient factors.
Stability and Storage
A significant differentiating factor for BoNTA-INCO
is its liberal storage requirement. Unopened vials
may be stored for 36 months at room temperature,
refrigerated, or frozen.34 Study of the formulation
has demonstrated its stability for up to 4 years at
room temperature and up to 6 months at 60°C.50
Unopened vials of BoNTA-ONA require refrigera-
tion but may be stored for up to 36 months.51
Similarly, unopened vials of BoNTA-ABO require
refrigeration; the manufacturer does not specify how
long the vial may be kept before use.33
All formulations require refrigeration after recon-
stitution.33,34,51 Manufacturer instructions state that
BoNTA-ONA and BoNTA-INCO are to be used
within 24 hours of reconstitution; BoNTA-ABO’s
manufacturer specifies 4 hours. In practice, physi-
cian experts report that reconstituted BoNTA may
be stored before use for longer periods with no
evident reduction in potency or increase in adverse
events.48,49,52,53 Studies confirm the clinical efficacy
and safety of BoNTA when used weeks or months
after reconstitution.54–58
Safety of BoNT
BoNT has a remarkable efficacy and safety profile
across many areas of medicine, but its popularity
may cause some healthcare providers and consumers
to forget that it is still a deadly neurotoxin—the
most powerful yet discovered. A discussion of
potential significant safety questions can help to
reestablish an awareness of BoNTA as a potent
therapeutic agent for use by educated physicians
who understand the product and patient factors that
may influence clinical outcomes.
Distant Spread
Distant spread is the unintended extension of BoNT
effect into areas noncontiguous to the injection site.
When considering issue, it is important to differen-
tiate spread from distant spread. Although BoNTA
injections can spread locally into areas adjacent to
the injection site (due primarily to controllable
factors, as discussed above), this rarely leads to
significant clinical concerns. Distant spread is asso-
ciated with higher-dose indications and may cause
life-threatening illness with symptoms consistent
with botulism. Hospitalizations and deaths attrib-
uted to botulism have been reported in ill and small-
for-dates children with cerebral palsy treated with
BoNT for muscle spasms and chronic spasticity, an
indication that typically uses doses as high as 25 U/
kg.59 Hospitalizations requiring ventilation have also
been reported in adults treated with BoNT (BoNTA-
ABO) for involuntary muscle movement and fre-
quent neck spasms, another group that may require
high doses.59 There have been no reports of distant
spread after the aesthetic use of any of the approved
BoNTA agents in normal healthy adults, but it is
important to remember this possibility when treating
patients with hyperhidrosis, for which the dose is
significantly higher than that used cosmetically.
THE CONVERGENCE OF MEDICINE AND NEUROTOXINS
DERMATOLOGIC SURGERY502
The potential safety outcomes of distant spread are
serious—enough so that the FDA took steps to
ensure that healthcare professionals and consumers
were well-aware of the associated risks. In April
2009, the agency announced requirements for
updated safety language in the prescribing instruc-
tions for all commercially available BoNT products,
as well as the requirement that manufacturers of
each formulation develop and implement Risk
Evaluation and Mitigation Strategies (REMS).60
The updated prescribing instructions included the
addition of a boxed warning about the risk of
serious adverse events due to distant spread. The
safety language and REMS are not indication
dependent; they are required for all products and all
indications. The FDA took additional steps to
reduce the risk of dosing errors by issuing unique
generic names for each commercially available
product and emphasizing that BoNT products are
not interchangeable.61
Immunoresistance
The risk of true immunoresistance with aesthetic use
of BoNTA is rare, but it behooves the injector to
understand the evidence behind this to ensure safe
long-term use of BoNTA products and to protect a
patient’s “responder” status. BoNTA immunoresis-
tance reports are largely based on the use of the
original batch of BoNTA-ONA (in use through
1997). The current batch of BoNTA-ONA has a
markedly lower protein load than the original and is
associated with less immunogenicity and a lower
rate of neutralizing antibody formation. Jankovic
and associates compared the incidence of antibody
formation between two groups of patients with
cervical dystonia: 42 treated exclusively with the
original batch of BoNTA-ONA and 119 treated
exclusively with the current batch.62 Four (9.5%)
patients treated with the original batch demon-
strated blocking antibodies, versus none of the
patients treated with the current batch (p < .004).
Naumann and associates conducted a meta-analysis
of antibody formation in five indications.63 The 16
clinical trials included in their analysis were con-
ducted between 1999 and 2007 and thus exclusively
used the current batch of BoNTA-ONA. Subjects
included in the analysis were antibody negative at
baseline. Across all indications, 11 of the 2,240
meta-analysis subjects (0.49%) converted from
antibody negative to antibody positive (through
mouse protection assay) at any follow-up visit, with
four (0.2%) remaining antibody positive at the final
posttreatment visit. Only three of the 11 antibody-
positive patients were clinically unresponsive to
BoNTA-ONA, highlighting the difficulty of corre-
lating antibody status with clinical response.
A few recent case reports describe isolated instances of
secondary nonresponse to BoNTA in the cosmetic
setting. Borodic reported a case in which a patient did
not respond to her fourteenth treatment with BoNT-
ONA (current lot) after 13 successful treatments.64
Neutralizing antibodies were detected, and she subse-
quently responded to treatment with BoNTB.
Similarly, Lee describes the case of a patient who did
not respond to her fifth treatment with BoNTA-ONA
(current lot) for masseteric hypertrophy; again,
neutralizing antibodies were detected.65 Recently,
Dressler reported fournewcasesof antibody formation
in patients who had received BoNTA-ABO (2
patients), BoNTA-ONA (1 patient), or both (1
patient).66 Dressler noted that although three of the
patients had risk factors for the development of
secondary nonresponse (e.g., booster injections,
increased immune system reactivity), one had no
apparent risk factors.
Neutralizing antibodies to BoNTA can be difficult
to detect using traditional assay methods because
of varying levels of specificity and sensitivity,67 as
results obtained during the evaluation of neutral-
izing antibody formation in subjects enrolled in the
BoNTA-ABO U.S. clinical trials for glabellar use
highlight. Five subjects (0.32% of study popula-
tion) tested positive for neutralizing antibodies
according to radioimmunoprecipitation assay; none
tested positive according to the mouse protection
assay.68
CARRUTHERS ET AL
39 :3 PART I I : MARCH 2013 503
Antibody formation was assessed in all U.S. clinical
studies of BoNTA-INCO for therapeutic indications.
Twelve subjects (1.1%) who were antibody negative
at baseline developed neutralizing antibodies during
the course of their respective study.69 None was
BoNT-na€ıve upon study entry, complicating
attempts to characterize the potential of antibody
formation with this formulation. In addition, those
who tested positive during the study had no detect-
able antibodies at the study’s conclusion.
Contraindications
Although BoNTA is safe, there are some contrain-
dications to its use. All commercially available
BoNTA products are contraindicated for use in
patients with a known hypersensitivity to BoNTA or
the components of the commercial formulation, and
in patients with an active infection at the injection
site.33,34,51 Beyond these absolute contraindications,
BoNTA use is cautioned in patients with neuro-
muscular disorders (including diseases of the neu-
romuscular junction) and in those who are receiving
concomitant treatment with agents that interfere
with neuromuscular transmission. Manufacturers
also caution against the possibility of drug interac-
tions with anticholinergic drugs. All FDA-approved
BoNTA products are classified pregnancy category
C, and their use should be avoided in patients who
are known to be pregnant or breastfeeding.
A Final Note on Safety
Serious safety problems associated with the aesthetic
use of BoNTA are rare. Complications and adverse
events after procedures are typically mild, transient,
and often preventable. Effective patient assessment
and pretreatment evaluation coupled with a
precise injection strategy helps ensure safe and
effective outcomes.
Select Current and Emerging Uses of BoNT
BoNT’s therapeutic applications have expanded
rapidly since its first approval in 1989. In this
section, we will briefly review some of its more
common applications, as well as promising
future uses.
Ophthalmology
BoNT has been used routinely in ophthalmology for 2
decades, mainly for the treatment of certain forms of
strabismus and benign essential blepharospasm.
Although surgery remains a cornerstone of strabis-
mus therapy, evidence suggests that BoNT and sur-
gery are comparable in their efficacy and safety.70,71
BoNT is a first-line therapy for blepharospasm
associated with facial dystonia. A 2005 literature
review of studies designed to evaluate the efficacy and
safety of BoNTA for blepharospasm found that this
therapy benefited approximately 90% of patients to
whom it was administered.72 A 2008 review found
BoNT to be the treatment of choice for blepharo-
spasm and hemifacial spasm.73
Dystonia
BoNT is considered one of themainstays of treatment
for most focal dystonias. One of the earliest and most
common uses of BoNT in clinical practice was to treat
the symptoms of cervical dystonia. In 1990, Jankovic
and Schwartz found that 71% of 205 patients treated
with injections of BoNTA-ONA for cervical dystonia
noted substantial improvement in neck movement.74
Of the 89 patients who reported pain, 76% reported
that the pain was almost completely relieved. Most
patients improved within 1 week of the injection.74
BoNTA is the first-choice treatment for primary
cranial or cervical dystonia and for other dystonias
such as writer’s cramp.75,76
Aesthetic
Perhaps no use of BoNT has garnered more atten-
tion than its use in aesthetic medicine. What started
as a simple treatment for glabellar lines has grown
into a flexible tool capable of producing dramatic
change in almost every area of the face.48,52,77–80
BoNTA is also extremely effective in combination
with other aesthetic modalities, such as dermal
THE CONVERGENCE OF MEDICINE AND NEUROTOXINS
DERMATOLOGIC SURGERY504
fillers, laser, skin resurfacing, and surgery.6,81–86
Specific aesthetic uses of BoNTA will be discussed in
Part II of this monograph.
Hyperhidrosis
Primary focal hyperhidrosis, particularly for the
axillae, palms, feet, and face, is one of the most
common conditions treated with BoNT. BoNTA has
been shown to safely and effectively reduce focal
sweating without major side effects87 and to mark-
edly improve quality of life.88,89 BoNTA-ONA is
approved for treatment of hyperhidrosis in the
United States.
Headache/Migraine
BoNT has been extensively studied as a possible
therapy for headache and migraine. Efficacy has not
been conclusively demonstrated with BoNT as a
treatment for tension-type headaches, but research
into migraine has yielded promising results. In the
first of two large-scale, phase III double-blind,
placebo-controlled clinical trials (Phase III REsearch
Evaluating Migraine Prophylaxis Therapy (PRE-
EMPT)-1), Aurora and colleagues demonstrated the
efficacy of BoNTA-ONA injections as a prophylactic
treatment in patients with chronic migraines.90
Patients were randomized to receive BoNTA-ONA
(155–195 U) or placebo injections into the head and
neck muscles. Results showed no significant differ-
ence for headache episodes, but there were statisti-
cally significant reductions in multiple headache
symptoms (headache day frequency, severity of
headache, and duration of headache) and improve-
ments in quality of life.90 A second clinical trial
(PREEMPT-2) of identical design also reported
improvements in headache day frequency and other
outcomes.91 BoNTA-ONA is approved in the United
States for prophylactic treatment of headaches in
adults with chronic migraines.
Urology
One of the most promising new indications for
BoNT is for the treatment of overactive bladder,
which affects approximately 16% of men and 17%
of women in the United States.92 Studies suggest that
BoNT injections significantly improve symptoms of
idiopathic overactive bladder by weakening the
activity of the neurogenic detrusor muscle or by
reducing afferent stimulation signals. A multicenter,
randomized, placebo-controlled trial with 275 sub-
jects demonstrated that BoNTA-ONA significantly
reduced urinary incontinence in patients with neu-
rogenic detrusor overactivity due to spinal cord
injury or multiple sclerosis.93 BoNTA-ONA was
recently approved by the FDA for treatment of
urinary incontinence in this population.
BoNT injections are also considered a potentially
effective therapy for benign prostatic hyperplasia
(BPH). In a 2008 literature review, Boy and
colleagues concluded that BoNTA injections into the
prostate improve peak flow rate, postvoid residual
volume, and prostate volume in a majority of
patients.94 Improvement was seen in patients with
varying degrees of BPH, and results lasted up to
12 months. No systemic side effects were reported,
nor did BoNTA affect sexual function.95 Several
large placebo-controlled trials of BoNTA in BPH are
under way.
Conclusion
Despite BoNT’s history and extensive use in medi-
cine for decades, it is our belief that we have only
scratched the surface of its potential. New formu-
lations, emerging uses, and continued research into
the science and uses of BoNTA will usher in
increasingly refined therapeutic approaches, as well
as exciting new applications that are perhaps
currently just a fantasy. Continued education is
important for physicians to optimize use of the agent
according to the most current evidence and
approaches. Part II of this piece, authored by our
colleagues Jean Carruthers, Nathalie Fournier,
Martina Kerscher, Javier Ruiz-Avila, and Ada
Trindade de Almeida, provides valuable insight
into contemporary approaches to aesthetic medicine
with BoNT.
CARRUTHERS ET AL
39 :3 PART I I : MARCH 2013 505
References
1. Carruthers JD, Carruthers JA. Treatment of glabellar frown lines
with C. botulinum-A exotoxin. J Dermatol Surg Oncol.
1992;18:17–21.
2. American Society for Aesthetic Plastic Surgery 2011 Cosmetic
Surgery National Data Bank Statistics. Available from: www.
surgery.org Accessed August 21, 2012.
3. Schantz EJ, Johnson EA. Botulinum toxin: the story of its
development for the treatment of human disease. Perspect Biol
Med 1997;40:317–27.
4. Scott A, Rosenbaum A, Collins C. Pharmacologic weakening of
extraocular muscles. Invest Ophthalmol 1973;12:924–7.
5. Dembek Z, Smith LA, Rusnak JM. Botulinum toxin. In: Dembek
Z, editor. Medical Aspects of Biological Warfare. Washington,
DC: Office of The Surgeon General, US Army Medical
Department Center and School, Borden Institute; 2007.
pp. 337–53.
6. Flynn T. Botulinum toxin: examining duration of effect in facial
aesthetic applications. Am J Clin Dermatol 2010;11:183–99.
7. De Paiva A, Meunier FA, Molgo J, Aoki KR, et al. Functional
repair of motor endplates after botulinum neurotoxin type A
poisoning: biphasic switch of synaptic activity between nerve
sprouts and their parent terminals. Proc Natl Acad Sci USA
1999;96:3200–5.
8. Chen F, Kuziemko G, Stevens R. Biophysical characterization of
the stability of the 150-kilodalton botulinum toxin, the nontoxic
component, and the 900-kilodalton botulinum toxin complex
species. Infect Immun 1998;66:2420–5.
9. Ohishi I, Sugii S, Sakaguchi G. Oral toxicities of Clostridium
botulinum toxins in response. Infect Immun 1977;16:107–9.
10. Sugii S, Ohishi I, Sakaguchi G. Intestinal absorption of botulinum
toxins of different molecular sizes in rats. Infect Immun
1977;17:491–6.
11. Chen F, Kuziemko GM, Amersdorfer P, Wong C, et al. Antibody
mapping to domains of botulinum neurotoxin serotype A in
the complexed and uncomplexed forms. Infect Immun
1997;65:1626–30.
12. Fujinaga Y. Interaction of botulinum toxin with the epithelial
barrier. J Biomed Biotechnol. 2010;2010:974943.
13. Inoue K, Sobhany M, Transue TR, Oguma K, et al. Structural
analysis by X-ray crystallography and calorimetry of a
haemagglutinin component (HA1) of the progenitor toxin from
Clostridium botulinum. Microbiology 2003;149:3361–70.
14. Jin Y, Takegahara Y, Sugawara Y, Matsumura T, et al.
Disruption of the epithelial barrier by botulinum haemagglutinin
(HA) proteins—differences in cell tropism and the mechanism of
action between HA proteins of types A or B, and HA proteins of
type C. Microbiology 2009;155:35–45.
15. Matsumura T, Jin Y, Kabumoto Y, Takegahara Y, et al. The HA
proteins of botulinum toxin disrupt intestinal epithelial
intercellular junctions to increase toxin absorption. Cell
Microbiol 2008;10:355–64.
16. Wenzel R, Jones D, Borrego JA. Comparing two botulinum toxin
type A formulations using manufacturers’ product summaries.
J Clin Pharm Ther 2007;32:387–402.
17. Friday D, Bigalke H, Fevert J. In vitro stability of botulinum
toxin complex preparations at physiological pH and temperature.
Naunyn-Schmeideberg Arch Pharmacol. 2002;365:R20,
Abstract 46.
18. Eisele KH, Fink K, Vey M, Taylor HV. Studies on the dissociation
of botulinum neurotoxin type A complexes. Toxicon
2011;57:555–65.
19. PurTox clinical trials page. National Institutes of Health clinical
trials website. http://clinicaltrials.gov/ct2/results?term=purtox
Accessed from: March 3, 2012.
20. Johnson & Johnson Selected Pharmaceutical in Late Stage US and
EU Development or Registration as of October 18, 2011.
Available from: http://files.shareholder.com/downloads/JNJ/
1466301044x0x509225/71182786-ff9c-4186-b754–9a7e9dbe301a/Q32011pipeline.pdf Accessed November 28,
2011.
21. Revance Therapeutics product pipeline. Available from: http://
www.revance.com/products.html Accessed November 28, 2011.
22. Brandt F, O’Connell C, Cazzaniga A, Waugh JM. Efficacy and
safety evaluation of a novel botulinum toxin topical gel for the
treatment of moderate to severe lateral canthal lines. Dermatol
Surg 2010;36:2111–8.
23. Carruthers JA, Lowe NJ, Menter MA, Gibson J, et al. A
multicenter, double-blind, randomized, placebo-controlled study
of the efficacy and safety of botulinum toxin type A in the
treatment of glabellar lines. J Am Acad Dermatol 2002;46:840–9.
24. Carruthers JD, Lowe NJ, Menter MA, Gibson J, et al. Double-
blind, placebo-controlled study of the safety and efficacy of
botulinum toxin type A for patients with glabellar lines. Plast
Reconstr Surg 2003;112:1089–98.
25. Carruthers A, Carruthers J, Lowe NJ, Menter A, et al. One-year,
randomized, multicenter, two-period study of the safety and
efficacy of repeated treatments with botulinum toxin type A in
patients with glabellar lines. J Clin Res 2004;7:1–20.
26. Dysport product information page. Dysport USA website.
Available from: http://www.dysportusa.com/hcp/ Accessed
March 7, 2012.
27. Brandt F, Swanson N, Baumann L, Huber B. Randomized,
placebo-controlled study of a new botulinum toxin type a for
treatment of glabellar lines: efficacy and safety. Dermatol Surg
2009;35:1893–901.
28. Rubin M, Dover J, Glogau R, Goldberg D, et al. The efficacy and
safety of a new US botulinum toxin type A in the retreatment of
glabellar lines following open-label treatment. J Drugs Dermatol
2009;8:439–44.
29. Kane MA, Brandt F, Rohrich RJ, Narins R, et al. Evaluation of
variable-dose treatment with a new US botulinum toxin type a
(Dysport) for correction of moderate to severe glabellar lines:
results from a phase III, randomized, double-blind, placebo-
controlled study. Plast Reconstr Surg 2009;124:1619–29.
30. Cohen JL, Schlessinger J, Cox SE, Lin X, Reloxin Investigational
Group. An analysis of the long-term safety data of repeat
administrations of botulinum neurotoxin type A-ABO for the
treatment of glabellar lines. Aesthet Surg J 2009;29:S43–9.
31. Monheit G, Cohen J. Long-term safety of repeated administration
of a new formulation of botulinum toxin type A in the treatment
THE CONVERGENCE OF MEDICINE AND NEUROTOXINS
DERMATOLOGIC SURGERY506
of glabellar lines: interim analysis from an open-label extension
study. J Am Acad Dermatol 2009;61:421–5.
32. Moy R, Maas C, Monheit G, Huber MB. Long-term safety and
efficacy of a new botulinum toxin type A in treating glabellar
lines. Arch Facial Plast Surg 2009;11:77–83.
33. Medicis Aesthetics Inc. DYSPORT [package insert]. Scottsdale,
Ariz: Medicis Aesthetics Inc; 2010.
34. Merz Aesthetics Inc. Xeomin [package insert]. San Mateo, Calif:
Merz Aesthetics Inc; 2010.
35. Sattler G, Callander MJ, Grablowitz D, Walker T, et al.
Noninferiority of incobotulinumtoxinA, free from complexing
proteins, compared with another botulinum toxin type A in
the treatment of glabellar frown lines. Dermatol Surg
2010;36:2146–54.
36. Roggenkamper P, Jost WH, Bihari K, Comes G, et al. Efficacy
and safety of a new botulinum toxin type A free of complexing
proteins in the treatment of blepharospasm. J Neural Transm
2006;113:303–12.
37. Benecke R, Jost WH, Kanovsky P, Ruzicka E, et al. A new
botulinum toxin type A free of complexing proteins for treatment
of cervical dystonia. Neurology 2005;64:1949–51.
38. Tang-Liu DD, Aoki KR, Dolly JO, de Paiva A, et al.
Intramuscular injection of 125I-botulinum neurotoxin complex
versus 125I-botulinum-free neurotoxin: time course of tissue
distribution. Toxicon 2003;42:461–9.
39. Carli L. Assay of diffusion of different botulinum neurotoxin type
A formulations injected in the mouse leg. Muscle Nerve
2009;40:374–80.
40. Kerscher M, Roll S, Becker A, Wigger-Alberti W. Comparison of
the spread of three botulinum toxin type A preparations. Arch
Dermatol Res 2012;304(2):155.61.
41. Nestor MS, Ablon GR. Comparing the clinical attributes of
abobotulinumtoxinA and onabotulinumtoxinA utilizing a
novel contralateral frontalis model and the frontalis
activity measurement standard. J Drugs Dermatol 2011;10:
1148–57.
42. Hexsel D, Dal’Forno T, Hexsel C, Do Prado DZ, et al. A
randomized pilot study comparing the action halos of two
commercial preparations of botulinum toxin type A. Dermatol
Surg 2008;34:52–9.
43. De Almeida AR, Marques E, de Almeida J, Cunha T, et al. Pilot
study comparing the diffusion of two formulations of botulinum
toxin type A in patients with forehead hyperhidrosis. Dermatol
Surg 2007;33:S37–43.
44. Moers-Carpi M, Tan K, Fulford-Smith A. A multicentre,
randomized, double-blind study to evaluate the efficacy of
onabotulinumtoxinA (20 units) in the treatment of
glabellar lines, when compared to incobotulinumtoxinA (30
units). Poster presented at: 7th European Masters in Anti-
aging Medicine (EMAA); September 30-October 1, 2011; Paris,
France.
45. Carruthers A, Carruthers J, Said S. Dose-ranging study of
botulinum toxin type A in the treatment of glabellar rhytids in
females. Dermatol Surg 2005;31:414–22.
46. Karsai S, Raulin C. Current evidence on the unit equivalence of
different botulinum neurotoxin A formulations and
recommendations for clinical practice in dermatology. Dermatol
Surg 2009;35:1–8.
47. Wohlfarth K, Sycha T, Ranoux D, Naver H, et al. Dose
equivalence of two commercial preparations of botulinum
neurotoxin type A: time for a reassessment? Curr Med Res Opin
2009;25:1573–84.
48. KaneM, Donofrio L, Ascher B, Hexsel D, et al. Expanding the use
of neurotoxins in facial aesthetics: a consensus panel’s assessment
and recommendations. J Drugs Dermatol 2010;9:7–22.
49. Hexsel DM, Spencer J, Woolery-Lloyd H, Gilbert E. Practical
applications of a new botulinum toxin. J Drugs Dermatol 2010;9:
s31–7.
50. Grein S, Gerd J, Fink M, Fink K. Stability of botulinum
neurotoxin type A, devoid of complexing proteins. Botulinum J
2011;2:49–57.
51. Allergan, Inc. BOTOX Cosmetic [package insert]. Irvine, Calif:
Allergan, Inc; 2011.
52. Carruthers J, Fagien S, Matarasso SL, Botox Consensus Group.
Consensus recommendations on the use of botulinum toxin A in
facial aesthetics. Plast Reconstr Surg 2004;114:1S–22S.
53. De Almeida AT, Secco LC, Carruthers A. Handling botulinum
toxins: an updated literature review. Dermatol Surg
2011;37:1553–65.
54. Hexsel DM, De Almeida AT, Rutowitsch M, De Castro IA, et al.
Multicenter, double-blind study of the efficacy of injections with
botulinum toxin type A reconstituted up to six consecutive weeks
before application. Dermatol Surg 2003;29:523–9.
55. Hexsel DM, Rutowitsch M, De Castro L, do Prado DZ, et al.
Blind multicenter study of the efficacy and safety of injections of a
commercial preparation of botulinum toxin type A reconstituted
up to 15 days before injection. Dermatol Surg 2009;35:933–40.
56. Hui J, Lee W. Efficacy of fresh versus refrigerated botulinum
toxin in the treatment of lateral periorbital rhytids. Ophthal Plast
Reconstr Surg 2007;23:433–8.
57. Parsa AA, Lye KD, Parsa FD. Reconstituted botulinum type A
neurotoxin: clinical efficacy after long-term freezing before use.
Aesthetic Plast Surg 2007;31:188–91.
58. Yang GC, Chiu RJ, Gillman GS. Questioning the need to use
Botox within 4 hours of reconstitution: a study of fresh vs 2-
week-old Botox. Arch Facial Plast Surg 2008;10:273–9.
59. US Food and Drug Administration. Postmarket Drug
Safety Information for Patients and Providers. Docket No.
FDA-2008-P-0061, April 30, 2009. Available from: http://
www.fda.gov/downloads/Drugs/DrugSafety/
PostmarketDrugSafetyInformationforPatientsandProviders/
DrugSafetyInformationforHeathcareProfessionals/UCM143989.
pdf. Accessed February 8, 2012.
60. US Food and Drug Administration. FDA requires boxed warning
for all botulinum toxin products [news release]. April 30, 2009.
Available from: http://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm149574.htm Accessed April 10, 2010.
61. US Food and Drug Administration. FDA gives update on
botulinum toxin safety warnings; established names of drugs
changed. August 3, 2009. Available from: http://www.fda.gov/
NewsEvents/Newsroom/PressAnnouncements/ucm175013.htm
Accessed March 7, 2012.
CARRUTHERS ET AL
39 :3 PART I I : MARCH 2013 507
62. Jankovic J, Vuong KD, Ahsan J. Comparison of efficacy and
immunogenicity of original versus current botulinum toxin in
cervical dystonia. Neurology 2003;60:1186–8.
63. Naumann M, Carruthers A, Carruthers J, Aurora SK, et al. Meta-
analysis of neutralizing antibody conversion with
onabotulinumtoxinA (BOTOX) across multiple indications. Mov
Disord 2010;25:2211–8.
64. Borodic G. Immunologic resistance after repeated botulinum
toxin type A injections for facial rhytides [Letter to the editor].
Ophthal Plast Reconstr Surg 2006;22(3):239–40.
65. Lee SK. Antibody-induced failure of botulinum toxin type A
therapy in a patient with masseteric hypertrophy. Dermatol Surg
2007;33:S105–10.
66. Dressler D, Wohlfahrt K, Meyer-Rogge E, Wiest L,
et al. Antibody-induced failure of botulinum toxin a
therapy in cosmetic indications. Dermatol Surg 2010;36:
182–7.
67. Hanna PA, Jankovic J, Vincent A. Comparison of mouse
bioassay and immunoprecipitation assay for botulinum
toxin antibodies. J Neurol Neurosurg Psychiatry 1999;66:
612–6.
68. Lawrence I, Moy R. An evaluation of neutralizing antibody
induction during treatment of glabellar lines with a new US
formulation of botulinum neurotoxin type A. Aesthet Surg J
2009;29:S66–71.
69. Xeomin clinical data page. Xeomin website. Available from:
http://www.xeomin.com/physicians/clinical-data/ Accessed
March 5, 2012.
70. Carruthers JD, Kennedy RA, Bagaric D. Botulinum vs
adjustable suture surgery in the treatment of horizontal
misalignment in adult patients lacking fusion. Arch Ophthalmol
1990;109:1432–5.
71. Rowe F, Noonan C. Complications of botulinum toxin A and
their adverse effects. Strabismus 2009;17:139–42.
72. Costa J, Espirito-Santo C, Borges A, Ferreira J, et al. Botulinum
toxin type A therapy for blepharospasm. Cochrane Database Syst
Rev 2005;25:CD004900.
73. Kenney C, Jankovic J. Botulinum toxin in the treatment of
blepharospasm and hemifacial spasm. J Neural Transm
2008;115:585–91.
74. Jankovic J, Schwartz K. Botulinum toxin injections for cervical
dystonia. Neurology 1990;40:277–80.
75. Albanese A, Asmus F, Bhatia KP, Elia AE, et al. EFNS guidelines
on diagnosis and treatment of primary dystonias. Eur J Neurol
2011;18:5–18.
76. Simpson DM, Blitzer A, Brashear A, Comella C, et al.
Therapeutics and Technology Assessment Subcommittee of
the American Academy of Neurology. Assessment:
Botulinum neurotoxin for the treatment of movement
disorders (an evidence-based review): report of the
Therapeutics and Technology Assessment Subcommittee of
the American Academy of Neurology. Neurology 2008;70:
1699–706.
77. Carruthers J, Carruthers A. Botulinum toxin A in the mid
and lower face and neck. Dermatol Clin 2004;22:
151–8.
78. Dayan SH, Maas CS. Botulinum toxins for facial wrinkles:
beyond glabellar lines. Facial Plast Surg Clin North Am
2007;15:41–9.
79. Kane MA. Botox injections for lower facial rejuvenation. Oral
Maxillofac Surg Clin North Am 2005;17:41–9.
80. Mazucco R, Hexsel D. Gummy smile and botulinum toxin: a new
approach based on the gingival exposure area. J Am Acad
Dermatol 2010;63:1042–51.
81. Carruthers A, Carruthers J, Monheit GD, Davis PG, et al.
Multicenter, randomized, parallel-group study of the safety and
effectiveness of onabotulinumtoxinA and hyaluronic acid
dermal fillers (24-mg/mL smooth, cohesive gel) alone and in
combination for lower facial rejuvenation. Dermatol Surg
2010;36:2121–34.
82. Carruthers JDA, Glogau RG, Blitzer A, and Facial Aesthetics
Consensus Group Faculty. Advances in facial rejuvenation:
botulinum toxin type A, hyaluronic acid dermal fillers, and
combination therapies—consensus recommendations. Plast
Reconstr Surg 2008;121:5S–30S.
83. Coleman KR, Carruthers J. Combination therapy with BOTOX
and fillers: the new rejuvenation paradigm. Dermatol Ther
2006;19:177–88.
84. Khoury JG, Saluja R, Goldman MP. The effect of botulinum
toxin type A on full-face intense pulsed light treatment: a
randomized, double-blind, split-face study. Dermatol Surg
2008;34:1062–9.
85. Klein A, Fagien S. Hyaluronic acid fillers and botulinum
toxin type A: rationale for their individual and combined use
for injectable facial rejuvenation. Plast Reconstr Surg
2007;120:81S–8S.
86. Zimbler MS, Holds JB, Kokoska MS, Glaser DA, et al. Effect of
botulinum toxin pretreatment on laser resurfacing results: a
prospective, randomized, blinded trial. Arch Facial Plast Surg
2001;3:165–9.
87. Grunfeld A, Murray CA, Solish N. Botulinum toxin for
hyperhidrosis: a review. Am J Clin Dermatol 2009;10:
87–102.
88. Naumann M, Hamm H, Lowe NJ, On behalf of the Botox
hyperhidrosis clinical study group. Effect of botulinum toxin type
A on quality of life measures in patients with excessive axillary
sweating: a randomized controlled trial. Br J Dermatol
2002;147:1218–26.
89. Solish N, Benohanian A, Kowalski W, On behalf of the Canadian
dermatology study group on health-related quality of life in
primary axillary hyperhidrosis. Prospective open-label study of
botulinum toxin type a in patients with axillary hyperhidrosis:
effects on functional impairment and quality of life. Dermatol
Surg 2005;31:405–13.
90. Aurora SK, Dodick DW, Turkel CC, DeGryse RE, et al.
OnabotulinumtoxinA for treatment of chronic migraine:
results from the double-blind, randomized, placebo-
controlled phase of the PREEMPT 1 trial. Cephalalgia
2010;7:793–803.
91. Diener HC, Dodick DW, Aurora SK, Turkel CC, et al.
OnabotulinumtoxinA for treatment of chronic migraine: results
from the double-blind, randomized placebo-controlled phase of
the PREEMPT 2 trial. Cephalalgia 2010;30:804–14.
THE CONVERGENCE OF MEDICINE AND NEUROTOXINS
DERMATOLOGIC SURGERY508
92. Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, et al.
Prevalence and burden of overactive bladder in the United States.
World J Urol 2003;20:327–36.
93. Cruz F, Herschorn S, Aliotta P, Brin M, et al. Efficacy and safety
of onabotulinumtoxinA in patients with urinary incontinence due
to neurogenic detrusor overactivity: a randomised, double-blind,
placebo-controlled trial. Eur Urol 2011;60:742–50.
94. Boy S. Botulinum toxin in the treatment of benign prostatic
hyperplasia: an overview. Urologe A 2008;47:1465–71.
95. Silva J, Pinto R, Carvalho T, Botelho F, et al. Intraprostatic
botulinum toxin type A administration: evaluation of effects on
sexual function. BJU 2011;107:1950–4.
Address correspondence and reprint requests to: JonKaeuper, Fortis Spectrum, 5150 Palm Valley Road, Suite200, Ponte Vedra Beach, FL 32082, email: [email protected]
CARRUTHERS ET AL
39 :3 PART I I : MARCH 2013 509
