Alternatives to Botox (Botulinum Toxin)
Wednesday, January 12, 2005
In this commentary:
How Botox Works
Treatment With BTX A
Treatment With BTX B
Treatment With Topicals
The use of botulinum toxin (BTX) for cosmetic enhancement was
introduced a little over 12 years ago1, and has rapidly
become one of the most popular cosmetic procedures performed today.
It is a relatively easy technique with an excellent safety profile
that produces an outstanding cosmetic result. BTX itself is a
natural, well-described protein and is thus unpatentable. However,
for a variety of reasons, most notably the secrecy and difficulty
encountered in the manufacturing process, there has been only one
commercial preparation available in the United States. However,
alternative preparations and approaches to producing a "Botox
effect" are now becoming available.
BTX is a protein produced by the anaerobic spore-forming
bacterium Clostridium botulinum. These bacteria are widely
distributed in the environment, principally as spores. Under the
proper conditions, the spores can germinate and produce infection.
Typically, spore-contaminated food is ingested, and then the spores
germinate in the digestive tract and elaborate one of a series of
highly potent neurotoxins (BTX). The toxin itself is rather small
but is complexed noncovalently with a group of additional proteins
that protect the neurotoxin from the acidic environment of the gut.
Once absorbed from the gut, the multiprotein complex dissociates in
response to the higher pH, and free neurotoxin is released. There
are 7 antigenically distinct serotypes of BTX, labeled A-G. One
strain of bacteria produces only 1 serotype.
All cholinergic nerves have receptors for BTX, and thus are
potential targets for BTX therapy. The principal use has been to
temporarily disrupt cholinergic nerve transmission to skeletal
muscle and thus produce a flaccid paralysis. This has been highly
effective in treating conditions characterized by hyperfunctional
muscles. When a cholinergic nerve fires, the action potential is
carried distally toward the neuromuscular junction. Preformed
vesicles containing the neurotransmitter acetylcholine are within
the terminal portion of the neuronal axon. In response to an action
potential, these vesicles dock and fuse with the membrane of the
terminal axon and release their content of acetylcholine into the
synaptic cleft, where it will cause muscle contracture. The
docking, fusing, and release of these acetylcholine vesicles are
orchestrated by a group of proteins known as the SNARE complex. The
BTX binds to specific membrane receptors on the neuronal axon, are
internalized, and then enzymatically inactivate a component of the
SNARE complex. For example, BTX A, the serotype currently in
commercial use, cleaves the protein SNAP-25, thus inactivating the
SNARE complex. BTX B cleaves an entirely different protein,
synaptobrevin, but the end result is the same: the inactivation of
the SNARE complex. With time, new sprouts from the axon
re-establish functional contact with the muscle. However,
ultimately the original motor end plate regains function, and the
sprouts regress. Thus the effects of BTX are temporary.
BTX is a well-described bacterial protein that was first
isolated and purified in the 1920s. It therefore cannot be patented
in the way that a new medication can. However, it is also
considered a potential biologic weapon, and thus the manufacturing
process is somewhat guarded. Furthermore, the manufacturing process
is a difficult one. In the United States, only 1 commercial
preparation of BTX was available for the first decade of use: BTX A
marketed as Botox (Allergan Inc., Irvine, California), approved for
use in 1989 and initially marketed under the name Oculinum. An
alternative preparation of BTX A has been marketed in Europe and
South America since 1991 under the name Dysport (Beaufour Ipsen
Pharmaceuticals, France). Phase III clinical trials are now under
way in the United States, and American physicians may expect to
have a choice of BTX A preparations in the future. In December
2000, a commercial preparation of BTX B (Myobloc in the United
States or Neurobloc in Europe, both from Solstice Neurosciences in
Ireland) was approved for therapy of cervical dystonia and has been
investigated for off-label cosmetic use. Physicians in the United
States now have a choice between BTX A and BTX B, and may soon have
an alternative preparation of BTX A as well. A comparison of these
products is warranted to guide clinical use.
Treatment With BTX
There are more than 10 years' experience in the cosmetic use of
Dysport in both Europe and South America. At this point, it seems
clear that it is safe and effective in cosmetic therapy. The only
FDA-approved cosmetic use of Botox is in the treatment of glabellar
rhytides. In a similar approach, a recent published trial of 119
patients treated with various doses of Dysport in the same
injection pattern used for the Botox FDA trial showed that Dysport
was both safe and effective in the treatment of glabellar
However, it is becoming apparent that there are differences
between Dysport and Botox. Although the toxin itself is the same,
there are differences in the manufacturing process that may produce
differences in clinical results. Dysport and Botox are derived from
different bacterial strains and purified by different chemical
means. As previously mentioned, naturally BTX is noncovalently
associated with nontoxin proteins. These proteins are important in
protecting the toxin during drying, reconstitution, and injection.
It is not clear to what extent the 2 preparations have the same
degree of intact multiprotein complex. Both require reconstitution
with sterile saline, but Botox is vacuum-dried while Dysport is
freeze-dried. One vial of Botox contains 100 units of toxin, 500 g
albumin, and 0.9 mg NaCl, while 1 vial of Dysport contains 500
units of toxin, 125 g albumin, and 2.5 mg lactose.
There is an apparent difference in potency when 1 unit of Botox
is compared to 1 unit of Dysport. How "units" are measured, as well
as additives to the preparations, may explain this discrepancy.
Botulinum toxins are extraordinarily potent, and an entire vial
contains toxin measured in the nanogram range. Although it is
customary to measure medications in units of mass (grams or
milligrams), BTX is measured in units of biologic activity. One
unit of BTX activity is the LD50 (lethal dose 50%) following
intraperitoneal injection of mice. However, the mice used to
measure the 2 preparations are not the same, and thus a discrepancy
is introduced. Furthermore, Botox contains a higher concentration
of albumin. It seems that albumin may block nonspecific binding of
the toxin, and thus Botox, with a higher albumin concentration, may
therefore be more potent. Clinical use has indicated 1 unit of
Botox has the potency of about 3-5 units of Dysport. However, it
does not seem that Dysport is exactly the same as Botox if the dose
is simply multiplied by 3-5 times. In animal studies, although the
therapeutic ratio is 1:3-5, the lethal doses of the 2 preparations
have a ratio of around 1:2. Further studies will better delineate
proper dosing and the duration of the 2 preparations in comparison
to each other.
Treatment With BTX
BTX B (Myobloc) has become available as an alternative to BTX A.
Myobloc comes as an intact multiprotein complex already as a liquid
at pH 5.6. It does not require reconstitution, and is stable for
months to years. It is FDA-approved for the treatment of cervical
dystonia, but preliminary studies have investigated its cosmetic
use. As with BTX A, "units" are defined as the LD50 in standardized
mice, and 1 unit of BTX A should equal 1 unit of BTX B. However,
response to BTX is species-specific, and the response of mice
cannot be used to assess the response of humans. Based on data from
treating cervical dystonia, it appears that 1 unit of Botox has the
potency of 50-100 units of Myobloc. Therefore, Myobloc comes as a
solution of 5000 units/mL in 0.5-mL, 1-mL, or 2-mL vials. Initial
testing for cosmetic use assumed a 1:50 "conversion factor" for
Botox to Myobloc. Myobloc was injected into the glabella and
forehead3 and the lateral canthus4 in the
pattern and with the dosing typically used for Botox, with a 1:50
dosing conversion factor. Both investigators noted a more rapid
onset than with Botox, and perhaps a superior cosmetic effect.
However, the effect wore off in about half the duration of action
of Botox - that is, in about 8 weeks. It is not clear if BTX B
simply has a shorter duration of action, or if the 1:50 conversion
is inaccurate and the patients were underdosed.
Spencer and colleagues tested escalating doses of Myobloc
(conversion ratios of 1:75, 1:100, and 1:125) and found the highest
dose did have a longer duration of action.5 However,
even the longer duration was not as long as with Botox (12 weeks vs
16 weeks). Perhaps higher doses will last even longer. However,
Myobloc is a liquid at a fixed concentration: As the dose
escalates, the volume injected increases and diffusion may become
an issue. Reformulating the product to a more concentrated liquid
would require additional FDA testing.
Perhaps owing to the success of BTX, some over-the-counter
cosmeceuticals are advertising themselves as alternatives to Botox.
Pentapeptides are protein fragments 5 amino acids long that are
thought to perhaps stimulate collagen synthesis. One such
preparation of a pentapeptide (StriVectin-SD) has been advertising
at cosmetic counters that it is "better than Botox." If this
product works at all, it does not do so by muscle paralysis and
thus in no way is a topical BTX. There is, however, a hexapeptide
(6-amino-acid chain), Argeriline, that has been promoted as
actually functioning as a topical BTX. There is a paper in the
cosmetic literature6 reporting a "30% improvement in
wrinkle depth after 30 days of use." It is difficult to imagine
that this preparation could penetrate to the level of the
neuromuscular junction and inhibit cholinergic nerve transmission,
but, as with many unproven cosmeceuticals, it is widely available
BTX has been an extraordinarily successful cosmetic treatment.
Physicians in the United States have essentially had only a single
choice in using muscle weakening for cosmetic benefit, and that is
Botox. It is quite likely that the idea of muscle weakening as
cosmetic therapy will lead to novel medications or devices and thus
offer patients and physicians alike a choice in therapy.
- Carruthers JD, Carruthers JA. Treatment of glabellar frown
lines with C. botulinum A exotoxin. J Dermatol Surg.
- Ascher B, Zakine B, Kestemont P, et al. A multicenter,
randomized, double-blind, placebo-controlled study of the efficacy
and safety of 3 doses of botulinum toxin A in the treatment of
glabellar lines. J Am Acad Dermatol.
- Sadick NS. Botulinum toxin type B for glabellar rhytides: a
prospective open-label response study. Dermatol Surg.
- Mattarraso SL. Comparison of botulinum toxins type A and B: a
bilateral and double-blind randomized evaluation in the treatment
of canthal rhytides. Dermatol Surg. 2003;29(1):7-13.
- Spencer JM, Gordon M, Goldberg DJ. Botulinum B treatment of the
glabella and frontalis region: a dose response analysis. J
Cosmetic Laser Ther. 2002;4(1):19-23.
- Mira-Blanes C, et al. A synthetic hexapeptide (Argeriline) with
anti-wrinkle activity. Int J Cometic Sci.