1. Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
2. Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, Canada

ABSTRACT

The tremendous success of botulinum toxin type A (BOTOX®, Allergan Inc.) in the cosmetic arena has acted as a stimulus for the development of other neurotoxins. After more than 2 decades of use, BOTOX® has become synonymous with wrinkle reduction and is considered to be the one of the most common non-surgical cosmetic procedures performed worldwide. Because of its vast popularity among patients seeking non-invasive methods to achieve facial rejuvenation, physicians from diverse specialties have integrated botulinum toxin injections into their existing practices. Herein, we present an overview of botulinum toxin products for cosmetic applications that have received regulatory approval or are under development.

Key Words:
botulinum toxin type A, botulinum toxin type A-Hall strain, botulinum toxin type B, BTX, wrinkles, aging

In 1982, one of us (JC) first brought the concept and the application of botulinum toxin (BTX) for clinical use in ophthalmology to Health Canada. This submission was approved and experimental use for misaligned eyes began in 1983. The subsequent use for benign essential blepharospasm led to its cosmetic use, which we developed in 1987. Following 25 years of therapeutic applications and over 20 years of cosmetic experience with this neurotoxin in Canada, its uses and development of new products continue to expand.¹

BTX Products Under Development in North America

In addition to the original product, several BTX injectables are in clinical development in North America (Table 1).

BOTOX® Cosmetic/Vistabel®/Vistabex® (Allergan Inc.)

This is the original botulinum toxin type A (BTX-A) product, which was initially purified in crystalline from by Shantz and adapted for clinical use by Scott in San Francisco.¹ There was a formulation change in 1997 in order to reduce the amount of immunogenic protein in the material, but there have been no modifications since. In order to gain European regulatory approval, production of a vial containing 50 units was required; it was previously only available as a 100 unit vial. BTX has a broad range of approvals for both therapeutic and cosmetic indications. This neurotoxin currently captures 85% of the worldwide BTX market and the majority of scientific peer reviewed articles on BTXs are about BOTOX®.¹

Dysport®/Reloxin® (Ipsen Inc./ marketed for cosmetic indications in North America by Medicis Inc.)

This formulation of type A neurotoxin is approved in over 65 countries, although, at the time of writing, it has not been approved for cosmetic use in North America or Europe. The difference between Dysport®/Reloxin® and its original counterpart is that BOTOX® is purified by repeated precipitation and redissolution, whereas Dysport®/Reloxin® is produced by purification using a column separation method.
The distinct processes used for purification produce some differences in the surrounding multi-protein complex that is formed around the neurotoxin; however, the clinical significance of this variation is still unclear.³ Another potential difference may reside in the diffusion characteristics of the injected materials, which may produce varying levels of adhesion and retention.

In North America, the vial size of Reloxin® will be 300 units. This formulation is currently under US FDA review for esthetic use. In Europe, a 125 unit vial is anticipated to become available.

PurTox® (Mentor Corporation)

Complexing proteins are therapeutically superfluous and present a high foreign protein load, which may in turn increase the potential for eliciting an immune response. PurTox® is an uncomplexed type A neurotoxin (i.e., the neurotoxin molecule is stripped of its complexing proteins) that is licensed to Mentor Corporation. It is currently in Phase 3 testing for glabellar frown lines, as well as in various stages of development for therapeutic indications. The neurotoxin units of PurTox® appear to be slightly less effective than that of BOTOX®, and they are subjected to different purification processes.

NT-201/ Xeomin® (Merz Pharmaceuticals)

This uncomplexed BTX-A is produced by Merz Pharmaceuticals and has received approval for the treatment of blepharospasm and cervical dystonia in some European countries, as well as in Mexico and Argentina. Currently, regulatory approval for the esthetic indication of treating glabellar frown lines has been obtained in Argentina only. In terms of potency, NT-201 appears to exhibit a 1:1 dose ratio when compared with BOTOX®, and it has a smaller molecule relative to the other BTX products discussed. In studies that compared NT-201/Xeomin® with BOTOX® for therapeutic indications, no significant differences were detected in both safety and efficacy.^4,5 Jost, et al. proposed that the absence of complexing proteins in NT-201 does not hinder its performance.4 Instead, uncomplexed forms of BTX-A may result in purer formulations that can potentially reduce sensitization and antibody formation, as well as improve clinical efficacy; this has been a concern with past formulations containing complexing proteins.

Myobloc®/NeuroBloc® (Solstice Neurosciences Inc./Eisai Co., Ltd.)

Myobloc®/NeuroBloc® is the only available botulinum toxin type B (BTX-B) product, and cervical dystonia is currently its sole approved indication. This BTX-B neurotoxin was originally developed by Elan Pharmaceuticals, but it is now produced by Solstice Neurosciences Inc.; Eisai Co., Ltd. holds the commercial rights to the product in Japan, Russia, European Union nations, as well as other countries. Myobloc®/NeuroBloc® is approved in Canada, US and Europe for cervical dystonia, and is available as a liquid with an acidic pH level of 5.5 to 5.6. Due to the elevated acidity, patients may find injections to be very painful. In addition, the units are substantially less effective when compared with BTX-A units. For example, in cervical dystonia, the ratio is estimated to be approximately 50:1, whereas for glabellar frown lines, the ratio is 100:1. When used for the temporary correction of glabellar frown lines, the clinical duration did not appear to be as long-lasting as BOTOX®.^6,7 However, Myobloc® does appear to exhibit a more rapid onset of action and a greater area of diffusion.⁸ Associated adverse effects, such as dry mouth and dysphagia, are generally mild-to-moderate, transient, and more common at higher doses.

Other BTX Products Under Global Development

CBTX-A (Lanzhou Institute of Biological Products)

This is the only BTX-A product that is approved in the People’s Republic of China; as well, it is marketed in Brazil as Prosigne®. The major difference between this preparation and the other BTX-A products is that a bovine gelatin protein is added to the vial in order to prevent the BTX from sticking to the wall of the vial, syringe, etc. Human serum albumin is almost always used, but in the case of CBTX-A, the gelatin utilized is of bovine derivation, which has the potential to induce allergic reactions, or possibly bovine spongiform encephalopathy, a neurological disease commonly known as “mad cow disease”.

CNBTX-A (Nanfeng Medical Science and Technology Development Co., Ltd.)

Although product orders may be placed via the internet, CNBTX-A is neither licensed nor approved in any country. The potency of CNBTX-A was recently investigated and found to contain significantly higher levels of botulinum neurotoxin than listed on the product’s label, which could constitute a severe health risk for patients.⁹ We are not aware of any additional details about this preparation.

Neuronox® (Medy-Tox Inc.)

This BTX-A preparation is produced by Medy-Tox in South Korea. It is widely used in Korea and South East Asia, and it appears to be effective. We are not aware of any additional details except that the worldwide licensing of its cosmetic use has been acquired by Q-Med Inc. (Sweden).

Conclusion

The use of botulinum toxin is continuing to increase rapidly, with a worldwide growth in sales that is forecasted to be in excess of 20% annually for the near future. A milestone was reached in 2006 when BOTOX® became a billion dollar drug for Allergan Inc.; the company continues to retain 85% of the worldwide neurotoxin market. However, competing products will receive regulatory approval for esthetic indications in the near future. Reloxin® will likely be approved in the US towards the end of 2008 or early 2009, and NT-201 and PurTox® are expected to follow suit in a couple of years. Other neurotoxins not discussed in this overview will undoubtedly appear, especially as the applications of BTX continue to expand.

At the present time, the most dramatic area of development of BTX is occurring in the field of urology, but it is highly likely that further innovative uses for this exceptional molecule will also emerge.

References

1. Carruthers J, Carruthers A. The evolution of botulinum neurotoxin type A for cosmetic applications. J Cosmet Laser Ther 9(3):186-92 (2007 Sep).
2. Wenzel R, Jones D, Borrego JA. Comparing two botulinum toxin type A formulations using manufacturers’ product summaries. J Clin Pharm Ther 32(4):387-402 (2007 Aug).
3. Spencer JM. Botulinum toxin B: the new option in cosmetic injection. J Drugs Dermatol 1(1):17-22 (2002 Jul).
4. Jost WH, Blumel J, Grafe S. Botulinum neurotoxin type A free of complexing proteins (XEOMIN) in focal dystonia. Drugs 67(5):669-83 (2007).
5. Roggenkamper P, Jost WH, Bihari K, et al. Efficacy and safety of a new Botulinum Toxin Type A free of complexing proteins in the treatment of blepharospasm. J Neural Transm 113(3):303-12 (2006 Mar).
6. Jacob CI. Botulinum neurotoxin type B–a rapid wrinkle reducer. Semin Cutan Med Surg 22(2):131-5 (2003 Jun).
7. Spencer JM, Gordon M, Goldberg DJ. Botulinum B treatment of the glabellar and frontalis regions: a dose response analysis. J Cosmet Laser Ther 4(1):19-23 (2002 Mar).
8. Flynn TC, Clark RE. Botulinum toxin type b (MYOBLOC) versus botulinum type a (BOTOX) frontalis study; rate of onset and radius of diffusion. Dermatol Surg 29(5):519-22 (2003 May).
9. Hunt T, Clarke K. Potency of the botulinum toxin product CNBTX-A significantly exceeds labeled units in standard potency test. J Am Acad Dermatol 58(3):517-8 (2008 Mar).

J. S. Dover, MD, FRCPC^1-3, A. Carruthers, MD, FRCPC⁴, J. Carruthers, MD, FRCSC⁵, M. Alam, MD^6
1SkinCare Physicians of Chestnut Hill, Chestnut Hill, MA, USA
²Department of Medicine (Dermatology), Dartmouth Medical School, Hanover, NH, USA
³Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA
⁴Division of Dermatology, University of British Columbia, Vancouver, BC, Canada.
⁵Department of Ophthalmology, University of British Columbia, Vancouver, BC, Canada.
⁶Section of Cutaneous and Aesthetic Surgery, Department of Dermatology, Northwestern University, Chicago, IL, USA

ABSTRACT

There is no ideal filler, nor will there be a single product that can satisfy all requirements. However, RESTYLANE^®, a non-animal, stabilized hyaluronic acid (NASHA, Medicis), is a very versatile augmenting agent. It has been in clinical use for 8 years and experience has shown it to be close to the ideal filler in many respects. This review will outline the background to the use of RESTYLANE^®, and will focus on the clinical use of this material.

Key Words: filler, hyaluronic acid, NASHA

The pace of development of filler substances in the last few years has been phenomenal. Consider that for more than 20 years there was only one US FDA approved cutaneous filler device, bovine collagen (Zyderm^®/Zyplast^®, Inamed Aesthetics). Bovine collagen has several distinct disadvantages. Two skin tests are necessary, producing a minimum 4- to 6-week treatment delay between the initial consultation and the first treatment. Results are short lived, and the thickest collagen, Zyplast^®, lasts only 2-4 months. Beading is relatively common because the product becomes firm and nonmalleable soon after injection.

In February 2003, human collagen (Cosmoderm?/Cosmoplast?, Inamed Aesthetics) was approved by the US FDA. In December 2003, the US FDA approved RESTYLANE^®, a cross linked nonanimal source hyaluronic acid. Two other forms of cross-linked hyaluronic acid, Hylaform^® and Hylaform^® Plus (Inamed Aesthetics) were approved by the US FDA in the summer and fall of 2004, respectively. RESTYLANE^® is made by Streptococci and Hylaform^® is derived from chickens’ combs. They also differ in the amount and degree of cross-linking, which affects, among other things, duration of effect. Many more fillers are under development, and some are pending US FDA approval.

Considering the complexity of the areas/conditions being treated, as well as the aims and desires of the individual being treated, there is no ideal filler. Futhermore, no single product will be able to satisfy all requirements. However, a product would be useful in the majority of clinical situations with the following properties:

• non-permanent but long-lasting
• have minimal side-effects
• not require allergy testing
• be easy to use/inject
• be cost-effective both to the physician and patient.

RESTYLANE^®, a non-animal, stabilized hyaluronic acid (NASHA) is not ideal, but is far closer to this set of criteria than previous fillers.

RESTYLANE^® has been available in Europe since 1996, and in Canada since 1998. It is used in more than 60 countries to correct a variety of wrinkles, lines, and contour defects and to enhance the lips. It was approved in the US in December 2003, for use in mid-to-deep dermal implantation for the correction of moderate-to-severe facial wrinkles and folds, such as the nasolabial folds.

Benefits of RESTYLANE^® include:

• having a very low allergic potential so that skin tests are unnecessary
• having a very natural look and feel
• lasting significantly longer than any of the collagens
• being moldable and very easy to work with.

Disadvantages include temporary redness and swelling at the injection site, which is most clinically significant when the lips are injected and most often resolves within 3-4 days. Allergic reactions are rare. Most of those reported occurred prior to 2000 when the level of contaminants in the product were dramatically reduced.¹

The best data on RESTYLANE^® comes from a study of 138 subjects that led to US FDA approval.² This was a bilateral paired comparison study of the efficacy and safety of RESTYLANE^® vs. Zyplast^® use in the nasolabial folds. The products were injected at baseline, followed by touch-ups as necessary to achieve “optimal cosmetic improvement”. Judging subjects’ folds using a 5-point scale (none, mild, moderate, severe, extreme), both products achieved a 1.5 point improvement. At 6 months, the RESTYLANE^® injected side still had a 1 point improvement, whereas the Zyplast^® injected side had a 1/3 point improvement. At 6 months after injection RESTYLANE^® was considered to be superior in 62% of patients vs. 8% of patients for Zyplast^®.

There were more adverse events in the Zyplast^®-treated side, but these were mainly minor lumpiness or material showing through the skin. Whereas on the RESTYLANE^®-treated side there was more swelling and tenderness (see Table 1).

Table 1: Adverse events in the Restylane^®/Zyplast^® study²

Other Forms of NASHA

The cross-linked structure of hyaluronic acid forms a gel with limitless molecular weight. This is then passed through screens with varying pore sizes to form the injectables with differing particle sizes. This difference between particle size and molecular weight is an important concept in the field of hyaluronic acid-based materials. Resulting from this, each form of cross-linked hyaluronic acid can be packaged as a number of different injectables. For example, NASHA is packaged as RESTYLANE^® Fine Lines (or RESTYLANE^® Touch), RESTYLANE^® Perlane^®, and RESTYLANE^® SubQ. Each of these products will be applicable in an appropriate clinical setting. Large studies done with hyaluronic acid show no difference in duration.2,3

Clinical Use

RESTYLANE^® is used on the face in a variety of places and for a variety of indications, so for the sake of clarity we shall discuss the uses in different categories, recognizing that, at times, this distinction can be artificial. RESTYLANE^® is a very flexible product that can be used for most of the NASHA indications but we shall indicate where we use the different forms of NASHA by preference. Care is always taken to ensure that the product is not injected into a vessel especially when injecting the periocular area.

Fine Lines

Good examples of areas where fine lines are treated would be the glabella, the cheeks, and the perioral area. In these areas we inject RESTYLANE^® in the mid-dermis or higher using a serial puncture technique. One should always feel the resistance of the dermis as one is injecting. The glabella and the perioral areas are usually treated in conjunction with BOTOX^® (botulinum toxin-A, Allergan) therapy. It is not unusual to have to use RESTYLANE^® only once in the glabella if good BOTOX^® therapy is maintained afterward. With regard to the fine perioral lines, it is of vital importance NOT to simply inject the lines since this will lift the surrounding skin, reversing the youthful “ski-jump” projection of the lips. We prefer to enhance the vermilion border and perhaps the lips themselves and to only inject the fine radial rhytids very gently. RESTYLANE^® Touch is designed for this kind of fine work.

Nasolabial Folds

We frequently use a threading technique along the nasolabial fold, concentrating on the upper Y-shaped area below the nares and lateral to the ala. Deepening of this area is related to age-induced loss of fat so correction will produce a more youthful appearance. Because there is less movement in this area close to the nose, correction persists well. The further down the nasolabial fold one is correcting, toward the smile lines beside the oral commissure, the shorter the duration of the correction. In addition, the smile lines are produced by the expression of a positive emotion and so correction of this area may be less of a priority. Discussion of this differential treatment of the nasolabial folds with the subject prior to treatment is very important. Injection is in the mid-to-deep dermis. Where it is available, RESTYLANE^® Perlane is often used for nasolabial fold correction.

Lips

The lips are one of the most important areas for the use of RESTYLANE^® and deserve separate discussion. The aim of lip injection is, in younger individuals, to enhance the size and shape of the lips. In older individuals the aim is more one of correction: to get the lips back to where they were rather than to increase their size. For many patients, the aim is a combination of the two. Injecting lips is more likely to produce adverse events than any other area. In particular, short-term swelling is common and bruising is also seen frequently if good technique is not used. In order to limit this effect, the application of ice or ice packs for 5-20 minutes after injection is favored by some.

Though there is nothing in the literature to support its use at this time, some experienced clinicians provide patients with prednisone 30mg to be taken the morning of the procedure and again the next morning; or 30mg to be taken at bedtime on the day of injection if their lips are swollen, and 30mg to take the following morning if their lips are swollen. Using this technique, minimizes swelling which allows the treated individual to continue with their business and social life rather than having to hide for a day or two. Lip injection is quite uncomfortable. Many use infraorbital and mental nerve blocks to limit discomfort while others prefer distraction techniques such as vibration analgesia.

To limit bruising the needle should be inserted gently through the lip mucosa close to the vermilion and gentle pressure exerted on the plunger. The needle tip can then be advanced using RESTYLANE^® to dissect ahead of the tip, and moving blood vessels out of the way (the “push-ahead” technique). It should be possible to reduce the bruising rate to well below 10% using this technique as well as to avoid the use of NSAIDs, etc.

We use a threading technique on the lips. The needle tip is inserted either just mucosal to the vermilion for vermilion enhancement, or 2-3mm on the mucosa for lip enhancement. Gentle pressure on the plunger should produce flow of the RESTYLANE^® across the lip in the chosen plane ahead of the needle tip. It is essential to continue the injection into the area of the commissure, and above and below the commissure. RESTYLANE^® is our NASHA of choice for lip enhancement.

Contouring

Because of the persistence of NASHA, especially in non-mobile areas, correction of volume loss or enhancement of volume is an increasingly important indication for the use of RESTYLANE^®, as well as Perlane^® and RESTYLANE^®SubQ. Some of the areas where it is used are:

• the temporal eyebrow area to produce a lateral eyebrow lift
• the nasojugal fold to soften the hollows under the eyes (inject just above the periosteum)
• the zygomatic area to enhance the cheekbone
• the infraorbital hollowing to correct age-related fat loss
• the sides of the chin to correct fat loss and to soften the jowls
• the tip of the chin to augment the mentum.

RESTYLANE^® is injected deep into these areas with no attempt at dermal injection. We will frequently use a 30 gauge 1″ needle, or an even longer needle in order to fan the material deep in the subcutis and then massage aggressively in order to avoid lumpiness. Bruising is a risk when injecting at this level because of the larger vessels so using the “push ahead” technique described under Lips described above will be helpful.

Conclusion

NASHA fillers are very effective. RESTYLANE^® lasts twice as long as collagen, no allergy testing is required, and it has an excellent safety profile. Results, however, are highly technique-dependent. The treating physicians must select the subjects and the type of wrinkle or crease carefully, with experience they can become highly skilled in the use of this filler.

References

1. Andre P. Evaluation of the safety of a non-animal stabilized hyaluronic acid (NASHA – Q Medical, Sweden) in European countries: a retrospective study from 1997 to 2001. J Eur Acad Dermatol Venereol 18(4):422-5 (2004 Jul).
2. Narins RS, Brandt F, Leyden J, Lorenc ZP, Rubin M, Smith S. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg 29(6):588-95 (2003 Jun).
3. Carruthers J, Carruthers A. A prospective, randomized, parallel group study analyzing the effect of BTX-A (Botox) and nonanimal sourced hyaluronic acid (NASHA, Restylane) in combination compared with NASHA (Restylane) alone in severe glabellar rhytids in adult female subjects: treatment of severe glabellar rhytids with a hyaluronic acid derivative compared with the derivative and BTX-A. Dermatol Surg 29(8):802-9 (2003 Aug).

1. Division of Dermatology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
2. Department of Ophthamology, Faculty of Medicine, University of British Columbia, Canada

ABSTRACT
The botulinum neurotoxins (BTX) are an exciting group of therapeutic agents with dramatically expanding clinical indications. The US FDA has approved BOTOX® (BTX-A, Allergan) and Myobloc™ (BTX-B, Elan Pharmaceuticals) for the treatment of cervical dystonia. TPP Canada has also approved BOTOX® for the treatment of glabellar frown lines. The US FDA is expected to approve this new indication before the end of 2002. These changes will dramatically expand the marketing of BTXs. Concerns about risks and side effects diminish as clinical experience increases with this “most poisonous of poisons”.² In particular, the incidence of secondary resistance to the toxin’s effect has been dramatically diminished with the reduction of the non-toxic protein in current batches of BOTOX®.³

Key Words:
botulinum toxin, cervical dystonia, glabellar frown lines, hyperhidrosis

Pharmacology

The botulinum toxins are produced by different serotypes of the bacterium, Clostridium botulinum. They act to block presynaptic release of acetylcholine,³ which in turn blocks neuromuscular transmission, causing weakening of the treated muscle or even flaccid paralysis. Reversal of the blockade occurs after approximately 3-4 months. The typical clinical response is in the same time range although much longer responses can be seen.

Drug interactions and contraindications⁴

Theoretical interactions with aminoglycoside antibiotics and calcium channel blockers have not proven to be of clinical significance. Of much greater importance is the possibility of exacerbating preexisting neurological disease. A myasthenic crisis was precipitated in a patient who developed unrecognized myasthenia gravis in between regular BTX injections for blepharospasm.⁵ Amyotrophic lateral sclerosis and Eaton-Lambert syndrome can also be worsened by BTX injection.⁴

The safety of BTX injections in pregnant and nursing women has not been established, though there is evidence that BTX does not cross the placenta.^6,7 Whether it is secreted in breast milk has not been substantiated. However, so little gets into the circulation that the tiny amounts to which a healthy breast-fed infant might be exposed would not pose any likely risk.^6,7

Commercially available preparations

BTX-A

BOTOX® was the first of the BTXs to be produced and used clinically, and experience with this toxin is far greater than with any of the other toxins. Early use of the BTXs caused a significant problem with secondary resistance to the toxin’s effect resulting from the induction of blocking antibody formation. Gradually, Allergan changed, worldwide, the supply of the toxin to a new, purer product. Secondary resistance has not been reported since this change.²

BOTOX® is approved in the US and Canada for the treatment of strabismus, blepharospasm, hemifacial spasm and cervical dystonia (CD) in adults. It was recently approved in Canada for the treatment of glabellar frown lines and approval for this indication in the US is anticipated in 2002. As well, TPP Canada approved this product for the treatment of hyperhidrosis in August 2001, and for the treatment of adult spasticity in November 2001. The European Commission of the European Union passed a positive opinion in October 2001, for the treatment of adult spasticity.

Dysport® was introduced in Europe soon after BOTOX® was launched in North America. It is also BTX-A, however, the Dysport® unit does not appear to be as effective as the BOTOX® unit. Studies suggest a 3-5 fold difference in potency,⁸ which is thought to be due to differences in product formulation (see Table 1). Dysport® has a similar incidence of secondary resistance in CD patients, to the original batch of BOTOX® (3-5%).⁹

BTX-B

Myobloc™ (Elan Pharmaceuticals) was the first available form of BTX-B (called NeuroBloc® outside North America) to be approved for the treatment of CD by the US FDA in December 2000. In studies published so far, the clinical effectiveness and the duration of response in CD appear to be similar to BOTOX® although the dose is dramatically higher.¹⁰ For effective treatment of CD, at least 10,000 mouse units of Myobloc™ are needed to produce the same effect as 200 mouse units of BOTOX® (see Table 1). This means a tenfold increase in the amount of neurotoxin protein delivered, although Myobloc™ has less inactive neurotoxin protein than BOTOX®.³ Myobloc does not appear to be accompanied by a similar development of clinical resistance to the affect of BTX-B.¹¹ According to information provided by the US FDA, there may be a reduction of treatment benefits with succeeding treatment sessions and/or a lessening of benefit with the uppermost level of dosing examined. Although no definite conclusions may be drawn, data provided by the US FDA suggests that resistance may be possible.¹²

Side effects of Myobloc™ seem to be similar to those of the other BTXs with the exception of dry mouth. Although mild, this occurs in up to 34% of CD patients treated with an effective dose of 10,000 units.¹¹ This is a systemic effect of the neurotoxin and is indicative of a difference between BTX-A and BTX-B. It may be possible to exploit this and other differences and find indications for which Myobloc™ is superior to BOTOX® and vice versa.

Table 1: A review of BTX forms currently available.

Indications

Cosmetic¹³

The principal area for cosmetic use of BTX is in the upper face. Glabellar frown lines, horizontal forehead lines and lateral orbital lines (crows feet) are commonly treated and respond well. More recently, the ability of BTX to produce a modest brow lift, to correct eyebrow asymmetry, to open the eyes, to soften perioral wrinkles, to lift the corners of the mouth, and to improve neck lines have excited interest in the mid and lower face.

Hyperhidrosis

BTX has been used successfully to treat hyperhidrosis affecting a number of areas. It was initially used in Frey’s syndrome, which led to treatment of the palms and axillae. The face and feet are also treated. More recently, the use of BTX to reduce sweating was shown to be effective in improving benign familial pemphigus.¹⁴ This may lead to the use of BTX for other intertriginous dermatoses where sweating is thought to play a role.

Headache and Migraine¹⁵

Early in the cosmetic use of BTX, alleviation of tension headaches was reported, and migraine headaches were also reported to have improved. Subsequent studies have provided conflicting results. Unquestionably, some patients have fewer and less severe migraines after BTX injection, but it has been difficult to establish a scientific basis for this in placebo-controlled, double blind studies. Further work in this important area will establish the indications, effective injection techniques, and possibly further define the pathogenesis of migraine, which should not respond to BTX injections according to current theories.

Conclusion

The clinical indications of the botulinum neurotoxins continue to expand dramatically. At the same time, our background knowledge is also expanding and a form of the B serotype is now commercially available. Differences have been established between BTX-A and BTX-B including different sites of action, different dosages and different side-effect profiles.¹⁶ Clinical experience with BTX-B is currently so limited that conclusions about these differences are premature.

References

1. Lamanna C. The Most Poisonous Poison. Science 130:763-72 (1959).
2. Brin MF, et al. An interim analysis of the clinical status of patients receiving current BOTOX (lot 2024 or subsequent lots) for the treatment of cervical dystonia. Presented at International Conference 1999: Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins, Orlando, Florida, November 16-18, 1999. Abstract: pg 21.
3. Simpson LL, editor. Botulinum neurotoxin and tetanus toxin. San Diego:Academic Press (1989).
4. Assessment: the clinical usefulness of botulinum toxin – A in treating neurologic disorders. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 40(9):1332- 6 (1990 Sep).
5. Borodic G. Myasthenic crisis after botulinum toxin. Lancet 352(9143):1832 (1998 Dec).
6. Polo JM, Martin J, Berciano J. Botulism and pregnancy. Lancet 348(9021):195 (1996 Jul).
7. Robin L, Herman D, Redett R. Botulism in pregnant women. N Eng J Med 335(11)823-4 (1996 Sep).
8. Marion MH, Sheehy M, Sangla S, Soulayrol S. Dose standardization of botulinum toxin. J Neural Neurosurg Psychiatry 59(1):102-3 (1995 Jul).
9. Poewe W, Wissel J. Experience with Botulinum Toxin in cervical dystonia. In: Jankovich J, Hallet M, eds. Therapy with Botulinum Toxin. New York:Marcel Dekker (1994) pg. 267-78.
10. Brashear A, Lew MF, Dykstra DD et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A responsive cervical dystonia. Neurology 53(7), 1439-46 (1999 Oct).
11. Myobloc™ package insert. Elan Pharmaceuticals, Dublin, Ireland.
12. US FDA. BLA 99-1396. Response Submission to Complete Review Letter. Elan Pharmaceuticals. Botulinum Toxin Type B for Treatment of Cervical Dystonia: Supplemental Clinical Review. (2000 Dec).
13. Carruthers A, Carruthers J. Botulinum Toxin Type A: History and Current Cosmetic Use in the Upper Face. Sem Cutan Med Surg 20(2):71-84 (2001 Jun).
14. Glogau RG. Treatment of Palmar Hyperhidrosis with Botulinum Toxin. Sem Cutan Med Surg 20(2):101-8 (2001 Jun).
15. Carruthers A, Langtry JA, Carruthers J, Robinson G. Improvement of Tension- Type Headache When Treating Wrinkles with Botulinum Toxin A Injections. Headache 39(9):662-5 (1999 Nov/Dec).
16. Carruthers A, Carruthers,J. Toxins 99, new information about the botulinum neurotoxins. Dermatol Surg 26:174-6 (2000 Mar).

Division of Dermatology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT

Botulinum toxin type-A (BTX-A) is a neurotoxin which blocks presynaptic release of acetylcholine. It interferes with neuromuscular transmission¹, temporarily paralyzing the affected muscle⁶. Of special interest for dermatologists is the unlabelled cosmetic applications, for conditions such as wrinkles and hyperhidrosis. Labelled indications in Europe are for cervical dystonia and cerebral palsy. In the US, it is approved for treatment of strabismus, blepharospasm and hemifacial spasm in adults². After repeated use of high doses, antibodies can develop in some individuals, making further treatment ineffective indefinitely. Even when used in high doses for neurological conditions, the development of antibodies occurs in < 5% of patients. In 1997, the US FDA approved a new bulk toxin source for use in the manufacture of BTX-A. It has a higher specific potency than original BTX-A formulations, reducing the amount of utilized neurotoxin protein, and thereby reducing antibody production⁹. Another form of this neurotoxin (type B) also appears to be effective in patients who have developed antibodies to BTX-A. It is awaiting US FDA approval for treatment of cervical dystonia.

Key Words:
Botulinum toxin, type-A, Hyperhidrosis

PHARMACOLOGY

Botulinum toxin type-A (BTX-A) is a neurotoxin produced by C. botulinum which blocks presynaptic release of acetylcholine. When a minute amount is injected into a muscle, it prevents neuromuscular transmission¹ temporarily paralysing the affected muscle, and can provide symptomatic relief for up to three months or more after a single injection⁶. This can be useful for a wide variety of conditions.

Cosmetic Uses

BTX-A has had a lot of publicity recently for its off-label cosmetic use in facial wrinkles¹¹. It is currently in widespread use for the treatment of glabellar frown lines, crow’s feet, and horizontal forehead lines¹. Other more recent uses include more extended management of cosmetic problems, including platysmal bands and horizontal neck lines as well as lines in the lower part of the face. The nasolabial fold, mental crease, and upper lip wrinkling have all been successfully treated using BTX-A although these indications are not without controversy³.

Hyperhidrosis

Hyperhidrosis is another condition that has been managed successfully using BTX-A intracutaneously^4,5, though some researchers report some associated muscle weakness5.

Refractory Pain Associated with Spasticity

BTX-A offers an alternative for patients with refractory pain associated with spasticity. This includes dystonia due to abnormal posture, sustained muscle spasm and tremor. Investigators are looking at a wide range of disorders characterized by chronic soft tissue pain. These include fibromyalgia, chronic fatigue syndrome and temporal mandibular joint pain. Headache that is secondary to pericranial muscle tension may also respond to injection of BTX-A^7,10.

LABELLED INDICATIONS

In Europe, BTX-A is approved for cervical dystonia and cerebral palsy, but in the US, the only approved indication is treatment of blepharospasm and strabismus associated with dystonia, although a supplemental NDA for cervical dystonia is pending. It is in late stage development in Europe and the US for upper limb spasticity, and in early phase development for headache/migraine and lower back spasm/pain¹¹.

A NEW GENERATION OF BOTULINUM TOXIN

While this drug is gaining popularity, it’s effect is temporary and most patients require repeat treatments. In some, BTX-A given in doses greater than 100u can induce the development of antibodies that make further treatment ineffective for an indefinite period⁸. However, even when used in high doses for neurological conditions, the development of antibodies occurs in < 5% of patients.

In 1997, the US Food & Drug Administration approved a new bulk toxin source for use in the manufacture of BTX-A. The new product, called current BOTOX®, is comparable in clinical efficacy to the original BOTOX®, but the higher specific potency reduces the amount of neurotoxin protein utilized, which in turn, leads to a reduction in the production of antibodies⁹.

NeuroBloc®, produced by Elan in Dublin, Ireland, is new and contains one of the other subtypes of botulinum toxin, type B. In clinical trials, this product has also been shown to be effective in patients who have developed antibodies and have stopped responding to BTX-A. It is currently awaiting US approval for use in the treatment of cervical dystonia¹¹.

Conclusion

BTX-A has had a lot of publicity recently for its off-label cosmetic use in facial wrinkles¹¹. These unlabelled cosmetic applications are of special interest for dermatologists. However, repeated use of this product can induce the development of antibodies in some individuals, making further treatment ineffective for an indefinite period. Treating patients with a preparation of botulinum toxin (type A or B) that minimizes exposure to neurotoxin complex proteins may be preferable for reducing the risk of antibody formation^9,11.

References

1. Carruthers A, Kiene K, Carruthers J. Botulinum A exotoxin use in clinical dermatology. J Am Acad Dermatol 34(5):788–797 (1996 May).
2. Carruthers JDA, Carruthers A. Botulinum A exotoxin in clinical ophthalmology. Can J Ophthalmol 31(7):389–400 (1996).
3. Carruthers A, Carruthers J. The Adjunctive usage of botulinum toxin. Dermatol Surg 24:1244-7 (1998).
4. Naumann M, Hofmann U, Bergmann I, Hamm H, Toyka KV, Karlheinz R. Focal Hyperhidrosis: Effective treatment with Intracutaneous botulinum toxin. Arch Dermatol 134(3):301-4 (1998 Mar).
5. Odderson IR. Hyperhidrosis treated by botulinum A exotoxin. Dermatol Surg 24(11):1237-41 (1998 Nov).
6. Girdler NM. Uses of botulinum toxin [letter]. Lancet 349(9056):953 (1997 Mar 29).
7. Schulte-Mattler WJ, Weiser T, Zierz S. Treatment of tension-type headache with botulinum toxin: A pilot study. Eur J Med Res 4(5):183-6 (1999 May 26).
8. Goschel H, Wohlfarth K, Frevert J, Dengler R, Bigalke H. Botulinum A toxin therapy: Neutralizing and nonneutralizing antibodies—therapeutic consequences. Exp Neurol 147(1):96–102 (1997 Sep).
9. Considerations in selecting a botulinum toxin: Relationship between specific potency, protein load and immunogenicity. The Botulinun Toxin Express™ Report discusses data from the poster presentation: Aoki KR, Merlino G, Spanoyannis A, Wheeler L. BOTOX (Botulinum Toxin Type A) purified neurotoxin complex prepared from the new bulk toxin retains the same preclinical efficacy as the original but with reduced immunogenicity. Poster 06.109, at the 51st Annual Meeting of the American Academy of Neurology, April 17–24, 1999, in Toronto, Ontario, Canada.
10. Wheeler AH. Botulinum toxin A, adjunctive therapy for refractory headaches associated with pericranial muscle tension. Headache 38(6):468-71 (1998 June).
11. Chustecka Z. New uses for Allergan’s Botox. Scrip World Pharmaceutical News No 2439:26 (1999 May 21).

FORMS OF BOTULINUM TOXIN — TYPES A & B

NeuroBloc®
(Elan)

Botulinum toxin — type B

Awaiting US FDA approval.