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SUMMARY
Botulinum toxin (BTx) is one of the most revolutionary treatments in facial aesthetics and rejuvenation. The cosmetic use of BTx in the upper third of the face began in the late 1980s and gradually advanced to applications in the mid and lower face, neck and other areas of the body. Its use has permitted a better understanding of the physiopathological process of aging, specifically the role of the muscles. Nowadays, more accurate techniques and the adjunctive use of BTx allow physicians to make more precise applications and achieve better, natural-looking results. Every year, new perspectives on the clinical and cosmetic uses of BTx show the utility and versatility of this therapeutic modality in dermatology and other specialized areas of medicine.
INTRODUCTION
Nowadays, the value of image plays an important role in our society. Since the development of numerous minimally invasive procedures for facial beauty and rejuvenation, it has become easy and safe for patients to improve their appearance. New and less invasive techniques for facial rejuvenation give quick results, with a low incidence of side effects and minimal downtime, as patients can return immediately to their normal daily activities.
Facial wrinkles are caused by several factors, including aging (intrinsic and photoaging), gravity, positional pressure (sleep lines) and facial expressions. Repeated muscular contractions involved in facial expression are one of the most important etiologic factors causing facial lines and rhytides, particularly in the upper third of the face. Glabellar, frontal and periorbital are the main areas involved in facial expression. Moreover, these muscular contractions may also contribute to the development of redundancies of the skin over these hyperkinetic muscles and lines. Some dynamic wrinkles that are initially caused by muscular movements become static with the addition of other factors such as chronic solar exposure and the development of cutaneous flaccidity.
Glabellar folds are usually interpreted as suggesting negative feelings, such as sadness, anger and frustration. Although small-to-moderate furrows may be interpreted positively for men, as indicating the ability to concentrate, leadership and even sensitivity, large furrows are more often perceived negatively.
In an attempt to diminish the undesirable expressive rhytides of the face, BTx has been widely used to produce precise and reversible weakness of the hyperfunctional mimetic muscles of facial expression. It is therefore currently considered the best alternative for the treatment of dynamic wrinkles, alone or in combination with other minimally invasive or invasive techniques.
BTx injections are of special benefit for patients between 30 and 50 years of age, since the etiology of facial lines in this group is more related to the underlying muscles than to other factors. The treatment of facial expression lines not only represents a matter of aesthetics and vanity, but also leads to improvement of self-esteem.
The medical literature of the cosmetic use of BTx is currently dominated by open-label reports, uncontrolled studies and personal experience reviews. A few double-blind, placebo-controlled studies have been published, some of them in the glabellar area. In the lateral periorbital area, BTx injections can be safely performed when strict attention is given to the reconstituted BTx pharmacology and to the anatomy of the periorbital muscles, although it is considered an off-label procedure.
HISTORY OF THE COSMETIC USE OF BOTULINUM TOXINS
BTx is known as the substance with the highest specific potency of all natural or synthesized compounds. It is produced by an anaerobic, Gram-positive, rod-shaped organism, Clostridium botulinum .
BTx became famous as the cause of botulism and as a biological weapon. Botulism is well known in historical accounts, and has probably been known since the beginning of the human race. In medieval times, it was known in Europe that production of sausages bore a high risk of food poisoning from BTx, so strict guild regulations were imposed on sausage production.
In 1822, Justinus Kerner, a physician in the state of Württemberg in South Germany, provided one of the earliest detailed descriptions of the clinical picture of botulism. He was also the first to speculate on a possible therapeutic use of BTx in conditions like Huntington’s chorea. In 1895, Emile Pierre Marie van Emergen identified botulinum neurotoxin as the cause of a botulism outbreak amongst musicians in the Belgian village of Ellezelles. In 1919, the isolation of different BTx types, known as A (BTx-A) and B (BTx-B) was achieved. In 1920, Hermann Sommer of the Hooper Foundation at the University of California concentrated BTx into a relatively pure form. Research and study into the activity of botulinum neurotoxins was stimulated by the events of World War II. Edward Shantz, Carl Lamanna and their colleagues at Fort Detrick successfully isolated BTx-A for the US Army in 1946, and in 1949 Burgen discovered BTx’s mechanism of action.
Medical use of BTx began in the 1950s with the work of Vernon Brooks. By the late 1960s, the inhibitory effects of BTx-A on acetylcholine release at the neuromuscular junction were shown in experimental animals. These studies were significantly advanced by ophthalmologist Alan Scott of the Smith-Kettlewell Institute of Visual Sciences in San Francisco in the 1970s. He used BTx-A for treatment of strabismus and blepharospasm. In 1977, the first treatment was attempted in humans.
The batch of BTx-A developed by Schantz under the name of Oculinum in 1979 was approved for human use in 1989, and later acquired by Allergan Inc. Under the name of Botox® it has been used as the primary treatment for focal dystonias since the late 1980s.
In 1987, while treating patients for essential blepharospasm, Jean Carruthers, an ophthalmologist, noted that these patients had significant improvement of dynamic rhytids in the glabella region. Alastair Carruthers, a dermatologist, together with his wife, started systematic studies of BTx for cosmetic use, which were published in 1992, demonstrating the safe and effective use of BTx-A in the treatment of dynamic rhytids in the glabella and bringing in the era of cosmetic use of BTx.
In 1993, Blitzer et al. described the use of BTx for wrinkles of the forehead. Later researchers, such as Arnold Klein, Nicholas Lowe, Patricia Wexler, Richard Glogau and Steven Fagien, contributed publications of their experiences to the widespread use of BTx-A. Subsequently, new indications for cosmetic use such as crow’s feet, and new areas as the perioral region and platysma were discovered. Botox® Cosmetic (in other countries Vistabel® or Vistabex®) was approved by the FDA in 2002. Other BTx-A products have been launched into the market in other countries. The most important are Dysport® by Ipsen, Prosigne® by Lanzhou and Xeomin® by Merz.
At first, BTx-A used the principle of identical doses and injection sites for all patients, but in recent years cosmetic treatment with BTx has become much more differentiated and today a more individualized approach prevails, aiming at a global rejuvenation: the BTx ‘face lift’. Frequent reports of potential novel uses of BTx-A in facial musculature indicate that we stand at the beginning of its use in aesthetic medicine.
CURRENTLY AVAILABLE BOTULINUM TOXINS
The toxin produced by Clostridium botulinum is isolated, purified and stabilized before it can be used as a drug. There are seven different types of BTx, which are known and designated by the letters A, B, C, D, E, F and G. The different BTx types differ slightly in the amino acid sequences of their neurotoxin and in their associated non-toxic proteins. All seven BTx-types share a similar molecular structure and have the same basic mechanism of action: they bind to the same glycoprotein structures and they all block the cholinergic synapse, preventing the release of acetylcholine at the neuromuscular junction of striated muscle fibers, creating a flaccid paralysis of the muscle. Differences in the intracellular protein target or target site cleaved by the light chain of each serotype lead to variations in duration of action and possibly other defects. Only the A and B toxins are available as drugs ( Table 8.1 ).
| XEOMIN® | Botox® | Vistabel® | Dysport®/Reloxin® | Dysport® Cosmetics® | Prosigne® | Neurobloc®/Myobloc® | |
|---|---|---|---|---|---|---|---|
| Company | Merz Pharmaceuticals | Allergan | Allergan | Ipsen/Medicis | Ipsen/Medicis | Lanzhou Institute of Biological Products | Solstice Neuroscience |
| Type | Type A | Type A | Type A | Type A | Type A | Type A | Type B |
| Approvals | Europe Union, Mexico, Argentina, Brazil | In over 75 countries all over the world | In 16 countries, including the USA, Canada, Italy and France | Dysport: In over 65 countries | Germany, some other European countries and the USA | China, North Korea, Morocco, the Philippines, Indonesian, Brazil, Peru, Ecuador, Chile, Paraguay, Uruguay, Venezuela, Thailand and some others | Europe and the USA |
| Active substance | Botulinum neurotoxin type A (150 kD) | Botulinum toxin type A complex (900 kD) | Botulinum toxin type A complex (900 kD) | Botulinum toxin type A complex (900 kD) | Botulinum toxin type A complex (900 kD) | Botulinum toxin type A complex (150 kD) | Botulinum toxin type B complex |
| Comparison of strength of action | 1 | 1:1 | 1:1 | Approx. 1:2.5 to 1:3 | Approx. 1:2.5 to 1:3 | 1:1 | 1:1000 |
| Indications |
| Many indications, including blepharospasm and cervical dystonia | Glabellar lines | Many indications, including blepharospasm and cervical dystonia | Glabellar lines | Blepharospasm, strabismus, hemifacial spasm and other dystonias | Cervical dystonia only |
| Mode of action | SNAP 25 | SNAP 25 | SNAP 25 | SNAP 25 | SNAP 25 | SNAP 25 | VAMP |
| Pharmaceutical form | Powder for solution for injection | Powder for solution for injection | Powder for solution for injection | Powder for solution for injection | Powder for solution for injection | Powder for solution for injection | Solution |
| Units/vial | 100 | 100 | 50 | 500 | 500 | 100 | 2500/5000/10 000 |
| Volume | max. 8 ml | max. 10 ml | 1.25 ml | max. 2.5 ml | max. 5 ml | max. 8 ml | 0.5 ml/1 ml/2 ml, max. 3.5 ml |
| Reconstitution | 0.9% NaCl solution | 0.9% NaCl solution | 0.9% NaCl solution | 0.9% NaCl solution | 0.9% NaCl solution | 0.9% NaCl solution | Prepared solution, dilutable |
| Storage | 25°C | 2–8°C or freezer −5°C | 2–8°C <−5°C | 2–8°C | 2–8°C | 2–8°C | 2–8°C, do not freeze |
| Shelf-life (unopened) | 36 months | 36 months | 36 months | 24 months | 24 months | 36 months | 24 months |
| Shelf-life reconstituted | 24 hours | 24 hours | 24 hours | 24 hours | 24 hours | 4 hours | 24 months (closed) |
| Auxilliary substances | Albumin 1 mg, sucrose 4.7 mg | Albumin 0.5 mg, NaCl 0.9 mg | Albumin 0.5 mg, NaCl 0.9 mg | Albumin 0.125 mg, lactose 2.5 mg | Albumin 0.125 mg, lactose 2.5 mg | Gelatin 5 mg, dextran 25 mg and sacarosis 25 mg | Albumin, NaCl, succinat, octanolat, tryptophan |
| pH-Wert | 5–7 | 5–7 | 5–7 | 5–7 | 5–7 | 5–7 | 5.6 |
| Foreign protein load in dose-equivalence range | 0.6 ng/100 U | 5 ng/100 U | 2.5 ng/50 U | 5 ng/500 U | 5 ng/500 U | 4–5 ng/100 U | 100 ng/10 000 U |
| Specific activity (MU per ng protein) | 166 MU/ng | 20 MU/ng | 20 MU/ng | 100 MU/ng | 100 MU/ng | 20–25 MU/ng | 100 MU/ng |
BTx-B (Myobloc®, Solstice Neuroscience) is less potent than BTx-A in humans and requires approximately 50–150 times the dose of BTx-A to achieve similar results in dynamic rhytides. It appears to have a shorter duration of action than type A, as well as more autonomic side effects. Myobloc® comes in the form of a solution.
In aesthetic medicine, BTx-A has been used the most so far, although some trials have been undertaken utilizing BTx-B.
MECHANISM OF ACTION
The activity of the different types of BTx is exerted through a multistep process which includes binding to nerve terminals, internalization and inhibition of neurotransmitter release.
The biologically active component is BTx neurotoxin, which consists of two polypeptide chains with molecular masses of 50 kDalton (kD) and 100 kD. These two polypeptide chains are linked together by a single disulfide bond. Thus, BTx neurotoxin is a complex and highly fragile macromolecule. Changes in pH or exposure to light or heat induce changes and finally destruction of the macromolecule, with loss of its biological activity. BTx neurotoxin is associated with various non-toxic proteins, some with hemagglutinating and some with non-hemagglutinating properties.
Clinically, BTx induces a blockade of the cholinergic innervation of the target tissue. When BTx is injected into muscle tissue, muscular paralysis results within 24–72 hours, reaching its maximum effect after 1–2 weeks. The degree of muscular paralysis can be controlled by the amount of BTx administered.
The mode of action of BTx is illustrated in Figure 8.1 . BTx neurotoxin with its heavy chain binds to BTx acceptors on the presynaptic nerve membrane. This binding is rapid and irreversible. Subsequently, the light chain is transported into the nerve cytoplasm. The synaptic fusion complex is made up of a group of proteins known as the SNARE proteins (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) that allow the preformed acetylcholine vesicles to dock and fuse to the membrane. This SNARE complex is the location of action for BTx. Inside the nerve ending, the light chains of BTx-A, C and E catalyze the cleavage of SNAP-25 (synaptosomal-associated protein), a 25 kDa protein of the SNARE complex. The different subtypes of BTx have unique areas on the nerve membrane to which they bind and have different proteins within the presynaptic nerve terminal that they cleave. They all have the same mechanism of action: to act as a zinc-dependent endoproteinase and inhibit the release of acetylcholine at the peripheral neuromuscular junction.
