The global medical aesthetic market is expected to grow 10.8% per year between 2010 an 2015 and many other companies throughout the world are beginning to develop toxins. The clinical trials used to be FDA approved have changed since Botox was approved. For example: the Xeomin trial was different, i.e., a two- point improvement on a four-point wrinkle scale by both the investigator AND the patient. as opposed to a 1 point improvement in the initial Botox clinical trials
It is important that practitioners use branded products from legitimate companies that are either FDA approved in the US or CE marked in Europe, or received regulatory approvals in your country. There are various unbranded and fake products out there; however, clinicians should use caution with regard to the use of these products due to safety and efficacy issues.
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It is important that clinicians understand the molecular structure of Botulinum neurotoxin type A. Botox and Dysport have an envelope of protein around it; xeomin; however, does not have these accessory proteins.
Differentiating Botulinum Toxins
Regulatory agencies worldwide have recognized that these products are not interchangeable. The units of biologic activity in each available product cannot be compared or converted into the units of any of the other available products, nor can the doses or preparations be interchanged. You need to learn how to use each product effectively.
New Data on Xeomin
In a head to head study comparing Xeomin to Botox for the treatment of cervical dystonia both products appear to be effective for this subset of patients.
What about the aesthetic use of Xeomin?
It’s important to note that the changes in FDA requirements over the fast few years are quite profound. The FDA now requires a two-grade improvement, whereas when Botox was conducting it’s clinical trials, the FDA only required a one-grade improvement. Overall, Xeomin and Botox appear to have similar efficacy.
Crow’s Feet
A small Xeomin study for the treatment of crow’s feet (N = 21) also demonstrated similar efficacy between both products.
Science and Data to Consider
We have very good safety and efficacy studies available. Patients seem to have a better quality of life, and look and seem happier. It is important to understand where not to inject. Over the last few years, we have seen success in treating crow’s feet and may begin to see more of a focus in this area. It’s imperative to look at each patient’s musculature when injecting toxins so as to achieve maximum results.
What’s new with botulinum toxin-A?
Combination Delivery
Dermatologists should be cautious of the dangers associated with delivering fillers and toxins simultaneously.
Zinc supplementation
A recent publication by Dr Koshy (April 2012) advocated the use of a proprietary zinc formulation to augment botulinum toxin efficacy for patients using toxins for aesthetic purposes. This paper presented many problems, mainly the fact that zinc augmentation of the botulinum toxin efficacy effect has never been described. And the actual study was done very poorly. Where does the idea to use zinc come from?
The neuronal receptor for botulinum toxin is comprised of a heavy chain and light chain. A zinc dependent metalloprotease is responsible for cleaving the botulinum protein for it to be effective. The article (above) suggests that we are zinc deficient and; therefore, we don’t have enough zinc. This effect remains to be seen and we should be skeptical of this study.
Dosing
If we look specifically at dosing, data used to suggest that higher botulinum toxin type A doses resulted in greater efficacy and longer duration of the effect. In 2008, experts developed a consensus (rewrite from 2004) with regards to how to best achieve an optimal, relaxed and natural outcome using botulinum toxin type A. This resulted in basically cutting the forehead doses in half.
We have choices and dermatologists should review the various recommendations and guidelines in order to obtain the best effect for their patients.
Dueling
Patient satisfaction is a key aspect of facial aesthetics. Various studies have looked at patient reported outcomes among the products available; however, it is often difficult to compare the results.
Onset
With regards to the use of Dysport, when patients were asked, it seemed to work within a couple of days. No one recorded that information with Botox. In general, botulinum toxin type A begins to work in about two days.
Duration
Across the board, looking at the glabellar lines, the duration of botulinum toxin type A is about four months in about 50% of patients. Data has also demonstrated that patients tend to have a cumulative effect; in that, the efficacy with repeated injections is extended over a longer period of time.
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In this presentation, Dr Jones reviews the data on Belotero, a novel therapeutic approach to dermal fillers.
CPM Technology
Belotero utilizes CPM Technology. This is the most important difference with regards to Belotero and other dermal fillers. Belotero utilizes CPM Technology, a key differentiator between Belotero and other hyaluronic acid dermal fillers. CPM Gel provides further cross-linking steps resulting in a coherent molecule with different density zones, resulting in a coherent molecule with unique density zones.
What does this mean clinically?
While particulate biphasic fillers may lift and enlarge dermal spaces leaving lumps, Belotero integrates into dermal spaces allowing for smooth transition between treated and untreated areas.
This is important clinically as it is hypothesized that using Belotero may reduce the Tyndall effect.
Belotero US Clinical Study
The Primary Phase was a 24 week initial study in comparison to Zyplast. 118 patients were enrolled and the researchers looked at the treatment of nasolabial folds (NLFs). The open-label extension phase (OLEX) was an extension of the evaluation from 24 weeks to 96 weeks that included 85 patients.
This is important as it was an FDA pivotal trial and Dr Jones encourages everyone to review the pivotal trials on Restylane and Juvederm as well to look at similarities and differences among the fillers.
The mean age on these studies was 52.4 and the subjects were predominantly female.
In order to be eligible for this study, patients had to be a two or a three on the Wrinkle Severity Rating Score (WSRS) and to be deemed a “responder” that had to have at least a one-point improvement on this scale that was persistent.
The results demonstrated that both Belotero and Zyplast performed similarly at week 2, but by week 24 the results greatly improved with the use of Belotero.
Regarding the responder analysis, well over 50% of the subjects had at least a one- point change on the WSRS by week 24 and the percentage of subjects maintaining correction from week two to week 24 was greatly superior for Belotero.
Efficacy measured in GAIS was significantly better with Belotero versus Zyplast. In looking at the Physician’s Preference Assessment, 100% of the physicians preferred Belotero to Zyplast with regards to storage and handling, 67% preferred Belotero regarding the comfort and design of the syringe, and 33% preferred Belotero regarding ease of injection “flow”. Overall, 83% of the physicians preferred Belotero to Zyplast.
Adverse events were very similar to what one would expect with a hyaluronic acid such as erythema, bruising, and swelling. The AEs observed were not statistically significant.
The results of the Primary Phase study conclude that Belotero is superior to Zyplast in the correction of the nasolabial fold when evaluated 12 weeks after treatment. More patients preferred Belotero and the treatments were safe and well tolerated.
Belotero Balance (OLEX)
This was an open-label extension trial consisting of treatment with Belotero on both sides at completion of the 24-week visit (visits at week 32, 48, 72, 96, after the last main study treatment). Patients received touch-up treatments with Belotero in both nasolabial folds at week 24 and could receive an optimal touch-up treatment at week 32 to balance an observed unevenness between the two sides. At each of the visits, adverse events and relevant medication use was noted. The subjects could also receive optimal touch-up injections at week 48 or week 72 if the WSRS on that side is two or three. Subjects who did not receive an optimal touch-up injection at weeks 48 or 72 had the option of receiving a touch-up at week 96.
After repeat treatment, the filler starts to hold and dermatologists can see that with the other fillers as well.
The mean GAIS score, as assessed by the treating physician, was between two (improved) and three (much improved) at all timepoints. The GAIS was greater on the side of the face previously injected with HA in the double-blind trial, indicating greater improvement on that side.
During the OLEX study, there was an injection-free phase of 48 weeks in 80.2% of the patients.
At all time points during the open-label extension the treating investigator assessed improvement by both the WSRS and GAIS on both NLF.
In conclusion, Belotero appears to be a safe and well-tolerated, novel dermal filler.
In this presentation, Dr Cohen reviews the complications that can occur when utilizing fillers and best practices on how to manage these various complications. Dermatologists use fillers across the world, millions of times per year, and most of the time, everything is fine; but understanding the complications and how to manage them is imperative for us aesthetic dermatologists.
Clinicians should be aware that there are new filler agents and new indications for the agents currently available, so it is important to understand these products and recognize what can potentially go wrong when using them in our patients.
Filler complications include:
Superficial injection
Vascular compromise
Bruising
Sensitivity
Granuloma
Infection (or possible ” biofilm”)
Superficial Injection
When injecting the peri-ocular area, it is critical that dermatologists understand the anatomy and how to inject these areas. When Dr Cohen injects these areas, he defines them by either “infra-orbital hollow” or “tear trough”.
Approach to Infra-Orbital Hollow injection
This is a much less common injection than the actual tear trough. Dr Cohen uses anesthetic eye drops, a jaeger retractor to protect the globe, and a 32 gauge needle above the level of the muscle. He discusses the importance of the 32 gauge needle as he believes it slows down the injection, or alternatively a 30g cannula can be used as well to try to decrease the incidence of bruising. This is an off-label area of injection and should be done very superficially, but it is very important to avoid superficial nodules—so inject slowly and avoid depositing clumps.
Injecting the Tear Trough
Dr Cohen injects very deep, below the muscle on the level of the periosteum. An anterior approach may help to lessen bleeding encounters.
Persistent Swelling
Persistent swelling has been documented across the board with various fillers. It is important to remember that this is an off-label area and dermatologists choose their agents based on personal preferences. Experts are not sure if the swelling is related to etiology, e.g., Botox a few weeks prior. Treatment for persistent swelling includes time, massage, caffeine, oral HCTZ, and hyaluronidase. Hyaluronidase can be helpful for an area that was superficially injected (very localized).
When injecting the glabella, you would want to see a little bleeding, you absolutely do not want to see it blanche. Bototulinum toxin immobilization prior to filler (sometimes a week or two prior), may provide a better, more durable response with the filler (Carruthers, Derm Surg, 2003).
Vascular Compromise and Necrosis
The glabella is an area at significant risk for impending necrosis. Vascular compromise and necrosis, albeit rare, are caused by compression and intravascular injection. In 2006, Dr Cohen and colleagues published a prevention and treatment protocol for injection necrosis of the glabella (Derm Surg, Feb 2006).
Understanding the facial arteries is of great importance for dermatologists who do soft tissue augmentation.
If you see a blanche, immediately stop the procedure. With some warm tap water gauze, try to tap the area and the warmth will facilitate vasodilation. If you have nitro paste in your office, you can apply that as well along with giving your patient aspirin to manage the headache associated with nitro paste.
Understanding the vessels and patterns is important not only to dermatologists, but to patients and office staff as well. Hyaluronidase with multiple stabs and perhaps into the adjacent artery has been demonstrated as a novel treatment for impending necrosis. It is very important as a healthcare provider to intervene immediately and not “wait and see what happens” in the cases of impending necrosis. A new article in Derm Surg suggests prostaglandin E may be helpful, and many experts also recommend hyperbaric oxygen be considered in some cases as well.
Scars
Fillers can be for postsurgical depressed scars on the ears, nose, and cheeks. Dr Cohen and colleagues published various case reports in 2008 on the use of fillers for postsurgical depressed scars after skin cancer reconstruction. The use of hyaluronic acid and calcium hydroxylapatite has proven successful to fill and blend these scars.
Bruising
Bruising may occur regardless of the injection site. The injection pattern is extremely important and it is critical that dermatologists understand the various approaches to injection. There are some things that patients can do to reduce bruising, such as avoiding non-therapeutic anticoagulant over-the-counter agents.. There are vitamins that can potentially interfere with bleeding; so again, something to keep in mind. Clinicians need to be realistic with their patients, so they can expect some bruising and/or swelling which may last up to ten days. It is important to communicate this as a reality with patients prior to the procedure.
Cannulas
There are a few cannulas available in the US. Dr Cohen uses cannulas most often in the hands, cheeks, infra-orbital, and décolleté. They seem to decrease bruising along with potentially decreasing pain in some areas, and this has been seen in two preliminary studies (Hexsel and Barrone).
Summary
In conclusion, there are a variety of fillers available for patients. It is important that dermatologists understand the anatomy of the face in order to optimize injection results and minimize potential complications.
In this presentation, Dr Werschler provides an overview of the fillers currently available on the market by class and by product, and how they can be utilized in clinical practice along with some key takeaway points for clinicians.
How did we get here today?
Beginning in 1981, bovine collagen was introduced to the US marketplace. As people began to get their winkles and fold augmented to look younger they discovered that,unfortunately, the duration of collagen was only three months or so, thus the market for collagen injections never grew to meet expectations And it was subsequently withdrawn from the market. In December, 2003, the US FDA approved Restylane (Hyaluronic Acid), whichrevolutionized the dermal filler market . With a duration of correction to 6+ months, no pre-treatment skin testing, ease of use, room temperature storage and modest cost, there was now a viable product for the emerging, if nascent, dermal filler market.
PMMA (Radiesse), a novel “next-generation” filler was approved in 2006 by the FDA for the correction of wrinkles and folds (such as Nasolabial Folds), and for the correction of HIV-associated lipoatrophy. Unique and distinctly different in its’ mechanism of action, Radiesse is termed a “stimulatory” or “collagen-stimulator” product. This differs from the previous generation “replacement” space occupying materials collagen and hyaluronic acid. With the addition of collagen stimulation, the duration of effect of Radiesse was extended to 9-18 months.
On the same day that Radiesse was approved, the FDA also approved the first and only “permanent” dermal filler, Artefill (collagen + PMMA). Artefill consists of bovine collagen in combination with polymethmethacrylate spheres. As these spheres are non-biodegradable, they represent a permanent placement into the tissue. Well tolerated with an excellent safety profile, Artefill does require pre-treatment skin testing because of the bovine collagen present. Special handling includes refrigeration, and collagen stimulation gradually anchors the PMMA spheres into place typically after 2-3 treatments.
In 2007/2008 Hyaluronic Acid plus manufacturer added lidocaine was FDA approved for the hyaluronic acids, Juvederm, Restylane and Perlane. Similarly, the FDA approved the mixing of lidocaine and Radiesse by the injector at the time of use. These approvals resulted in greater patient comfort during injection and further expanded the dermal filler marketplace. Stabilized Porcine Collagen came onto the market briefly during this time, however due to problems with patient tolerance and complications, the manufacturer withdrew the product and it is no longer available.
In 2009, the FDA approved Sculptra, poly L lactic acid, for aesthetic use (it received FDA approval in 2004 for HIV associated facial lipoatrophy). A pure collagen stimulator, Sculptra is technically not a dermal filler, however it is best thought of in this category. Sculptra is routinely mixed with lidocaine and sterile water for injection, requires 3-5 injections sessions to gradually grow new collagen leading to the clinical effect developing over a period of 3-6 months. Duration is a 2+ years effect based on extensive clinical trials and experience.
More recently, an advanced technology hyaluronic acid (Belotero) and an autologous cultured dermal fibroblast (LAVIV) were approved. Belotero is a “cohesive polydensified matrix” hyaluronic acid which possess different tissue integration properties than previous generation products. The net clinical result is that the product may be injected more superficially than other HAs without risk of the Tindall or Rayleigh effect tinting the skin blue.
Laviv, like Sculptra, is technically not a dermal filler but rather a tissue stimulator that upregulates native collagen production. This process includes harvesting tissue from the patient (post-auricular) and sending it to a processing laboratory which then amplifies the cell count and returns a viable culture for re-injection. The first FDA approved tissue therapy for aesthetics, Laviv presents a multitude of intriguing possibilities in the future.
Ever since fillers first came onto the market, experts have been trying to develop a methodology to differentiate them and there are many ways to do so:
Chemical components
Duration of action
Natural/Synthetic
MOA
Replacement Filler or Bio-Stimulatory/collagen stimulator
Looking at fillers by their MOA has seemed to work very well when differentiating the products.
Dermatologists should be aware that fillers exist in two primary categories:
Volume Replacement
Collagen Stimulation
When you use the above descriptive methodology, you can see that collagen and hyaluronic acids are replacement fillers and PLLA and LAVIV are bio-stimulatory. And notably, CaHA ad PMMA are blends of both MOAs.
There are many ways to categorize fillers within a class.
Volume Replacement
Hyaluronic Acid
HAs have a very simple chemical structure and is identical in all species and tissues; thus it is non-immunogenic. It is found in all vertebrates and synthesized by some bacteria. The identical structure of HA from all sources makes it an ideal substance for use as a biomaterial in health and medicine. HAs are highly hydrophilic; therefore, they absorb water, i.e., their principal method of giving a volumizing effect. They are also rapidly metabolized in vivo.
Gel Mass Sizing
In addition to crosslinking, manufacturers use other techniques to improve HA filler properties. For example, Medicis uses a process that creates specific sizes and shapes to form granular consistency gels Restylane® and Perlane®.
In creating the JUVÉDERM® family of products, Allergan uses Hylacross™ Technology to create random sizes and shapes that form a smooth cohesive gel. While the new to market Beletero uses yet another technology (CPM) to achieve unique properties.
Does this make a difference clinically? It depends on who you ask…
Hyaluronic acids can be used virtually everywhere for anything and everything and they are the most versatile of all of the filler products. These fillers may be ideal for novice patients because they have an “eraser” (hyaluronidase) which can be injected to make the product dissolve, if so desired for either aesthetic effect or for treatment of necrosis. . This is a unique feature of this category.
New Approaches to Fillers: Pure Neocollagenesis
PLLA
The question is…Are these products really stimulators? Dr Werschler believes, they are for lack of a better descriptive term. Through a variety of mechanisms of action, they stimulate fibroblasts to make collagen.
PLLA was first approved for HIV-related facial lipoatrophy in the United Sates in 2004 and the aesthetic approval was received in 2009. It is the only approved pure collagen stimulator currently available in the US; therefore, it is considered “stimulatory” and “biodegradable” in classification. PLLA is indicated for the correction of nasolabial folds. Of note, Dermik aesthetics, a division of sanofi-aventis, recently sold the product to Valeant Pharmaceuticals Intl. based in Canada.
What is the composition of PLLA?
Poly-L-lactic acid
Sodium carboxymethylcellulose (CMC)
Non-pyrogenic mannitol
Sterile water (added) for injection (USP)
Lidocaine (optional—most dermatologists and plastic surgeons add lidocaine for patient comfort)
Sculptra™ is composed of microparticles of PLLA, a biocompatible, biodegradable, synthetic polymer from the alpha-hydroxy-acid family. It is derived from natural components, it is a crystalline, amorphous mixture with microparticles averaging 40 to 63 μm in size. The slow resorption of PLLA after implantation is due to the high molecular weight (140,000 Daltons) of the polymer and the irregular crystalline shape of the microparticles.
Lactic acid can be converted through polymerization to a variety of polymers, including poly-L-lactic acid. Many of these polymers, including polylactic acid, have been used for many years in medical devices and sutures, including absorbable sealants, flow restrictors, fixation systems, suture anchors/absorbable sutures, fixation screws, and tissue regeneration.
The slide below is very important looking at skin thickness of HIV patients using ultrasound. The plot includes the data points for all patients in the VEGA study. All patients experienced increases in skin thickness in the treatment area (minimum increase of 2.2 mm noted at Week 8 visit).
Statistically significant increases above baseline values of mean skin thickness were noted at all time points (Weeks 8, 24, 48, 72, and 96) during the study. This slide demonstrates the product’s MOA of growing collagen and therefore, thickening the dermis.
The slide below demonstrates marked improvement in wrinkle assessment score (WAS) utilizing Sculptra®Aesthetic at all time points through 25 months.
Each Wrinkle Assessment Score, or WAS, at the time points shown represented the median of 3 investigator’s scores, and each of the investigator’s evaluations represented an average of scores for the left and right nasolabial folds.1
In the WAS coding system, 0 equals no wrinkles; 1 refers to a just-perceptible wrinkle; 2 indicates a shallow wrinkle; 3, a moderately deep wrinkle; 4, a deep wrinkle with well-defined edges; and 5, a very deep wrinkle or redundant fold.2
Investigator evaluations throughout the study confirmed that improvements in facial appearance with Sculptra®Aesthetic achieved improvement in WAS. As this graph shows, improvements from baseline at 25 months proved to be consistent, progressive, and statistically significant at each time point (P<0.001): 100% of patients improved at week 3; 88.7% at month 13; and 86.3% at month 25.1
How long does it last? Maybe two to three years. It is important to remember that it is difficult to establish exact duration of the product because of one’s natural course of aging.
Poly-L-lactic acid treatment primarily to add volume, and as such is used to thicken dermis and to stimulate collagen growth in the pre-periosteal plane. Placement may include the temporal hollows, across the zygomata, in the mid face, nasolabial folds, labiomental sulcus, prejowl sulcus, mandibular sweep, angle and for genioplasty. Sculptra is not recommended for use in areas of concentric movement such as the lips and eyelids.
Personalized Dermal Technology
LaViv is an innovative technology to isolate, purify, and regenerate a patient’s own fibroblast cells for re-injection.
Fibroblast cells produce collagen and play key role in the continued health of skin. Collagen provides firmness and structure to the skin and is essential in supporting the dermis.. As skin ages, fibroblast cells decrease and the collagen matrix that provide the skin its structure breaks down.
This is a way to restore the equilibrium. LaViv is the first autologous cell therapy for use in aesthetics filed with the FDA. There is strict release testing on each clinical lot to ensure performance and safety including:
Collagen content testing results must achieve specification for each prepped injection, indicating cells are biologically active and produce collagen
Cell suspension must consist of at least 98% fibroblasts prior to release
Cells in suspension must achieve a viability level of at least 85%
The LaViv Treatment Process:
Extraction
A small cell sample (ideally three small skin bioposies) is removed behind the ear from a small skin punch biopsy with the use of local anesthetics
Purification & Culturing
A proprietary manufacturing process multiplies fibroblasts from the sample into tens of millions of new cells in approximately 3 months
Fibroblasts are tested by quality control and released by quality assurance prior to shipment
Cells are frozen for use in potentially multiple treatment sessions
Injection
Recommended regimen is three treatment sessions at 3-6 week intervals
In clinical trials, a statistically significant difference between LAVIV™ and placebo was seen by the time of the third treatment
As far as side effects with LaViv, there is an increase in erythema, swelling, pain, and a slight urticarial-like response.
New Approaches to Fillers: Volume Replacement + NeoCollagenesis
Calcium Hydroxylapatite (CaHa)-Radiesse
CaHa is best used for facial contouring. It’s mechanism of action is to serve as a filler material initially (particles + gel) then provide long term benefit through natural collagen integration in and around the particles. The result is a long lasting, but not permanent correction augmentation that feels like the patient’s own tissue.
The advantages of Radiesse include immediate site-specific correction in one to two sessions and strong structural tissue support withno Tyndall effect. CaHa is malleable up to two weeks and has a long duration of nine to 18 months. No pretreatment testing is required, it is also cost-effective and does not migrate or obscure radiographic studies and it doesn’t ossify in the skin.
Radiesse received approval in the United Sates in 2006 for both HIV and aesthetic use and is the only approved biodegradable dual collagen stimulator and replacement filler currently available in the US. When utilizing Radiesse, no skin or allergy testing is needed and there is no special handling. The product is available in 0.3, 0.8 and 1.5 mL and recently approved 3.0 mL syringes through Merz Aesthetics.
Where is it used?
CaHA is used most everywhere; however, it is not ideally used in the lips or the eyelids. Some people do use the product in those areas; however, Dr Werschler does not recommend it.
PMMA Dermal Filler-Artefill
Artefill was approved in the United Sates in 2006 and is the only approved PMMA-enhanced dermal filler currently available in the US. It is indicated for the correction of nasolabial folds. Suneva Medical acquired (ARTES) Artefill in 2009 and is currently manufacturing, selling, and distributing Artefill in the US.
The slide above depicts that initially your percent implant volume is mostly collagen. The bovine collagen goes away rather quickly and you have the PMMA microspheres that stay in the skin. (Of note, PMMA is similar to Lucite, in that, it is a non-biodegrable substance that will remain in the skin forever.) The remaining PMMA elicits this fibroplasia-like response, the autologous collagen is produced by fibroblasts, it surrounds the microspheres, anchors them in place and that is what gives patients the long-term effect.
There is a long-term extended duration of action which is what one would expect.
Conclusions
Injectables are:
FACIAL SHAPING AGENTS (FSA)
They can enhance natural features
They can rejuvenate fading youth
They can restore aged, facial features
They can even improve natural beauty
Each product has features that result in certain benefits in clinical use
Put another way, they are not all alike!
Clinical Pearls
Use filling agents appropriate to the requirements of the job
Not all products are created equal – understand the differences!
Some areas are more difficult to correct than others (e.g. lips and tear troughs) so master the basic indications first such as NLF
Evaluate and approach filling from a multi-step progression:
Volume, shape, contour, wrinkle, line and crinkle filling.
Product duration claims are a slippery slope- be careful with those and be conservative with your ranges. Underpromise and over deliver.
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Dermatologists should be aware that the global medical aesthetic market is expected to grow 10.8% per year between 2010 an 2015 and many other companies are joining the toxin “band-wagon”.
Products Under Development/Currently Approved in Other Countries
Medy-Tox – Neuronox (South American and Korea)
Siax – Neuronox (Colombia)
ChinaTox –Lanzhou Biological Products Institute, Nanfeng Medical Science and Tech co.
Lantox (South America)
Mentor is currently developing a product called PurTox, which is about one year away from filing with the FDA for approval. There are also several products currently available in Asia and South America. Dermatologist should recognize that in some instances where non-approved Botox formulations were used in the United States, patients required hospitalization due to paralysis and physicians were subject to major sanctions, fines, etc.
Summary
It is important that practitioners use branded products from legitimate companies that are either FDA approved in the US or CE marked in Europe, or received regulatory approvals in your country. There are various unbranded products available on the internet; however, clinicians should use caution with regard to the use of these products due to safety and efficacy issues.
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Botox, Dysport, and Xeomin are all FDA approved for glabellar lines. The products are also used for the forehead and crow’s feet.
Dangers
Dermatologists should be cautious of the dangers associated with delivering fillers and toxins simultaneously.
Dosing
Data suggest that higher botulinum toxin type A doses resulted in greater efficacy and longer duration of the effect. In 2008, experts developed a consensus with regards to how to best achieve an optimal, relaxed and natural outcome using botulinum toxin type A. This resulted in basically cutting the forehead doses in half.
Dermatologists should also understand gender differences that exist in upper face musculature. In a 1998 cadaver study by Dr Macdonald, et al, males were shown to have greater corrugator thickness at both the medial canthus and mid-pupil regions versus females. An understanding of these anatomic differences can facilitate proper injection technique.
Potency
Dr. Cohen indicates that he does not think physicians should be desperately trying to find the right conversion ratio between products. He feels that the reality is that each of these products is it’s own neuromodulator. As such, he indicates, that if we decide to use that specific neuromodulator, then we should know that neuromodulator independently—and thus how to specifically use that product.
Dueling
Patient satisfaction is a key aspect of facial aesthetics. Various studies have looked at patient reported outcomes among the products available; however, it is often difficult to compare the results.
Duration
Across the board, looking at the glabellar lines, the duration of botulinum toxin type A is about four months. Data has also demonstrated that patients tend to have a cumulative effect; in that, the efficacy is stretched out over a longer period of time.
Delivery
Drs. Richard Glogau, Fred Brandt and others have begun to research topically applied botulinum toxin type A for the treatment of primary axillary hyperhidrosis as well as lateral canthal rhytid studies. Results have shown that topically applied BTX-A appears to be safe and effective.
Revance, a California-based company, has developed a proprietary platform that enables transcutaneous flux. The Revance technology works by employing two complementary and distinct pathways that are both present in human skin:
The first pathway is energy independent and therefore can occur in non-living cells. like the stratum corneum. It could also occur in living cells. The second pathway is energy dependent and only occurs across living cells.
Devices
Myoscience is currently investigating a hand-held cryotherapy medical device for the treatment of facial wrinkles between the brow, forehead lines and crow’s feet. It has shown promising results in difficult patients, i.e., complete treatment of dynamic horizontal forehead lines, constant brow position, immediate onset, and it proves to be a potentially new option for toxin-averse patients. The device uses a 27-30-gauge needle placed near motor nerves that innervate frontalis muscle.
Summary
It is important that dermatologists convey the message that botulinum toxin type A has been studied and BTX injections can be beneficial for patients who want to delay the outward appearance of aging, for patients who believe their faces are not communicating their emotions properly and/or for patients who simply want to look their best.
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In this presentation, Dr Cohen reviews the use of botulinum toxins in clinical practice. He reviews the three Type A toxins such as Botox, Dysport, and Xeomin.
Science and Data To Be Considered
It is important that clinicians understand the molecular structure of Botulinum neurotoxin type A.
The core neurotoxin protein in all agents used clinically is 150kD BoNT/A. Botox and Dysport both have accessory proteins that surround the core neurotoxin, while Xeomin lacks accessory proteins.
Botulinum toxin Type A works via chemodenervation, in that the internalized toxin binds to the SNAP-25 target protein and then blocks the exocytosis of acetylcholine into the synaptic cleft following a neural impulse. This effectively denervates the segment of muscle supplied by the affected cholinergic nerve terminal.
Differentiating Botulinum Toxins
Regulatory agencies worldwide have recognized that these products are not interchangeable. The units of biologic activity in each available product cannot be compared or converted into the units of any of the other available products, nor can the doses or preparations be interchanged.
Immunogenicity
Dermatologists should be aware that botulinum toxin itself could be immunogenic. The protein added to stabilize the product also has immunogenic properties. If antibodies occur, the question is whether or not they are neutralizing “critical domain” antibodies or non-neutralizing “non-critical domain” antibodies. Antibody detection can measured through two tests. The Mouse Protection assay is the most widely used with the highest specificity. The patient’s serum is taken and given to a mouse. The mice are then given a lethal dose of BTX-A. If the mouse lives, the patient has antibody; in most cases the mouse would die. The rapid immunoassays (ELISA, W. BLOT) have a lower specificity and a lack of correlation between detected abs and clinical resistance.
Various data and studies suggest that overall, few patients may develop antibodies; however, they if they do develop antibody, they seem to continue to respond to the products.
https://mauiderm.com/wp-content/uploads/2013/04/MD-WebLogo.jpg00Maui Derm Newshttps://mauiderm.com/wp-content/uploads/2013/04/MD-WebLogo.jpgMaui Derm News2012-10-30 14:27:292014-01-13 13:07:28Botulinum Toxin 2012: Where are we now? Part 1
Clinical Pearls: When Combining Devices with Injectables and Other Devices
In this presentation, Dr Kilmer reviews the techniques for combining the various technologies that are currently available for facial rejuvenation in order to obtain optimal cosmetic improvement for patients.
Dr Kilmer stresses the importance of remembering the 4 Rs:
Relax
Refill
Resurface
Redrape
During her initial consult with patients Dr Kilmer discusses the 4 Rs and how the various techniques that she uses in combination for facial rejuvenation can aide in maximizing the outcomes. It is also important, as dermatologists that full disclosure regarding outcomes is presented. Dr Kilmer informs her patients that she does not “have a magic wand or a crystal ball”; therefore, she can’t predict the outcomes of any given patient.
Relax
It is important to relax the skin with a botulinum toxin to keep both the muscles and the skin from moving as much as it otherwise would. If she is going to laser the skin, the results are improved when the skin/muscles are not moving. Dr Kilmer also uses fillers, in conjunction with the toxins and lasers to fill in lines, tighten up the skin and remove brown/red spots.
Clinical Pearl: Never use toxins, lasers, or any other device that can cause significant swelling on the same day. This can result in the toxin migrating to other places where you do not want it.
Refill-Restore Volume Loss
When using dermal fillers, the objective is to restore volume based on a patient’s specific needs. Fillers can be placed in various areas locally such as the nasolabial folds, marionette lines, deep glabellar rhytids, tear troughs, and the nasal bridge. Fillers can also be used globally in the cheeks and temples. It is important to remember that there may be a lag time resulting in delayed gratification.
It is very important to keep in mind that one can’t massage post poly-L-lactic acid (Sculptra) in areas where Botulinum toxin was placed.
If all of these procedures are being done in one patient, Dr Kilmer typically tries to slow down the movement and relax the muscles. Discussions with patients regarding the overall procedures that could be performed are very important. Considerations for patients include money, down time, and fear factor, i.e., what are they willing to go through? In these consultations, Dr Kilmer and her patients decide on the best approach based upon their issues and the issues that she sees.
Combination Treatments
Best order
Start with toxins to stop movement and relax muscles.
Relax frown, smile and lip lines when doing facial rejuvenation
Relax DAOs and neck bands when doing fillers, tightening or resurfacing
May need less filler and patients are happy sooner with tightening devices
Then filler or laser depending on a patient’s specific needs (and ability for downtime)
Never do toxins and lasers that cause swelling at the same time because toxins can migrate.
Typically end with filler if still needed after toxins and laser
Sometimes the combination will diminish the need for filler
If able to tell that will need volume, can do before or at same time as laser
Caveats of Combining Treatments
Toxin with Filler
Can’t massage post poly-L-lactic acid (Sculptra) in areas where Botulinum toxin was placed
Toxin with Laser
Can’t do toxin same day as Fractional lasers – swelling can lead to migration
Can do botulinum toxin with PDL, IPL, CoolTouch, SmoothBeam, Thermage, Titan
Filler with Laser
Can do filler same day but do first if doing fractional as swelling can mask need for filler.
Fractional with nonablative RF tightening
Same day – do Thermage 1st because need intact skin but when you do the fractional laser the skin may still be sensitive. (wait an hour or two because the sensation will decrease with time)
Combining Fractional with other Devices
Fractional laser with other lasers/txs
Lentigines – pre-tx QS lasers, KTPs, etc
AKs – LN2
Sebaceous hyperplasia, nevi – 1450 nm
Vascular lesions – PDL, KTP, Alex
Downtime from other treatment is simultaneous and shortened
Fractional resurfacing with ablative resurfacing
Almost always do fully ablative to upper eyelids
More tightening/more predictable – do inner canthi
Can ablate/sculpt edges of scars, upper lip lines and elevated lesions
Ablative fractional and nonablative fractional resurfacing
Nonablative fractional to face, ablative to neck for more tightening /crepiness – useful for those with hx ablative resurfacing/chemical peels/dermabrasion
Other Combination Therapy
Other combination therapy includes fat loss and tissue tightening (CoolSculpting + RF tissue tightening, lipo/laser lipo + tissue tightening); Fractionated RF ((ePRime) + QS/KTP/PDL); and Fractionated US ((Ulthera) + QS/KTP/PDL).
Now that the 4Rs have been implemented, dermatologists need to be particularly aware of reassessing. Combination treatments may minimize the need for other treatments; therefore, increasing the interval for maintenance. For example, one can decrease the need for the amount and frequency of dermal fillers and one can conduct fewer fractional treatments when lentigines are specifically targeted. There may also be the possibility of foregoing vascular laser treatment if the fractional laser used to treat facial vessels was sufficient. Patient concerns should be addressed, i.e., were his/her expectations met? Is there anything new on the patient that has become noticeable since the initial treatment needs have been performed and met? Normally, with time, additional needs will become apparent.
Summary
In summary, botulinum toxins, fillers and lasers can be used synergistically to minimize the signs and sun damage and aging. To produce the optimal results, expertise in the techniques are required, one should use the best possible modalities and watching and treating for any possible complications is imperative. Combining these modalities may obviate the need for more invasive procedures.
This is a technique with limited, but real efficacy. It is important that Dermatologists critically assess these technologies in this emerging field. There are many different technologies for fat removal, the first of which is Focused Ultra Sound, known commercially as “Ultra Shape”. This is mechanical, non-thermal energy. It is currently not FDA approved. The initial study looked at 30 patients treated at 3 monthly sessions. The researchers did bilateral treatments, with no control, of thighs, abdomen, and flanks and achieved a circumference reduction of 2-3 cms. LFTs, lipids, & liver ultrasound showed no adverse systemic effects and there were similar findings in a subsequent study. The problem that clinicians face is that there was no untreated control so it is difficult to ascertain the true degree of efficacy. Circumference, when subject to mathematical analysis, is an inherently imprecise measure of improvement. MRI could provide a more objective improvement; however, it was performed in this study.
A subsequent study in Hong Kong using this device treated 51 subjects, with 3 monthly treatments. They didn’t see any significant change in ultrasound, circumference or caliper measurements and it resulted in poor patient satisfaction.
High-Intensity Focused Ultrasound is commercially known as Lipo Sonix, was recently FDA-cleared. This features rapid heating of adipocytes producing coagulative necrosis and cell death in adipose tissue. There is a published retrospective study that looked at 85 patients with1 treatment session. On average a 4.6 cm decrease in waist circumference was seen after 3 months and lipids, LFTs, and CBC were within normal limits. Temporary adverse effects in 11.8% of patients (4-12 weeks) included prolonged tenderness, ecchymosis, nodules, edema, and procedural pain in one patient that required discontinuing the procedure. Unfortunately, this was not an ideal study because it was retrospective and diet was not controlled. Dr Avram felt that this, in fact, undermines the findings of the study.
In a recent poster presentation, diet was controlled and there was a statistically significant circumference improvement at 12 weeks in treated patients versus sham patients. Yet, it was unclear how circumference measurement was validated.
Adverse events were more common than in the published study and included procedural pain in 90% of patients, post-treatment pain in 57%, bruising in 66%, and swelling in 9%.
Monopolar radiofrequency has been shown to produce lipoatrophy in some patients and is still awaiting clinical studies. Bipolar radiofrequency which is combined with infrared light and vacuum massage, is FDA approved; however, its efficacy is yet to be determined.
Low level light therapy (LLLT), which is, FDA-cleared, is a multiple head low-level diode laser at 635 nm. An LLLT study (blinded bi-lateral treatments) looked at 59 patients who received three treatments per week for 2 weeks some improvement was reported however, at a minimum, further study is needed. There were no data of efficacy more than 2 weeks out. There were no data on ultrasound or other non-invasive evidence of decreased fat layer and no histology.
Cryolipolysis is a technique that was developed at Massachusetts General Hospital and is FDA-approved for non-invasive fat removal.
Cryolipolysis is the non-invasive cooling of fat to selectively cause fat cell death without damage to surrounding tissue types. It is based on the concept of the clinical phenomenon of “popsicle panniculitis”. The mechanism of action involves the selective crystallization of lipids in fat cells at temperatures above freezing. This results in apoptotic fat cell death followed by slow dissolution of cells and gradual release of lipids; therefore, causing an inflammatory process resulting in fat layer reduction over 2-3 months. After the animal studies, there was a human study where 32 subjects in the “love handle” group were analyzed. One side was treated and there was a contra-lateral side untreated control. The parameters ranged from CIF 33 (-64 mW/cm2) for 60 minutes to CIF 42 (-72 mW/cm2) for 45 minute. The researchers evaluated efficacy 4 months post-treatment utilizing visual assessment as primary a endpoint, as well as ultrasound and histology. Ultrasound showed a 22.7% decrease in fat layer thickness. Post-procedure side effects included redness that lasted for a few minutes to a few hours, bruising and temporary dulling of sensation in treated area. There were no changes in pigmentation and type VI skin types have been successfully treated. No laboratory abnormalities were detected. A rare side effect (1 in 1,500) is the report of significant pain lasting about 2 weeks and resolves without sequelae. The mechanism for this side effect is unknown.
Treated and Control Side
In conclusion, the data regarding cryolipolysis (Zeltiq) indicates clear, but limited non-invasive fat removal. It not a replacement for liposuction and is not a weight loss device. It is best suited for local fat removal resistant to exercise in relatively fit patients. The best areas to treat are the love handles and lower abdomen. It is important that clinicians recognize that patient selection is crucial.
We can see that non-invasive fat removal is here. It cannot be compared to liposuction. There are several different technologies presently available. Proper patient selection is important as some devices work, and others do not.
Tissue Tightening
Many different technologies exist for tissue tightening. They all attempt to tighten skin laxity by the deposition of heat.
The temperature-related effects will differ depending on the amount of heating that one chooses to perform:
42-52 ºC
reversible injury, heat shock
> ~52 ºC
cell apoptosis, necrosis
> ~68 ºC
type I collagen denaturation
> ~100 ºC
vaporization
The mechanism of action is tissue contraction; therefore, each device produces heating of the dermis in order to cause significant shortening of collagen structures. The devices also want to achieve a secondary wound healing response with collagen deposition. This has been demonstrated using monopolar radiofrequency (Thermage technology) using animal histology.
Tissue Tightening Technologies
The good news is that these technologies can achieve a certain degree of tissue tightening and they are continuing to improve and, for the most part, they are rather safe. The bad news is that the results can be unpredictable and in many cases are not seen. Each patient has to be looked at individually and they must realize that the results can take months before they are actually manifested. These treatments can often be painful and quite expensive and many times patients may require multiple treatments. It is important that physicians counsel patients and give them a proper sense of potential results.
Ablative Fractional Resurfacing
Ablative fractional resurfacing can produce some modest tissue tightening. However it is very important to resist the temptation to be aggressive in order to maximize the clinical benefit. Hypertrophic scarring of the neck has been reported with ablative fractional resurfacing. (Avram MM, Tope WD, Yu T, Szachowicz E, Nelson JS. Hypertrophic scarringof the neck following ablativefractional carbon dioxide laserresurfacing. Lasers Surg Med. 2009 Mar;41(3):185-8.)
Radiofrequency
There are monoploar, bipolar and fractional bipolar radiofrequency devices. The mechanism of action of monopolar radiofrequency devices is that the current runs through the dermis but does not conduct well in the fat however it conducts along the septae in the fat causing heating of the septae and surrounding fatty tissue. Monopolar radiofrequency devices that are combined with a superficial radial cooling component (Thermage device) allows the user to change cooling and heating parameters to deliver heat to the deeper tissue in a given targeted area while protecting the epidermis with the cooling system. There is also no patient recovery time. It often takes up to 3-6 months to see the results.
Biopolar radiofrequency consists of two electrodes. The heat runs between them and many of these devices are coupled with a suction device to maximize the tissue between the electrodes allowing clinicians to achieve deeper penetration. It may provide a mild benefit for tissue tightening.
Fractional bipolar radiofrequency utilizes a fractional pattern of bipolar RF heating that is delivered by a micro-needle electrode array directly into the deep dermis .It provides real time dermal temperature monitoring. The treatment is painful and requires significant anesthesia. However, its efficacy is yet to be determined.
Focused ultrasound (US) allows for deep, non-invasive treatment at any tissue depth. US can treat far below the dermis. Treatments are guided by real time imaging. The key to success and avoiding complications is to target carefully using imaging to guide the treatment of the skin and SMAS. It is important to remember that one should avoid targeting any arteries or nerves. It has great potential for not only targeting tissue for aesthetic purposes but for other medical therapies.
Skin Imaging
Issues around US include clinical questions regarding pattern, depth, density and the number of necessary treatments. US looks like a promising technology; yet, its efficacy still requires more proven results.
Its important to remember that there are limits to tissue tightening technologies. It is important to discuss these issues with patients and consider that the current treatment paradigm may need to be approached in a different manner. Perhaps dermatologists need to consider restoring elasticity, rather than tightening. We do know that tissue tightening can improve non-invasive skin elasticity, the results are unpredictable, this should not be looked at like a face-lift and patient education and communication is key its the success.
00Maui Derm Newshttps://mauiderm.com/wp-content/uploads/2013/04/MD-WebLogo.jpgMaui Derm News2011-12-01 09:00:072011-12-01 09:00:07Non-invasive Fat Removal and Tissue Tightening: What’s the Truth?
