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Figure 1. Abobotulinum toxin A injections were placed in the first prominent horizontal crease located between 2.5 and 3.0 cm above the orbital rim. Orbital rim measurement is independent of brow location, which is variable and should not be used in determining injection sites in both clinical and research settings.

Figure 1. Abobotulinum toxin A injections were placed in the first prominent horizontal crease located between 2.5 and 3.0 cm above the orbital rim. Orbital rim measurement is independent of brow location, which is variable and should not be used in determining injection sites in both clinical and research settings.

Figure 2. Wrinkle reduction response data are depicted using the histogram by treatment side, an effective graph for portraying dispersion and central tendency. The A side is the more concentrated and the B side the more dilute preparation of abobotulinum toxin A. Under the assumption of normality, which was confirmed via the Anderson-Darling test, both the conventional t test (A vs B means) and the paired difference t test (A-B differences by subject) were applied to test the response in wrinkle reduction. Both t test results were statistically significant with greater than 98% and 99% confidence, respectively, confirming that B-side treatment resulted in a higher mean (SD) reduction in wrinkles: 794.1 (345.6) mm2 vs 476.6 (101.3) mm2.

Figure 2. Wrinkle reduction response data are depicted using the histogram by treatment side, an effective graph for portraying dispersion and central tendency. The A side is the more concentrated and the B side the more dilute preparation of abobotulinum toxin A. Under the assumption of normality, which was confirmed via the Anderson-Darling test, both the conventional t test (A vs B means) and the paired difference t test (A-B differences by subject) were applied to test the response in wrinkle reduction. Both t test results were statistically significant with greater than 98% and 99% confidence, respectively, confirming that B-side treatment resulted in a higher mean (SD) reduction in wrinkles: 794.1 (345.6) mm2 vs 476.6 (101.3) mm2.

1.
Hsu TS, Dover JS, Arndt KA. Effect of volume and concentration on the diffusion of botulinum exotoxin A.  Arch Dermatol. 2004;140(11):1351-1354PubMedArticle
2.
Francisco GE, Boake C, Vaughn A. Botulinum toxin in upper limb spasticity after acquired brain injury: a randomized trial comparing dilution techniques.  Am J Phys Med Rehabil. 2002;81(5):355-363PubMedArticle
3.
Glogau RG. Aesthetic and anatomic analysis of the aging skin.  Semin Cutan Med Surg. 1996;15(3):134-138PubMedArticle
4.
Klein AW, Carruthers A, Fagien S, Lowe NJ. Comparisons among botulinum toxins: an evidence-based review.  Plast Reconstr Surg. 2008;121(6):413e-422ePubMedArticle
5.
Carruthers A, Bogle M, Carruthers JDL,  et al.  A randomized, evaluator-blinded, two-center study of the safety and effect of volume on the diffusion and efficacy of botulinum toxin type A in the treatment of lateral orbital rhytides.  Dermatol Surg. 2007;33(5):567-571PubMedArticle
Research Letter
Jan 2012

A Small Study of the Relationship Between Abobotulinum Toxin A Concentration and Forehead Wrinkle Reduction

Author Affiliations

Author Affiliations: Summit Medical Group, Berkeley Heights, New Jersey (Dr Abbasi); American Society for Quality, Milwaukee, Wisconsin (Ms Durfee); SkinCare Physicians, Chestnut Hill, Massachusetts (Ms Petrell and Drs Arndt and Dover).

Arch Dermatol. 2012;148(1):119-121. doi:10.1001/archdermatol.2011.611

Botulinum toxin A has been used in the cosmetic treatment of facial rhytids for decades. Previous studies have examined the role of volume and concentration on the spread of onabotulinum toxin A, both on and off the face, and on the treatment of dynamic rhytids1 and muscle spasticity.2 Our clinical experience suggests that abobotulinum toxin A may in fact spread differently than its counterparts. To determine if this was true, we treated 10 patients with each of 2 concentrations of abobotulinum toxin A to assess differences in rhytid reduction on contralateral sides of the forehead. We hypothesized that dilution may affect capacity of the toxin to spread to neuromuscular receptors, which may in turn affect surface area of effect.

Methods

After the research protocol was approved by the New England institutional review board, 10 patients, aged 35 to 65 years, with moderately severe forehead rhytids (Glogau II and III)3 were recruited to participate in a study involving the delivery of 6 U of abobotulinum toxin A (Dysport; Medicis) to the right and left forehead. On one side, 6 U were diluted in 0.1 mL of sterile preserved saline solution. On the other side, 6 U were diluted in 0.3 mL of sterile preserved saline solution. The product was diluted in a 20-mL syringe after extraction from its original bottle to achieve the dilutions required by the study protocol.

Subjects were randomized with regard to who received which concentration on a particular side, and on both sides the product was delivered to prominent horizontal rhytids measuring between 2.5 and 3.0 cm above the orbital rim in the mid-pupillary line (Figure 1). Abobotulinum toxin A was injected with minimal pressure at a 90 ° angle of incidence to a depth of approximately 1 mm below the surface of the skin. Exclusion criteria included pregnancy; history of botulinum toxin injection to the forehead in the prior 12 months or long-acting dermal filler injection (including silicon, Sculptra [sanofi-aventis], and Radiesse [Merz]) to the forehead at any time; history of neuromuscular disease or palsy; prior hypersensitivity to a botulinum toxin; and concomitant use of medications affecting neuromuscular blockade including aminoglycosides, anticholinesterases, lincosamides, and polymyxins.

All patients were photographed at rest and at maximum brow elevation, and distances from the orbital rim to the injection site were carefully measured. The same unblinded physician (N.R.A.) treated and photographed all subjects, while a separate, blinded physician (K.A.A.) recorded rhytid reduction on actual subjects (ie, not photographs) at 14 days post treatment. The blinded physician marked the horizontal and vertical extent of wrinkle reduction in millimeters around the original injection site with a red pen. Subsequently, wrinkle reduction was measured in millimeters squared on each side of the forehead, and the 2 treated sides were compared.

Results

Nine men and 1 woman between the ages of 35 and 63 years were recruited. All participants experienced visible rhytid reduction to both sides of the forehead, and none had adverse reactions including bruising, headache, and eyebrow or eyelid ptosis.

Statistical analysis of rhytid reduction revealed a marked and statistically significant difference between contralateral sides of the forehead vis- à-vis abobotulinum toxin A concentration. Consistently, the more dilute concentration of the product produced a larger surface area of rhytid reduction. The more concentrated solution produced a mean wrinkle reduction of 476.6 mm2, while the more dilute solution produced a mean wrinkle reduction of 794.1 mm2 (Figure 2). P values for both data sets supported statistical significance. Paired t tests and box plot analyses confirmed these findings (data not shown).

Photographs revealed that the pattern of wrinkle reduction in most subjects did not exhibit a perfectly circular pattern but rather varied from ovoid to irregular, with some patients clearly exhibiting more wrinkle reduction on one side of the injection site.

Comment

There is no standard conversion ratio for comparing different formulations of botulinum toxins, making the comparison of one type with another difficult.4 Moreover, there is no consensus among practitioners whether low-volume/high-concentration injections of botulinum toxins or higher-volume/lower-concentration injections produce better clinical outcomes.5 While there are data to support the value of lower-concentration/ “more spread ” techniques in particular muscle groups including the frontalis muscle,1 other studies report no advantage to variations in concentration of onabotulinum toxin A when treating periocular rhytids5 or muscle spasticity.2 Abobotulinum toxin A diffusion has been little studied owing to its more recent emergence into clinical practice.

In certain clinical situations, such as in the injection of glabellar muscles, clinicians may be rightly concerned about unwanted spread producing complications including muscle ptosis. In the injection of larger or broader muscle complexes, including the frontalis, the concept of spread may prove advantageous to clinical outcome. The variation in spread across patients in a small study such as this one makes generalizations about product spread across a larger population difficult. However, our findings reinforce the principle that product diffusion is a complex phenomenon likely influenced by factors including bulk of muscle mass, dynamic movement of muscles, and actual dose delivered.

This study suggests that dilution of abobotulinum toxin A may help to improve delivery to a wider surface area and thus may allow clinicians to achieve desired clinical outcomes while using modest doses of toxin. Longevity of rhytid reduction on each side of the forehead was not assessed because the treatment resulted in marked asymmetry of rhytids at 2-week follow-up that required correction with additional product. Future studies to assess the relationship between product dilution and longevity would be useful, as would specific comparisons of the diffusion properties of different botulinum toxins used in medical practice.

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Article Information

Correspondence: Dr Abbasi, 9 Edwards Pl, Short Hills, NJ 07078 (nabbasi@smgnj.com).

Accepted for Publication: August 28, 2011.

Author Contributions: Dr Abbasi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Abbasi, Dover, and Arndt. Acquisition of data: Abbasi, Petrell, and Dover. Analysis and interpretation of data: Abbasi, Durfee, and Dover. Drafting of the manuscript: Abbasi and Dover. Critical revision of the manuscript for important intellectual content: Abbasi, Durfee, Petrell, Dover, and Arndt. Statistical analysis: Durfee. Obtained funding: Dover. Administrative, technical, and material support: Abbasi, Petrell, and Dover. Study supervision: Abbasi, Dover, and Arndt.

Financial Disclosure: Dr Dover is a consultant for Medicis.

Funding/Support: This study was supported in large part by a grant from Medicis.

Role of the Sponsors: The sponsors had no role in the design and conduct of the study; in the collection, analysis, or interpretation of data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: Erin Archard, BA, Joaninha Depina, BA, and Shivani Patel, BA, provided invaluable assistance with administrative and clinical tasks related to this study.

References
1.
Hsu TS, Dover JS, Arndt KA. Effect of volume and concentration on the diffusion of botulinum exotoxin A.  Arch Dermatol. 2004;140(11):1351-1354PubMedArticle
2.
Francisco GE, Boake C, Vaughn A. Botulinum toxin in upper limb spasticity after acquired brain injury: a randomized trial comparing dilution techniques.  Am J Phys Med Rehabil. 2002;81(5):355-363PubMedArticle
3.
Glogau RG. Aesthetic and anatomic analysis of the aging skin.  Semin Cutan Med Surg. 1996;15(3):134-138PubMedArticle
4.
Klein AW, Carruthers A, Fagien S, Lowe NJ. Comparisons among botulinum toxins: an evidence-based review.  Plast Reconstr Surg. 2008;121(6):413e-422ePubMedArticle
5.
Carruthers A, Bogle M, Carruthers JDL,  et al.  A randomized, evaluator-blinded, two-center study of the safety and effect of volume on the diffusion and efficacy of botulinum toxin type A in the treatment of lateral orbital rhytides.  Dermatol Surg. 2007;33(5):567-571PubMedArticle
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