Section 4 Plastic and Reconstructive Problems

TR I NDADE DE ALME I DA ET AL

efficacy in the treatment of glabellar frown lines for up to 4 months. 52 In the 2004 consensus panel, 73% of panelists stored onabotulinumtoxinA for more than 4 hours. 22 Lizarralde and colleagues studied 30 patients injected for external canthus dynamic lines with onabotulinumtoxinA reconstituted 1 week before its use. They found clinical results similar to those with freshly reconstituted toxin. 53 Another study 54 demonstrated that onabotulinumtoxinA used after 2 weeks of refrigeration had no changes in time of onset or efficacy in the treatment of lateral or- bital rhytides, and a recent experimental trial in mice did not find loss of efficacy in onabotulinum- toxinA vials reconstituted for up to 6 weeks before use. 47 A study with abobotulinumtoxinA 55 reconstituted 2 weeks before injection in 105 patients found no difference in safety or efficacy. A consensus panel in 2010 32 found that reconstituted abobotulinumtox- inA can be used within 2 to 3 weeks without adverse effects. In animal models, Gartlan and Hoffmann 27 and Jabor and colleagues 28 found loss of efficacy if the onabotulinumtoxinA was frozen for longer than 2 weeks. Greene 29 ‘‘argued that in vitro experiments may not reflect clinical practice.’’ His opinion that the frozen toxin remained effective for several weeks was similar to clinical study results 30,31 that found no loss of activity or additional side effects for up to 8 weeks. Parsa and colleagues 4 compared reconstituted onabotulinumtoxinA frozen for up to 6 months with onabotulinumtoxinA not frozen and used within 4 hours after reconstitution in 118 sites in 80 patients and concluded that reconstituted onabotulinumtoxinA may be frozen, thawed, and injected without losing its potency for up to 6 months. Kane found that these conclusions Fresh or Frozen

were consistent with anecdotal reports from many injectors. 56

The ultrastructural alterations of the muscle and nerve after the injection of fresh versus stored onabotulinumtoxinA were evaluated using electron microscopy. 57 Fifteen rabbits were injected with toxin freshly reconstituted or stored for 2 weeks under refrigeration and had muscles and motor nerves harvested at 5 days and 12 weeks. No dif- ferences were found at the 5-day evaluation. At 12 weeks, the group that used stored toxin showed less- severe atrophic changes in the muscle, whereas no differences were encountered on nerve evaluation. In the same experimental trial in mice cited above, Shome and colleagues 47 did not find loss of efficacy in onabotulinumtoxinA vials reconstituted and kept refrigerated for up to 6 weeks before use. Yang and colleagues, 58 in a prospective, double- blind, randomized controlled trial with 40 subjects treated for horizontal forehead rhytides, found no difference in potency or duration of efficacy of abobotulinumtoxinA after 2 weeks of refrigeration or freezing from that of freshly reconstituted abobotulinumtoxinA. Because storing and reusing reconstituted toxin for a period of weeks has become a frequent practice, sterility assessment is an important issue that some authors have addressed. Alam and colleagues 59 evaluated 127 vials of onabotulinumtoxinA reconstituted using preserva- tive-containing saline, stored, and reused, simulating the routine storage and extraction methods per- formed in clinical practice. Each vial underwent an average of 4.5 access procedures during a period of up to 7 weeks, and contamination was not evidenced in sterility analysis. Sterility

Menon 60 analyzed 11 consecutive bottles of abobotulinumtoxinA left for 4 hours at room

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