Efficacy and Safety of AbobotulinumtoxinA for the Treatment of Glabellar Lines in Chinese Patients: A Pivotal, Phase 3, Randomized, Double-Blind and Open-Label Phase Study.

BACKGROUND: Various botulinumtoxinA formulations are approved for glabellar lines treatment worldwide, including abobotulinumtoxinA (Dysport®). OBJECTIVES: Assess abobotulinumtoxinA superiority versus placebo and non-inferiority versus active comparator (onabotulinumtoxinA; Botox®), for the treatment of Chinese patients with moderate/severe glabellar lines. METHODS: Phase 3, randomized study (NCT02450526) comprising a double-blind (cycle 1) phase and an open-label (cycles 2-5) phase. Patients received abobotulinumtoxinA 50 units or matching placebo (5:1), active comparator (onabotulinumtoxinA 20 units) or matching placebo (5:1). In cycles 2-5, eligible patients were retreated with abobotulinumtoxinA only. Responders had glabellar lines of none/mild severity. PRIMARY ENDPOINT: responder rates at cycle 1, day 29 at maximum frown with abobotulinumtoxinA versus placebo (for superiority; by investigator's live assessment [ILA] and subject's self-assessment [SSA]), and versus active comparator (for non-inferiority; by ILA). Treatment-emergent adverse events were recorded. RESULTS: Overall, 520 patients were randomized. Superiority and non-inferiority, respectively, were demonstrated for abobotulinumtoxinA versus placebo (ILA, SSA; both p < 0.0001) and abobotulinumtoxinA versus active comparator. AbobotulinumtoxinA efficacy was maintained over open-label cycles; median time to onset of efficacy was 2.0 days. After 6 months, 17% of patients treated with abobotulinumtoxinA remained responders. AbobotulinumtoxinA was well-tolerated. Safety results were in line with the known profile of abobotulinumtoxinA; adverse events rate decreased with repeated treatment. CONCLUSIONS: After a single injection, abobotulinumtoxinA demonstrated superiority versus placebo and non-inferiority versus onabotulinumtoxinA for the treatment of moderate-to-severe glabellar lines in Chinese patients. Multiple injections of abobotulinumtoxinA demonstrated efficacy and safety in the treatment of glabellar lines in Chinese patients. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Botulinum toxin injections can be used to smooth frown lines that appear between the eyebrows (known as glabellar lines) in patients who have moderate or severe frown lines. This study looked at how injections of a botulinum toxin (abobotulinumtoxinA [aboBoNT-A]) could help with smoothing frown lines in patients from China compared with an injection of another botulinum toxin called onabotulinumtoxinA (onaBoNT-A) or placebo (saltwater, no treatment). The study included 520 patients from China, 18­65 years old, who had moderate or severe frown lines. All patients received a first injection of either aboBoNT-A, onaBoNT-A, or saltwater, and were studied for 12 weeks. After the first injection, patients could receive up to four more injections of aboBoNT-A, given at 12-week intervals, if their frown lines became moderate or severe again. Most patients (92%) had not previously received any botulinum toxin injections. The results showed that single and repeat injections of aboBoNT-A helped to smooth moderate and severe frown lines. The researchers found that after a single injection, aboBoNT-A was superior to no treatment and was similar to onaBoNT-A. Patients recorded a response to aboBoNT-A after 2 days and the response lasted for 6 months in 17% of patients. The effect on frown lines was maintained after repeat injections and aboBoNT-A was well tolerated by patients. These results suggest that aboBoNT-A is a suitable treatment for smoothing frown lines in patients from China with moderate to severe frown lines.

Postmarket Safety Surveillance of Delayed Complications for Recent FDA-Approved Hyaluronic Acid Dermal Fillers.

OBJECTIVE: To review postmarketing data for delayed (≥14 days post-treatment) adverse events (AEs) of interest (inflammatory and noninflammatory nodules, hypersensitivity, granulomas) for newer hyaluronic acid (HA) fillers FDA-approved within the last 5 years (2016-2020). METHODS: Reports from the Manufacturer and User Facility Device Experience (MAUDE) database were extracted for HAREF, HADEF, HAKYS, HAVER, HAVLR, HAVOB, HARH2, HARH3, and HARH4 from January 2016 to January 2021. Keywords from event narratives were used to identify and categorize AEs and then verified through inclusion/exclusion criteria. Percentages are based on the total combined events of interest to provide an overall perspective of the events reported during the search period. RESULTS: Of 585 MAUDE reports, there were 195 (33.3%) delayed AEs of interest. Of those, 71.8% were nodules (42.1% inflammatory and 29.7% noninflammatory), 21.5% hypersensitivity, and 6.7% granulomas. The combined total events of interest, ordered by frequency reported, were HAVLR (74.4%), HAVOB (12.3%), HADEF (5.1%), HARH4 (3.6%), HAREF (2.6%), and HARH2 (2.1%), with no reports for HARH3, HAVER, and HAKYS. CONCLUSION: Although delayed nodules and inflammatory events are rare, reports for these events were extracted from the MAUDE database from 2016 to 2020 for HAVLR, HAVOB, HADEF, HARH4, HAREF, and HARH2 (most to least frequent).

Liquid AbobotulinumtoxinA: Pooled Data From Two Double-Blind, Randomized, Placebo-Controlled Phase III Studies of Glabellar Line Treatment.

BACKGROUND: AbobotulinumtoxinA (aboBoNT-A) solution is a new ready-to-use formulation developed to reduce preparation time and improve reproducibility of injections. OBJECTIVE: To further evaluate treatment of moderate-to-severe glabellar lines (GLs) using pooled data from 2 Phase III studies. METHODS: Following double-blind treatment with 50 U aboBoNT-A solution (n = 251) or placebo (n = 123), GL severity was assessed by investigators (ILA) and subjects (SSA). Other assessments included subject-reported time to onset, subject satisfaction, FACE-Q, and adverse events. RESULTS: One month after aboBoNT-A solution treatment, 88% had none-or-mild GLs at maximum frown and 93% had ≥1-grade improvement in ILA (similar for SSA), 24% to 27% remaining improved at Month 6. Glabellar lines responder rates remained higher than placebo throughout Month 6 ( p < .001). Almost two-thirds of subjects reported onset within 3 days, nearly a quarter reporting effect by Day 1. Subject satisfaction with GL appearance, and FACE-Q satisfaction with facial appearance overall and psychological well-being were also improved over placebo throughout Month 6, p < .05. Treatment-related adverse events were nonserious and mild or moderate. CONCLUSION: Pooled analysis confirmed a duration of effect on GLs of up to 6 months for aboBoNT-A solution, with onset starting within 24 hours, high subject satisfaction, and improved psychological well-being. The treatment was well tolerated.

Expert Recommendations on the Use of Hyaluronic Acid Filler for Tear Trough Rejuvenation.

Restylane® Lidocaine is one of the most widely used hyaluronic acid (HA) fillers to replace lost or displaced volume during tear trough correction. Patient goals for tear trough correction include looking less tired or removing dark circles and this may be achieved by administering HA filler into the infraorbital region to correct the lower eyelid relative to the volume deficit, thereby smoothing the transition from the lower eyelid to the cheek. To achieve patient satisfaction and consistent results with Restylane, optimal application is essential; however, clinical guidance based on experience is limited. This paper reflects the recommendations of an interdisciplinary expert panel for the use of Restylane in correcting tear trough deformity, including patient selection, dosing, injection technique, and post-treatment care. Recommendations were discussed and agreed as a consensus, according to cross-sectional expertise and clinical experience. J Drugs Dermatol. 2022;21(4):387-392. doi:10.36849/JDD.6597.

Long-term Efficacy and Safety of Liquid AbobotulinumtoxinA Formulation for Moderate-to-Severe Glabellar Lines: A Phase III, Double-Blind, Randomized, Placebo-Controlled and Open-Label Study.

BACKGROUND: A ready-to-use liquid formulation of abobotulinumtoxinA (aboBoNT-A solution) has been developed. OBJECTIVES: The aim of this study was to assess the long-term efficacy and safety of aboBoNT-A solution for the treatment of glabellar lines. METHODS: This was a multicenter, multinational, Phase III study (NCT02493946), with randomized double-blind placebo-controlled (DBPC; 2:1 aboBoNT-A solution 50 U/placebo) and open-label (4 cycles aboBoNT-A solution) periods; additional patients were recruited into the open-label period. Patients were 18 to 65 years old, BoNT-naïve, and dissatisfied/very dissatisfied with moderate/severe glabellar lines at maximum frown. Investigator's live assessment (primary endpoint)/subject's self-assessment of glabellar line severity at maximum frown, patient satisfaction with glabellar line appearance, and FACE-Q patient-reported scales (facial appearance overall, psychological well-being, aging) were assessed. Adverse events were monitored. Analyses were performed on DBPC and long-term analysis (LTA; all patients receiving ≥1 aboBoNT-A solution injection) populations. RESULTS: Responder rates for the investigator's live assessment, the subject's self-assessment, and patient satisfaction were consistent at Day 29 postinjection across repeat LTA cycles (82.2%-87.8%, 62.8%-80.6%, and 72.2%-87.8%, respectively), with statistically significantly higher responder rates vs placebo (DBPC cycle: 81.6% vs 0.8%, 68.1% vs 2.3%, and 83.1% vs 5.7%, respectively; all P < 0.0001). Consistent improvements on FACE-Q scales occurred with repeat cycles (DBPC cycle: aboBoNT-A solution vs placebo, P < 0.0001). No new or unexpected adverse events, or neutralizing antibodies, were observed. CONCLUSIONS: These results support the long-term efficacy and safety of aboBoNT-A solution, and its superiority over placebo, for treatment of glabellar lines in adults.

Chart Review Presenting Safety of Injectable PLLA Used With Alternative Reconstitution Volume for Facial Treatments.

BACKGROUND: Since the approval of Sculptra Aesthetic, the amount of sterile water used to reconstitute the product has gradually increased in clinical practice. A retrospective chart review was conducted to evaluate patient safety associated with a larger reconstitution volume, and to investigate specific parameters for how Sculptra Aesthetic is used in a real-world clinical setting. OBJECTIVE: The primary objective of the study was to evaluate the safety of Sculptra Aesthetic when using a reconstitution volume of 7 to 10 mL, via collection of adverse events related to the product or injection procedure reported in medical records. METHODS: This was a multi-center, retrospective chart review conducted in the US. Medical records for subjects treated in the facial area with Sculptra Aesthetic reconstituted to 7–10 mL were reviewed to obtain information about demographics, treatment data, and adverse events. Each injector completed a questionnaire regarding reconstitution and injection procedures generally used. RESULTS: There were 4483 treatments performed in 1002 subjects; nearly half (48%) had 3 or 4 treatments during the studied period. Subjects most commonly received treatment in the midface/cheek area (97%), temple (94%), and jawline (54%). All injectors indicated adding lidocaine to the solution, resulting in total volumes of 8–10 mL. Adverse events were reported by 3.6% of subjects, all mild in intensity. Nodules were reported by 4 subjects (0.4%). CONCLUSION: The low number of AEs reported in this retrospective chart review suggests that facial aesthetic treatment with PLLA reconstituted to a final volume of 8–10 mL, including anesthetics, is associated with a favorable risk benefit ratio. J Drugs Dermatol. 2021;20(1):18-22. doi:10.36849/JDD.5631.

Efficacy and Safety of Microencapsulated Benzoyl Peroxide Cream, 5%, in Papulopustular Rosacea in Elderly Patients: Post-hoc Analysis of Results from Two Randomized, Phase III, Vehicle-controlled Trials.

Objective: We sought to compare the efficacy and safety of encapsulated benzoyl peroxide (E-BPO) cream, 5%, versus vehicle in subjects <65 years of age versus subjects ≥65 with moderate to severe papulopustular rosacea. Methods: This analysis used pooled results from two 12-week, randomized, vehicle-controlled Phase III trials (NCT03564119, NCT03448939) of E-BPO cream, 5%. These trials included 733 subjects randomized 2:1 to E-BPO or vehicle. The primary endpoints were success in the Investigator's Global Assessment (IGA) score and reduction in mean inflammatory lesion count at Week 12. Results: Our analysis shows that E-BPO cream, 5%, was significantly superior to vehicle in achieving IGA success and reducing inflammatory lesions in both age groups. IGA success was achieved in 48.3% of subjects who received E-BPO versus 25.4% for vehicle in the intent-to-treat population. The E-BPO and vehicle IGA success percentages for subjects <65 were 45.7% and 23.8%, respectively, and those for subjects ≥65 were 60.0% and 28.1%, respectively. The absolute reduction from baseline in inflammatory lesions was -19.3 for subjects who received E-BPO versus -11.4 for those who received vehicle. The E-BPO and vehicle absolute reduction values for subjects <65 were -19.6 and -11.2, respectively, and 17.5 and -10.4 for subjects ≥65. There were no significant differences in the frequencies of adverse events or cutaneous tolerability. Limitations: E-BPO was not compared to nonencapsulated BPO. Conclusion: This combined analysis of results from the two Phase III, randomized, double-blind controlled studies of E-BPO cream, 5%, showed it was efficacious, tolerable, and safe, regardless of age.

Patient Satisfaction with AbobotulinumtoxinA for Aesthetic Use in the Upper Face: A Systematic Literature Review and Post-hoc Analysis of the APPEAL Study.

BACKGROUND: AbobotulinumtoxinA (AboBoNT-A; Dysport®; Ipsen, Boulogne-Billancourt, France/Azzalure®; Galderma, Lausanne, Switzerland) is a botulinum neurotoxin type A approved for aesthetic use in the treatment of glabellar lines in adult patients under 65 years in Europe, the United States, and other countries. OBJECTIVE: We sought to analyze current literature on patient satisfaction with aboBoNT-A for upper facial aesthetic indications. METHODS: A systematic review of literature databases (PubMed/MEDLINE, Embase, the Cochrane Library, and Google Scholar) was performed to identify English-language publications reporting on patients with aesthetic indications (including glabellar lines and wrinkles) receiving aboBoNT-A, that assessed patient and/or physician satisfaction with treatment, with no restrictions on comparator studies. Structured data extraction was used to enable inter-study analysis. A post-hoc analysis was also performed to assess patient satisfaction by sex and age, using results from the noninterventional APPEAL study of patients' satisfaction with aboBoNT-A for treating glabellar lines. RESULTS: Overall, 22 original research papers were identified. Patient satisfaction rates for aboBoNT-A treatment were significantly higher versus placebo from two weeks to between three and five months postinjection. At two to three weeks postinjection, patient satisfaction rates were 52% and 99% across studies. In studies with later time points, patient satisfaction rates were 85 to 87 percent at 5 months and between 25 and 100 percent at 6 months post-injection. Physician satisfaction was also high (97%-100%, across three treatments). No notable differences in patient satisfaction by sex or age were observed in the APPEAL study. CONCLUSION: High rates of patient satisfaction have been achieved with aboBoNT-A treatment for upper facial aesthetic indications. Despite the current recommended interval of ≥12 weeks, satisfaction with the aesthetic results of aboBoNT-A therapy is still evident up to 6 months post-injection in some patients.

Onset and Duration of AbobotulinumtoxinA for Aesthetic Use in the Upper face: A Systematic Literature Review.

OBJECTIVE: We sought to analyze the current literature regarding time to onset and duration of effect of abobotulinumtoxinA (aboBoNT-A, Dysport®/Azzalure®) for upper facial aesthetic indications. METHODS: We conducted a systematic review of literature databases (PubMed/MEDLINE, Embase, Cochrane Library, and Google Scholar) to identify English-language publications relevant to: population (patients with aesthetic indications [including glabellar lines and wrinkles]); interventions (aboBoNT-A); comparators (no restrictions); outcomes (efficacy, including onset of action and duration of effect); and settings (clinical). A manual search of review paper bibliographies was performed. Structured data extraction was used to enable interstudy analysis. RESULTS: Overall, 42 original research papers relevant to aboBoNT-A onset and/or duration were identified. All 24 studies assessing efficacy within one week post-injection demonstrated some response at the first time point assessed, and all 37 studies assessing duration showed some response after 12 weeks. Although methodologies for assessing onset and duration differed, when outcomes were refined by reported mean/median, at least 50 percent of patients responding to treatment, or significance versus placebo or baseline at a given time point, onset was most often reported within 2 to 3 days (7 studies), and as early as 24 hours (2 studies). Duration was most often reported as four months (18 studies), although four studies provided evidence that aboBoNT-A efficacy was maintained at five months and three studies at or after six months post-injection. CONCLUSION: This review indicates that aboBoNT-A has a median onset of efficacy of 2 to 3 days and a longer duration of action (3-6 months across studies) than the current labelled minimum treatment interval (12 weeks).

Sodium nitroprusside promotes IRP2 degradation via an increase in intracellular iron and in the absence of S nitrosylation at C178.

In iron-replete cells the posttranscriptional regulator IRP2 undergoes ubiquitination and proteasomal degradation. A similar response occurs in cells exposed to sodium nitroprusside (SNP), an NO-releasing drug. It has been proposed that nitroprusside ([Fe(CN)5NO]2-) fails to donate iron into cells and that it promotes IRP2 degradation via S nitrosylation at C178. This residue is located within a stretch of 73 amino acids, earlier proposed to define an iron-dependent degradation domain. Surprisingly, we show that IRP2 bearing a C178S mutation or a Delta73 deletion is sensitive to degradation not only by ferric ammonium citrate (FAC) but also by SNP. Moreover, FAC and SNP attenuate the RNA-binding activities of IRP2 and its homologue IRP1 with similar kinetics. Actinomycin D, cycloheximide, succinylacetone, and dimethyl-oxalylglycine antagonize IRP2 degradation in response to both FAC and SNP, suggesting a common mechanistic basis. IRP2 is not only sensitive to fresh, but also to photodegraded SNP and remains unaffected by S-nitrosoglutathione (GSNO), an established nitrosation agent. Importantly, both fresh and photodegraded SNP, but not GSNO, promote a >4-fold increase in the calcein-accessible labile iron pool. Collectively, these results suggest that IRP2 degradation by SNP does not require S nitrosylation but rather represents a response to iron loading.

Sustained hydrogen peroxide induces iron uptake by transferrin receptor-1 independent of the iron regulatory protein/iron-responsive element network.

Local and systemic inflammatory conditions are characterized by the intracellular deposition of excess iron, which may promote tissue damage via Fenton chemistry. Because the Fenton reactant H(2)O(2) is continuously released by inflammatory cells, a tight regulation of iron homeostasis is required. Here, we show that exposure of cultured cells to sustained low levels of H(2)O(2) that mimic its release by inflammatory cells leads to up-regulation of transferrin receptor 1 (TfR1), the major iron uptake protein. The increase in TfR1 results in increased transferrin-mediated iron uptake and cellular accumulation of the metal. Although iron regulatory protein 1 is transiently activated by H(2)O(2), this response is not sufficient to stabilize TfR1 mRNA and to repress the synthesis of the iron storage protein ferritin. The induction of TfR1 is also independent of transcriptional activation via hypoxia-inducible factor 1alpha or significant protein stabilization. In contrast, pulse experiments with (35)S-labeled methionine/cysteine revealed an increased rate of TfR1 synthesis in cells exposed to sustained low H(2)O(2) levels. Our results suggest a novel mechanism of iron accumulation by sustained H(2)O(2), based on the translational activation of TfR1, which could provide an important (patho) physiological link between iron metabolism and inflammation.

Expression of the subgenomic hepatitis C virus replicon alters iron homeostasis in Huh7 cells.

BACKGROUND/AIMS: Infection with hepatitis C virus (HCV) is associated with alterations in body iron homeostasis by poorly defined mechanisms. To seek for molecular links, we employed an established cell culture model for viral replication, and assessed how the expression of an HCV subgenomic replicon affects iron metabolism in host Huh7 hepatoma cells. METHODS: The expression of iron metabolism genes and parameters defining the cellular iron status were analyzed and compared between parent and replicon Huh7 cells. RESULTS: By using the IronChip microarray platform, we observed replicon-induced changes in expression profiles of iron metabolism genes. Notably, ceruloplasmin mRNA and protein expression were decreased in replicon cells. In addition, transferrin receptor 1 (TfR1) was also downregulated, while ferroportin levels were elevated, resulting in reduced iron uptake and increased iron release capacity of replicon cells. These responses were associated with an iron-deficient phenotype, manifested in decreased levels of the "labile iron pool" and concomitant induction of IRE-binding activity and IRP2 expression. Furthermore, hemin-treated replicon cells exhibited a defect in retaining iron. The clearance of the replicon by prolonged treatment with interferon-alpha only partially reversed the iron-deficient phenotype but almost completely restored the capacity of cured cells to retain iron. CONCLUSIONS: We propose that Huh7 cells undergo genetic reprogramming to permit subgenomic viral replication that results in reduction of intracellular iron levels. This response may provide a mechanism to bypass iron-mediated inactivation of the viral RNA polymerase NS5B.

Hepcidin generated by hepatoma cells inhibits iron export from co-cultured THP1 monocytes.

BACKGROUND/AIMS: The antimicrobial peptide hepcidin is generated in the liver and released into the circulation in response to iron, oxygen and inflammatory signals. Hepcidin serves as a hormonal regulator of duodenal iron absorption and iron trafficking in the reticuloendothelial system. The aim of this study is to explore the effects of this regulatory peptide in macrophage iron metabolism. METHODS: Hepcidin-mediated iron efflux and parameters of cellular iron homeostasis were studied in THP1 monocytic cells co-cultured with hepcidin-producing hepatic cells. RESULTS: Stimulation of hepcidin expression in Huh7 cells with interleukin-6 promoted a significant approximately 30% decrease in 59Fe efflux from THP1 cells, previously loaded with 59Fe-transferrin. Similar results were obtained with HepG2 cells transfected with a hepcidin cDNA. Importantly, hepcidin expression from Huh7 cells elicited a decrease in the levels of the iron-sensitive post-transcriptional regulator IRP2 in THP1 cells, accompanied by de novo synthesis of the iron storage protein ferritin. CONCLUSIONS: Physiologically generated hepcidin inhibits iron efflux and promotes iron accumulation in monocytic cells, mimicking a pathophysiological response commonly observed in the anemia of inflammation. Our results highlight the crucial role of hepcidin in the control of macrophage iron homeostasis.

ANP-induced decrease of iron regulatory protein activity is independent of HO-1 induction.

Atrial natriuretic peptide (ANP)-preconditioned livers are protected from ischemia-reperfusion injury. ANP-treated organs show increased expression of heme oxygenase (HO)-1. Because HO-1 liberates bound iron, the aim of our study was to determine whether ANP affects iron regulatory protein (IRP) activity and, thus, the levels of ferritin. Rat livers were perfused with Krebs-Henseleit buffer [+/-ANP, 8-bromo-cGMP (8-Br-cGMP), and tin protoporphyrin, 20 min], stored in University of Wisconsin solution (4 degrees C, 24 h), and reperfused (120 min). IRP activity was assessed by gel-shift assays, and ferritin, IRP phosphorylation, and PKC localization were assessed by Western blot. Control livers displayed decreased IRP activity at the end of ischemia but no change in ferritin content during ischemia and reperfusion. ANP-pretreated livers showed reduced IRP activity, an effect mimicked by 8-Br-cGMP. Ferritin levels were increased in ANP-pretreated organs. Simultaneous perfusion of livers with ANP and tin protoporphyrin did not reduce ANP-induced action, arguing against a role for HO-1 in changes in IRP activity. ANP and 8-Br-cGMP decreased membrane localization of PKC-alpha and PKC-epsilon, but this modulation of PKC seems unrelated to inhibition of IRP binding. This work shows the cGMP-mediated attenuation of IRP binding activity by ANP, which results in increased hepatic ferritin levels. This change in IRPs is independent of ANP-induced HO-1 and reduced PKC activation.