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.

AbobotulinumtoxinA for the Treatment of Moderate-to-Severe Glabellar Lines: A Randomized, Dose-Escalating, Double-Blind Study.

OBJECTIVE: To evaluate the efficacy and safety of AbobotulinumtoxinA (ABO) dose escalation in the correction of moderate-to-severe glabellar lines. DESIGN: Phase 2, 36-week, multicenter, randomized, dose-ranging, double-blind, placebo-controlled study. METHODS: Adults with moderate-to-severe glabellar lines received a single ABO treatment, dosed at 50, 75, 100, or 125 U, or placebo. Primary endpoint was week 4 composite ≥2-grade responder rate among those achieving a severity score of 0 (none) or 1 (mild) at maximum frown, evaluated using concurrent investigator and subject assessments. Secondary endpoints included ≥1-grade severity improvement, duration of effect, and reporting of treatment-emergent adverse events (TEAEs). RESULTS: Overall, 399 subjects were included (88.2% were female). Week 4 composite ≥2-grade ABO responder rate was 80.0% (50 U), 88.8% (75 U), 90.0% (100 U) and 95.1% (125 U), versus 2.6% with placebo (P<0.001). Responder rate (≥1-grade) ranged between 53% (50 U) and 69% (125 U) at week 24 and between 18% (50 U) and 31% (125 U) at week 36. Median time (weeks) to return to baseline severity/worse, among those scoring 0 (none) or 1 (mild), was 32.3 (50 U), 34.3 (75 U), 36.0 (100 U) and 36.6 (125 U), versus 23.7 (placebo). ABO-related TEAEs were reported in 4% of subjects (80% were mild). No seroconversion to ABO neutralizing antibodies was seen. CONCLUSION: A single ABO treatment provided rapid and effective improvements in glabellar line severity at all doses. Higher doses tended to demonstrate elevated response rates and longer duration of effect. All ABO doses were well-tolerated with low TEAE incidence. J Drugs Dermatol. 2021;20(9):980-987. doi:10.36849/JDD.6263.

Randomized, Evaluator-Blinded Study Comparing Safety and Effect of Two Hyaluronic Acid Gels for Lips Enhancement.

BACKGROUND: Hyaluronic acid (HA) fillers may differ in terms of gel characteristics and ease of use and it is of interest whether this might affect safety and duration of effect. OBJECTIVE: To compare the long-term safety and effect of 2 HA fillers produced by 2 different technologies for lip enhancement. MATERIALS AND METHODS: Subjects with very thin to moderately thick lips were randomized and treated with HA-RK (N = 31) or HA-JV (N = 29) to improve lip fullness by ≥ 1 grade on a 5-point scale, using a maximum of 3 mL of product. RESULTS: A smaller volume of HA-RK compared with HA-JV was required to improve lip fullness by ≥ 1 grade (mean: 1.54 mL vs 1.94 mL, p < .001). Despite the smaller volume, lip fullness and global aesthetic improvement were comparably sustained in both groups. At 6 months, 60.0% versus 57.7% of subjects (HA-RK vs HA-JV) had improved lip fullness. At 12 months, 71.4% versus 76.0% had aesthetic improvement (blinded evaluations) and 85.7% versus 86.2% felt more attractive. Both products were well tolerated. CONCLUSION: Both products achieved durable improvement in lip fullness and aesthetic appearance. A significantly smaller amount of HA-RK was required compared with HA-JV to achieve optimal treatment effect.

Enterovirus markers and serum CXCL10 in children with type 1 diabetes.

Most patients with type 1 diabetes are considered to have a T-cell mediated autoimmune disease. The chemokine CXCL10 promotes the migration of activated T-cells. Virus infections might contribute to the pathogenesis of type 1 diabetes and enterovirus protein and/or genome have been detected in beta-cells from a majority of tested newly diagnosed children with type 1 diabetes. The chemokine CXCL10 is induced in human islet cells by enterovirus infections in vivo and in vitro, but is not expressed in islets from normal organ donors. Since CXCL10 is a chemokine known to be induced by virus infections and/or cellular damage, our aim was to study if levels of CXCL10 are elevated in serum from children with type 1 diabetes and whether it correlates to the presence of enterovirus markers. CXCL10, neutralizing antibody titer rises against certain enterovirus, and antibodies against GAD65 were measured in serum, and enterovirus PCR was performed on whole blood from 83 type 1 diabetes patients at onset, 48 siblings and 69 controls. CXCL10 was also measured in serum from 46 patients with proven enterovirus infection and in serum from 46 patients with other proven virus infections. The CXCL10 serum levels were not elevated in children at onset of type 1 diabetes and there was a considerable overlap between the groups with 99 (8-498) pg/ml in serum from children with type 1 diabetes, 120 (17-538) pg/ml in serum from controls, and 117 (7-448) pg/ml in siblings of the children with type 1 diabetes. The CXCL10 serum levels in patients with proven enterovirus infection were slightly increased compared to the levels in the other groups, 172 (0-585) pg/ml but there was no statistically significant difference. In contrast, CXCL10 serum levels in patients with other proven virus infections were clearly elevated 418 (34-611) pg/ml. Despite that elevated CXCL10 levels have been demonstrated in some groups of patients with type 1 diabetes, in this study the mean CXCL10 serum levels were not elevated in patients with type 1 diabetes neither in patients with proven enterovirus infection. In contrast, in patients with other virus infections the CXCL10 levels were elevated, presumably reflecting the severity or the site of infection. This suggests that local production of CXCL10 in the affected organ cannot be measured reproducible in serum and that its potential use in clinical practice is limited.

Antiviral treatment of Coxsackie B virus infection in human pancreatic islets.

Enterovirus infections of the pancreatic islets are believed to trigger or precipitate the near total destruction of beta-cells that constitutes type 1 diabetes (T1D). This study investigated the ability of an anti-picornaviral compound, pleconaril, to block the replication of two beta-cell tropic Coxsackie B4 virus (CBV-4) strains in isolated human islets. The two strains, VD2921 and V89 4557, with demonstrated abilities to cause non-lytic persistence or lytic infection, respectively, in islets, represented two different potential mechanisms behind virus-induced T1D. The virus replication in the islets was studied with and without addition of pleconaril. In addition, islet morphology was studied every day. To test the effects of pleconaril and/or DMSO on the beta-cells' insulin secretion, glucose perifusions were performed on treated and untreated islets. Virus titrations showed a clear reduction of the replication of both strains after pleconaril treatment. The VD2921 strain was inhibited to undetectable levels. The V89 4557 strain, however, showed an initial reduction of titers but virus titers then increased despite the addition of a second dose of pleconaril. This incomplete inhibition of viral replication suggested the existence of a resistant subtype within this strain. Pleconaril treatment reduced the beta-cells' insulin secretion in response to glucose stimulation in some experiments and induced slight morphological changes to the islets compared to untreated controls. In summary, pleconaril reduced the replication of the two beta-cell tropic CBV-4 strains in human islets. However, genetic differences between these strains influenced the effectiveness of pleconaril treatment. This stresses the importance of using multiple viral strains in antiviral tests.

Enterovirus RNA is found in peripheral blood mononuclear cells in a majority of type 1 diabetic children at onset.

We have studied the occurrence of enterovirus (EV)-RNA at the onset of childhood type 1 diabetes in all 24 new cases of childhood type 1 diabetes during 1 year in Uppsala county, Sweden. We also studied 24 matched control subjects and 20 siblings of the patients. RNA was isolated from peripheral blood mononuclear cells and EV-RNA detected by RT-PCR. Primers (groups A and B) corresponding to conserved regions in the 5' noncoding region (NCR) of EV were used in the PCRs, and the amplicons were sequenced. By the use of group A primers, EV-RNA was found in 12 (50%) of the 24 type 1 diabetic children, 5 (26%) of 19 siblings, and none of the control subjects. Both patients and siblings showed a higher frequency of EV-RNA compared with the control subjects. The group B primers detected EV-RNA in all three groups but did not show statistically significant differences between the groups. The EV-RNA positivity with the group B primers was 11 (46%) of 24 in the type 1 diabetic children, 11 (58%) of 19 in the siblings, and 7 (29%) of 24 in the control subjects. The significant difference between groups seen with the group A primers but not with the group B primers might indicate the existence of diabetogenic EV strains. The phylogenetic analysis of the PCR products revealed clustering of the sequences from patients and siblings into five major branches when the group A PCR primers were used. With the group B primers, the sequences from patients, siblings, and control subjects formed three major branches in the phylogenetic tree, where 6 of the 7 control subjects clustered together in a sub-branch of CBV-4/VD2921. Seven of the type 1 diabetic children clustered together in another sub-branch of CBV-4/VD2921. Five of the type 1 diabetic children formed a branch together with the CBV-4/E2 strain, four clustered together with CBV-5, and one formed a branch with echovirus serotype. The presence of EV-RNA in the blood cells of most newly diagnosed type 1 diabetic children supports the hypothesis that a viral infection acts as an exogenous factor. In addition, sequencing of the PCR amplicons from the type 1 diabetic children, their siblings, and matched control subjects might reveal differences related to diabetogenic properties of such a virus.

dsRNA formed as an intermediate during Coxsackievirus infection does not induce NO production in a beta-cell line with or without addition of IFN-gamma.

Virus infection is one environmental factor that has been implicated as a precipitating event initiating beta-cell damage during the development of type 1 diabetes. One aim of this study was to investigate how permissive an insulin-producing beta-cell line, RINm5F, is to enterovirus (EV) infections. A second aim was to study if the viral replicative intermediate, double-stranded RNA (dsRNA), together with IFN-gamma results in nitric oxide (NO) production. Monolayer cultures of RINm5F cells were not permissive to infection with seven different strains of EV. However, when the growth pattern of the beta-cell line changed and the cells started to grow as free-floating RIN cell clusters (RCC), all EV strains replicated. Immunostaining for the Coxsackie-adenovirus-receptor (CAR) detected the protein on the free-floating RIN cell clusters, but not on the RINm5F cells cultured as a monolayer of beta-cells. This shows that the CAR expression can change and/or the CAR protein can be redistributed on the cell surface as a consequence of altered growth pattern thus allowing viral replication in a previously non-permissive beta-cell line. As expected, NO production was significantly increased (p<0.05) by addition of synthetic dsRNA and IFN-gamma to the RCC. In contrast, the dsRNA formed during virus infection with a Coxsackievirus B4 strain (E2) with or without addition of IFN-gamma did not induce NO production in these cells. This indicates that synthetic dsRNA does not mimic a real viral infection in that respect, and suggests an NO-independent mechanism for virus-induced beta-cell damage.

Complete nucleotide sequence of a Coxsackievirus B-4 strain capable of establishing persistent infection in human pancreatic islet cells: effects on insulin release, proinsulin synthesis, and cell morphology.

The aim of the present investigation was to study the effect of infection of human pancreatic islet cells with a strain (VD2921) of Coxsackie B virus serotype 4 capable of establishing persistent infection in these cells, as well as to sequence the strain, to study the determinants of virulence and persistence. Groups of islets were infected and assessments of proinsulin, insulin content, and virus replication were made. Insulin release in response to high glucose was measured. Infected and control islets displayed a strong insulin response to high glucose 3-4 days as well as 7-8 days post-infection (dpi). At 11-17 dpi, the infected islets did not respond at all to high glucose, and the response of the control islets was at this late time point somewhat reduced. The insulin and proinsulin content of the infected islets did not differ significantly from that of the control islets. TCID(50) titrations showed that the VD2921 strain replicated in the islet cells during the whole study. Electron microscopic examination of infected islets did not reveal any virus-induced changes of cell morphology compared with the controls, although higher magnifications of the infected beta-cells showed virus-like particles in the cytoplasm. These results show that certain strains of Coxsackievirus B-4 in vitro can establish a persistent infection that might mimic, the more gradual loss of beta-cell function seen during the clinical course of autoimmune diabetes. The ability of this Coxsackievirus B-4 strain to establish a persistent infection might be due to substitution of 11 amino acids located at the surface of the structural protein VP1, adjacent to the predicted receptor binding canyon of the virus.