Formulation of a new broad-spectrum UVB + UVA and blue light SPF50+ sunscreen containing Phenylene Bis-Diphenyltriazine (TriAsorB), an innovative sun filter with unique optical properties.

Accumulating evidence from numerous comprehensive studies has demonstrated that blue light, in particular high-energy visible light, can exert a range of harmful effects on skin cells. These forms of radiation are now known to be able to trigger oxidation reactions, DNA damage, erythema and pigmentary changes, and may also be associated with photoaging. Sunscreens protecting the skin from only ultraviolet (UV)-B and UVA rays can therefore no longer be regarded as sufficient to help prevent skin damage from sunlight, and products containing filters that can provide broad-spectrum photoprotection are required. To meet this need, a new sunscreen formulation that provides photoprotection against solar radiation with wavelengths ranging from UV to visible light has been developed, using an innovative organic sun filter with unique optical properties: phenylene bis diphenyltriazine (TriAsorB™). This article outlines the development and characteristics of this innovative filter and describes new key results from studies performed to assess the effectiveness and safety of the filter and the new sunscreen product. The studies conducted so far demonstrate that the filter has a good human and environmental safety profile. In addition, the sunscreen, which contains TriAsorB in combination with three other UV filters to offer broad-spectrum sun protection with a high sun protection factor (SPF50+ ), appears to effectively prevent multiple forms of cellular photodamage, in particular blue light-induced oxidatively generated DNA lesions. Overall, the available data indicate that regular use of the TriAsorB-containing sunscreen could help prevent solar radiation-induced skin damage and the development of signs of premature skin aging, as well as photodermatoses caused or exacerbated by visible light.

Circulating FVIII-specific IgG, IgA and IgM memory B cells from haemophilia A patients.

INTRODUCTION: Approximately, 25% of haemophilia A (HA) patients treated by factor VIII (FVIII), develop antibodies, known as inhibitors, neutralizing the activity of infused FVIII. This immune response involves B cells (BC), including FVIII-specific memory B cells (MBC). Production of anti-FVIII antibodies after stimulation of FVIII-specific MBC suggests a role of these cells in the immune response to FVIII. Animal models allowed the study of circulating FVIII-specific cells, however few data are available on HA patients. AIM AND METHODS: In the present study, we simultaneously detected, via ELISpot assay, different isotypes of MBC in the blood of HA patients, after polyclonal activation. Patients included: three with active inhibitors; three with a history of inhibitors; six without any past or active inhibitor. RESULTS: FVIII-specific MBC were detected in peripheral blood of HA patients: (i) patients with active inhibitors (IgG: 4-5.2/10(6) BC; IgA: 2.9-4/10(6) BC) (ii) patients with a past of inhibitors (no IgG BC; IgA: 5-7.5/10(6) BC) (iii) patients without inhibitors (no IgG BC or IgA BC except one patient had two FVIII-specific IgA BC/10(6) BC). CONCLUSION: FVIII-specific IgA MBC were detected in HA patients with past and current immune responses against FVIII and FVIII-specific IgG MBC were found only in those with positive inhibitors. This study shows the possibility to detect and characterize easily and simultaneously the MBC from patient blood and that MBC seem different according to anti-FVIII immune history. It could be a useful tool to study anti-FVIII response and Immune Tolerance Induction cellular mechanisms.

Anti-A2 and anti-A1 domain antibodies are potential predictors of immune tolerance induction outcome in children with hemophilia A.

BACKGROUND: Hemophilia A (HA) is a congenital bleeding disorder resulting from factor VIII deficiency. The most serious complication of HA management is the appearance of inhibitory antibodies (Abs) against injected FVIII concentrates. To eradicate inhibitors, immune tolerance induction (ITI) is usually attempted, but it fails in up to 30% of cases. Currently, no undisputed predictive marker of ITI outcome is available to facilitate the clinical decision. OBJECTIVES: To identify predictive markers of ITI efficacy. METHODS: The isotypic and epitopic repertoires of inhibitory Abs were analyzed in plasma samples collected before ITI initiation from 15 children with severe HA and high-titer inhibitors, and their levels were compared in the two outcome groups (ITI success [n = 7] and ITI failure [n = 8]). The predictive value of these candidate biomarkers and of the currently used indicators (inhibitor titer and age at ITI initiation, highest inhibitor titer before ITI, and interval between inhibitor diagnosis and ITI initiation) was then compared by statistical analysis (Wilcoxon test and receiver receiver operating characteristic [ROC] curve analysis). RESULTS: Whereas current indicators seemed to fail in discriminating patients in the two outcome groups (ITI success or failure), anti-A1 and anti-A2 Ab levels before ITI initiation appeared to be good potential predictive markers of ITI outcome (P < 0.018). ROC analysis showed that anti-A1 and anti-A2 Abs were the best at discriminating between outcome groups (area under the ROC curve of > 0.875). CONCLUSION: Anti-A1 and anti-A2 Abs could represent new promising tools for the development of ITI outcome prediction tests for children with severe HA.

The IgG autoimmune response in postpartum acquired hemophilia A targets mainly the A1a1 domain of FVIII.

BACKGROUND: Acquired hemophilia A (AHA) is a severe life-threatening autoimmune disease due to the development of autoantibodies that neutralize the procoagulant activity of factor VIII (FVIII). In rare cases, AHA occurs in the postpartum period as a serious complication of an otherwise normal pregnancy and delivery. Due to its rarity, little is known about the features of the antibody response to FVIII in AHA. OBJECTIVES: Our study wanted to (i) determine the epitope specificity and the immunoglobulin (Ig) subclasses of anti-FVIII autoantibodies in plasma samples from a large cohort of AHA patients, and (ii) compare the epitope specificity of anti-FVIII autoantibodies in plasma samples from postpartum AHA and other AHA patients. PATIENTS/METHODS: Seventy-three plasma samples from patients with postpartum AHA (n = 10) or associated with malignancies (n = 16) or autoimmune diseases (n = 11) or without underlying disease (n = 36) were analyzed with three multiplexed assays. RESULTS AND CONCLUSIONS: Our results showed a stronger response against the A1a1-A2a2-B fragments of FVIII and more specifically against the A1a1 domain in patients with postpartum AHA than in the other AHA groups (P < 0.01). Moreover, although IgG4 was the predominant IgG subclass in all groups, anti-A1a1-A2a2-B and anti-A1a1 domain autoantibodies of the IgG(1) and IgG3 subclasses were more frequently detected in postpartum AHA than in the other AHA groups. These findings support the involvement of the Th1-driven response in the generation of autoantibodies in women with postpartum AHA compared with the other groups of AHA patients in whom production of Th2-driven IgG4 was predominant.

Prevalence and epitope specificity of non-neutralising antibodies in a large cohort of haemophilia A patients without inhibitors.

Antibodies (inhibitors and non-neutralising antibodies [NNA]) directed against factor VIII (FVIII) remain the main iatrogenic complication in haemophilia A (HA) patients. Inhibitors reduce FVIII pro-coagulant properties, whereas NNA are directed against non-functional epitopes. NNA are poorly studied and their prevalence, epitope specificity and physiopathology inadequately defined. The aim of this study was first to evaluate NNA prevalence in a French retrospective multicentric series of 210 patients without inhibitors, then to determine their epitope specificity (against the heavy chain [HC] or the light chain [LC] of FVIII) and particularly to assess the prevalence of anti-B domain NNA using specifically designed x-MAP assays. NNA occurred in 18.1% of patients (38/210) and their prevalence was not influenced by the severity of the disease. Among the 38 patients with NNA, 73.7% had anti-FVIII Abs against the HC, 13.2% against the LC and 13.2% had anti-FVIII Abs against both chains. There is thus a clear immuno-dominance of the HC of FVIII in the epitope profile of NNA, whatever the severity of HA. The proportion of NNA that recognised the B domain was 18.4% (n=7/38). A multivariate analysis did not highlight differences in NNA occurrence between patients treated with recombinant FVIII or with plasma- derived FVIII (19.6% vs. 14.9%, p=0.53).

Involvement of the sigma1 (sigma1) receptor in the anti-amnesic, but not antidepressant-like, effects of the aminotetrahydrofuran derivative ANAVEX1-41.

BACKGROUND AND PURPOSE: Tetrahydro-N, N-dimethyl-5, 5-diphenyl-3-furanmethanamine hydrochloride (ANAVEX1-41) is a potent muscarinic and sigma(1) (sigma (1)) receptor ligand. The sigma (1) receptor modulates glutamatergic and cholinergic responses in the forebrain and selective agonists are potent anti-amnesic and antidepressant DRUGS. WE HAVE HERE ANALYSED THE SIGMA (1) COMPONENT IN THE BEHAVIOURAL EFFECTS OF ANAVEX1-41. EXPERIMENTAL APPROACH: Binding of ANAVEX1-41 to muscarinic and sigma (1) receptors were measured using cell membranes. Behavioural effects of ANAVEX1-41 were tested in mice using memory (spontaneous alternation, passive avoidance, water-maze) and antidepressant-like activity (forced swimming) procedures. KEY RESULTS: In vitro, ANAVEX1-41 was a potent muscarinic (M(1)>M(3), M(4)>M(2) with K(i) ranging from 18 to 114 nM) and selective sigma (1) ligand (sigma (1), K(i)=44 nM; sigma (2), K(i)=4 microM). In mice, ANAVEX1-41 failed to affect learning when injected alone (0.03-1 mg kg(-1)), but attenuated scopolamine-induced amnesia with a bell-shaped dose response (maximum at 0.1 mg kg(-1)). The sigma (1) antagonist BD1047 blocked the anti-amnesic effect of ANAVEX1-41 on both short- and long-term memories. Pretreatment with a sigma (1) receptor-directed antisense oligodeoxynucleotide prevented effects of ANAVEX1-41 only in the passive avoidance procedure, measuring long-term memory. ANAVEX1-41 reduced behavioural despair at 30 and 60 mg kg(-1), without involving the sigma (1) receptor, as it was not blocked by BD1047 or the antisense oligodeoxynucleotide. CONCLUSIONS AND IMPLICATIONS: ANAVEX1-41 is a potent anti-amnesic drug, acting through muscarinic and sigma (1) receptors. The latter component may be involved in the enhancing effects of the drug on long-term memory processes.