Vortioxetine for Major Depressive Disorder in Adolescents: 12-Week Randomized, Placebo-Controlled, Fluoxetine-Referenced, Fixed-Dose Study.

OBJECTIVE: To evaluate the efficacy and safety of vortioxetine in adolescents with major depressive disorder (MDD). METHOD: After 4 weeks of single-blind lead-in treatment with a Brief Psychosocial Intervention (BPI) plus placebo, patients (aged 12-17 years) with MDD (DSM-5) who did not meet response criteria (Children's Depression Rating Scale-Revised [CDRS-R]; total score ≥40 plus <40% reduction and a Parent Global Assessment score >2) were randomized 1:1:1:1 to 8 weeks of BPI plus double-blind treatment with vortioxetine 10 mg, vortioxetine 20 mg, fluoxetine 20 mg, or placebo. The primary endpoint was change from randomization in CDRS-R total score at week 8; the primary comparison was the average effect of 2 vortioxetine doses vs placebo. RESULTS: Of 784 patients enrolled in the lead-in, 616 were randomized. At week 8, the mean change in CDRS-R total score averaged for vortioxetine doses was -18.01 (SE = 0.98) and the mean difference vs placebo was 0.21 (P = .878; not significant). For fluoxetine, the mean change in CDRS-R total score was -21.95 and the mean difference vs placebo was -3.73 (P = .015). Treatment-emergent adverse events occurring in ≥5% of patients in either vortioxetine arm and at least twice more frequently than placebo were nausea, headache, vomiting, and dizziness. CONCLUSION: Patients in all groups showed reduction in CDRS-R scores by the end of the study, with no difference between combined doses of vortioxetine and placebo. The primary endpoint was not met, thereby rendering the study negative. The overall favorable safety profile of vortioxetine in an adolescent patient population was consistent with that seen in adults. CLINICAL TRIAL REGISTRATION INFORMATION: Active Reference (Fluoxetine) Fixed-Dose Study of Vortioxetine in Paediatric Patients Aged 12 to 17 Years With Major Depressive Disorder (MDD); http://clinicaltrials.gov; NCT02709746.

Fixed-Combination Calcipotriene Plus Betamethasone Dipropionate Aerosol Foam Is Well Tolerated in Patients with Psoriasis Vulgaris: Pooled Data from Three Randomized Controlled Studies.

The authors performed a pooled analysis of three randomized, 4-week, phase II/III studies in adult patients with mild to severe psoriasis and assessed the safety/tolerability of aerosol foam fixed-combination calcipotriene 0.005% (Cal) plus betamethasone dipropionate 0.064% (BD) versus different comparators. Overall, 1104 patients were randomized to Cal/BD aerosol foam (n=564), Cal aerosol foam (n=101), BD aerosol foam (n=101), aerosol foam vehicle (n=152), Cal/BD ointment (n=135), or ointment vehicle (n=51). A total of 543 Cal/BD patients in the aerosol foam group (96.3%) completed the studies, with only two patients (0.4%) withdrawing as a result of adverse events (AEs). Ninety-five AEs were reported in 78 patients (13.8%) receiving Cal/BD aerosol foam; similar event rates were observed in other groups. The most common AEs with Cal/BD aerosol foam were nasopharyngitis (n=6, 1.1%) and application-site pain (n=4, 0.7%); most AEs were mild (n=71/95; 74.7%). Adverse drug reactions (ADRs) experienced by two or more patients receiving Cal/BD aerosol foam were application-site pain (n=4; 0.7%) and application-site pruritus (n=2; 0.4%). There were no clinically relevant changes in calcium homeostasis. Cal/BD aerosol foam has a positive benefit-risk profile for the treatment of psoriasis vulgaris; the superior efficacy versus Cal/BD ointment and the individual active ingredients is not associated with poorer tolerability.

Efficacy and Safety of Calcipotriol Plus Betamethasone Dipropionate Aerosol Foam Compared with Betamethasone 17-Valerate-Medicated Plaster for the Treatment of Psoriasis.

BACKGROUND: Fixed combination calcipotriol as hydrate (Cal) 50 µg/g plus betamethasone as dipropionate (BD) 0.5 mg/g aerosol foam is an alcohol-free treatment for psoriasis. Betamethasone 17-valerate 2.25 mg (BV)-medicated plasters are recommended for treating psoriasis plaques localized in difficult-to-treat (DTT; elbow, knee, anterior face of the tibia) areas. OBJECTIVE: The aim of this study was to compare the efficacy of Cal/BD foam with BV-medicated plaster in patients with plaque psoriasis. METHODS: In this phase IIa, randomized, single-center, investigator-blinded, 4-week study, both Cal/BD foam and BV-medicated plaster were applied once daily to six test sites (three for each treatment). The primary efficacy endpoint was absolute change in total clinical score (TCS; sum of erythema, scaling, and infiltration); secondary endpoints were changes from baseline in each individual clinical score, ultrasonographic changes (total skin and echo-poor band thickness), and safety; and post hoc analysis was change from baseline in TCS on DTT areas. RESULTS: Thirty-five patients were included. Least-squares mean change in TCS from baseline was significantly greater for Cal/BD foam (-5.8) than BV-medicated plaster (-3.7; difference -2.2; 95% confidence interval -2.6 to -1.8; p < 0.001); greater changes for Cal/BD foam were observed from day 8 for each clinical sign. Absolute total skin and echo-poor band thickness change was significantly greater for Cal/BD foam than for BV-medicated plaster (both p < 0.001). Post hoc analyses showed that Cal/BD foam was significantly more effective than BV-medicated plaster on DTT areas after 4 weeks (p < 0.001), and both treatments were well tolerated. CONCLUSION: Cal/BD foam demonstrated superior efficacy versus BV-medicated plasters, including on DTT areas, in patients with plaque psoriasis. CLINICAL TRIAL REGISTRATION NUMBER: NCT02518048.

Calcipotriol Plus Betamethasone Dipropionate Aerosol Foam is Effective, Independent of Body Mass Index and the Extent and Severity of Psoriasis.

INTRODUCTION: Good treatment adherence is important in the effective management of psoriasis and is related to both the frequency of applications and the amount of product used versus the recommended dose. The efficacy and safety of fixed combination calcipotriol 50 µg/g (Cal) and betamethasone 0.5 mg/g as dipropionate (BD) in the treatment of psoriasis is well established; an aerosol foam formulation has been developed to enhance adherence. This subanalysis from the Phase III PSO-FAST study evaluates the amount of Cal/BD foam used during treatment and the association between the extent and severity of baseline disease. METHODS: Patients (≥18 years) with mild-to-severe body psoriasis were randomized 3:1 to once-daily Cal/BD foam or vehicle. The amount of Cal/BD foam and vehicle used over the 4-week study period was evaluated according to three baseline disease assessments: extent of body surface area (BSA) affected by psoriasis, physician's global assessment of disease severity (PGA) and modified psoriasis area and severity index (mPASI). Treatment success and mPASI75 rates were assessed according to body mass index (BMI) and body weight. RESULTS: 323 patients were randomized to Cal/BD foam and 103 to vehicle. At week 4, the mean total amount of Cal/BD foam used was 120.8 g (n = 293), which was similar to the amount of vehicle used (128.9 g; n = 98). The total amount of Cal/BD foam used at week 4 was greater with increasing BSA and increasing severity of baseline PGA and mPASI. Throughout the study, 93.1% of patients in the Cal/BD foam group and 99.0% of patients in the vehicle group missed ≤10% of treatment applications. Treatment success and mPASI75 rates were generally similar when stratified according to BMI and body weight. CONCLUSIONS: This subanalysis demonstrates that Cal/BD aerosol foam is used appropriately and is effective for the treatment of psoriasis, independent of BMI and the extent or severity of disease. CLINICAL TRIALS NUMBER: NCT01866163. FUNDING: LEO Pharma A/S.

Aerosol Foam Formulation of Fixed Combination Calcipotriene Plus Betamethasone Dipropionate is Highly Efficacious in Patients With Psoriasis Vulgaris: Pooled Data From Three Randomized Controlled Studies.

BACKGROUND: Calcipotriene 0.005% (Cal)/betamethasone dipropionate 0.064% (BD) aerosol foam was developed as a new treatment option for patients with psoriasis. This pooled analysis evaluated the efficacy of this formulation for 4 weeks of treatment.
METHODS: Patients aged ≥18 years with mild-severe psoriasis were enrolled into three Phase II/III studies (nCT01536886, nCT01536938, nCT01866163); each study evaluated Cal/BD aerosol foam versus different comparators. Endpoints included: proportion of patients clear/almost clear with ≥2-step improvement in physician's global assessment of disease severity ('treatment success'); modified (excluding head) psoriasis area and severity index (mPASI); proportion of patients with ≥75% reduction in mPASI (PASI75); change in itch (according to visual analog scale [VAS]).
RESULTS: 1104 patients were included in the pooled analysis: Cal/BD aerosol foam (n=564), Cal/BD ointment (n=135), BD aerosol foam (n=101), Cal aerosol foam (n=101), aerosol foam vehicle (n=152), ointment vehicle (n=51). At week 4, 51% of Cal/BD aerosol foam patients achieved treatment success, a higher proportion than in all other groups (Cal/BD ointment, 43%; BD aerosol foam, 31%; Cal aerosol foam, 15%; aerosol foam vehicle, 5%; ointment vehicle, 8%). Greater percentage mean decrease in mPASI with Cal/BD aerosol foam was noted versus other treatments at week 4 (72% vs 63%, 53%, 43%, 32%, and 33%, respectively); week 4 PASI75 rate was also greater (51% vs 41%, 34%, 18%, 7%, and 10%, respectively). Cal/BD aerosol foam was efficacious irrespective of baseline disease severity and on all body areas assessed (arms, legs, trunk). Cal/BD aerosol foam alleviated itch as early as week 1 (change in itch VAS: -30 mm), maintained to week 4 (change in itch VAS: -41 mm).
CONCLUSIONS: Cal/BD aerosol foam was significantly more effective than Cal/BD ointment and the individual active ingredients for treating psoriasis vulgaris, resulting in greater and faster reduction in disease severity and rapid, effective relief of itch.

J Drugs Dermatol. 2016;15(8):951-957.

DNA binding and telomere length regulation of yeast RAP1 homologues.

The repressor activator protein 1 (RAP1) has many important functions in Saccharomyces cerevisiae. At the chromosome ends, it is a negative regulator of telomere length. Here, we show that Saccharomyces castellii/Saccharomyces dairensis telomeric sequences inserted into a S.cerevisiae telomere are counted as part of the telomere, consistent with the presence of high-affinity Rap1p binding sites within these sequences. We show that S.castellii Rap1p (scasRap1p) can regulate telomere length in a S.cerevisiae strain, albeit less stringently. Cloning of the S.dairensis RAP1 homologue (sdaiRAP1) revealed that it encodes the largest RAP1 protein identified to date. Despite its large size, binding analyses of the recombinant sdaiRap1p revealed that the protein binds with the same spacing and with similar affinity to yeast telomeric sequences, as the scer- and scasRAP1 proteins. According to the Rap1p counting model for telomere length regulation, a low density of Rap1p binding sites in a telomere would result in a longer telomere in S.cerevisiae. We have compared the lengths of two individual S.dairensis telomeres and find that their lengths are not regulated to give the same number of high-affinity binding sites. This may be due to other factors than Rap1p having influence on the telomere length regulation.

Telomere terminating with centromere-specific repeats is closely associated with a transposon derived gene in Chironomus pallidivittatus.

We provide evidence that centromere-specific 155 bp DNA repeats terminate one pair of telomeres at the telocentric, left end of the short fourth chromosome in Chironomus pallidivittatus. Earlier evidence indicated that all other telomeres are terminated by 340 bp telomere-specific repeats. DNA that borders the 155 bp repeat contains a transcriptionally active 396 codon open reading frame (ORF) a few kilobases away from the repeat array. The conceptual product of the ORF has regions with similarities to transposase, DNA binding and endonuclease motifs and is likely to have an evolutionary origin in a transposon. It is flanked, within degenerate inverted repeats, by a modified form of an element, Cp80, that has previously been found to insert only into 155 bp repeats and that contains a putative CENP-B box and a region that is prone to recombine. The ORF may therefore have a functional relation to the centromeric region.

Chromosome ends in Chironomus tentans do not have long single-stranded overhangs characterizing canonical telomeres.

Single-stranded overhangs of the G-rich strand belong to the conserved features of telomeres composed of short telomeric repeats. These structures are thought to be essential for the maintenance of proper telomeric structure and function and the mechanism of their generation is telomerase-independent. We have examined the presence of single-stranded overhangs in Chironomus tentans, a dipteran insect lacking canonical telomeres that uses 350-bp repeats to terminate its chromosomes. Using a non-denaturing in-gel hybridization technique, we found that C. tentans telomeres are unlikely to have single-stranded overhangs longer than 30 nt found in most other higher eukaryotes. These differences might reflect special capping mechanisms for telomeres terminated with long complex repeats.