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Background/Objective: Optimal vitamin D levels are required for bone health and proper functionality of the nervous, musculoskeletal and immune systems. The objective of this study was to assess the efficacy and safety profiles of new weekly calcifediol formulations with the potential to improve adherence and outcome. Methods: A Phase II-III, double-blind, randomized, multicentre trial (EudraCT 2020-001099-14 and NCT04735926). Subjects were randomized 2:2:1 to calcifediol 75 µg, 100 µg and placebo. 25(OH)D levels were measured at 4, 16, 24, 32 and 52 weeks. The main outcome was the percentage of subjects who achieved a response defined as 25(OH)D levels ≥20 ng/mL and/or ≥30 ng/mL at week 16. Results: 398 subjects (51.1 ± 15.96 years, 74.2% females, 98.7% Caucasian) with plasma 25(OH)D levels between 10 and 20 ng/mL were randomized. A total of 376 subjects completed 16 weeks of treatment, and 355 subjects completed the study. Six patients withdrew due to an adverse event, all unrelated to treatment. At week 16, 93.6% and 74.4% of subjects receiving calcifediol 75 µg achieved response levels of ≥20 ng/mL and ≥30 ng/mL, respectively. The calcifediol 100 µg group showed 98.7% and 89.9% of responders for ≥20 ng/mL and ≥30 ng/mL, respectively. Both calcifediol groups showed superiority over placebo at each response level at all time points analyzed (p < 0.0001). Calcifediol treatments increased 25(OH)D levels from baseline to week 24 and remained stable thereafter. The frequency of treatment-emergent adverse events was balanced between groups. Conclusions: New weekly calcifediol 75 and 100 µg formulations showed an effective and sustained response with a good long-term safety profile. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate bilastine dosing recommendations in older adults and overcome the limitation of insufficient data from phase I studies in this underrepresented population. This was achieved by integrating bilastine physicochemical, in vitro and in vivo data in young adults and the effect of aging in the pharmacology by means of two alternative approaches: a physiologically‐based pharmacokinetic (PBPK) model and a semi‐mechanistic population pharmacokinetic (Senescence) model. Intestinal apical efflux and basolateral influx transporters were needed in the PBPK model to capture the observations from young adults after single i.v. (10 mg) and p.o. (20 mg) doses, supporting the hypothesis of involvement of gut transporters on secretion. The model was then used to extrapolate the pharmacokinetics (PKs) to elderly subjects considering their specific physiology. Additionally, the Senescence model was develop starting from a published population PK) model, previously applied for pediatrics, and incorporating declining functions on different physiological systems and changes in body composition with aging. Both models were qualified using observed data in a small group of young elderlies (N = 16, mean age = 68.69 years). The PBPK model was further used to evaluate the dose in older subjects (mean age = 80 years) via simulation. The PBPK model supported the hypothesis that basolateral influx and apical efflux transporters are involved in bilastine PK. Both, PBPK and Senescence models indicated that a 20 mg q.d. dose is safe and effective for geriatrics of any age. This approach provides an alternative to generate supplementary data to inform dosing recommendations in under‐represented groups in clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy/safety of bilastine in pruritus relief in patients with chronic spontaneous urticaria (CSU) or other pruritic skin diseases. Methods: In this multicenter, open-label, exploratory study (EudraCT No.: 2016-001505-17), 115 adults with CSU (n = 34), eczema/dermatitis (n = 30), prurigo (n = 25) or cutaneous pruritus (n = 26), received bilastine 20 mg once daily for 8 weeks, or in non-responder patients (<30% improvement in pruritus score at week 2), 40 mg/day from week 2. Results: The mean change in weekly pruritus severity score from baseline to week 8 (primary endpoint) was reduced with bilastine (overall and by disease group); overall, percentage and absolute reductions were 71.16% and 1.63 points, respectively (p <.001). Updosed non-responders (n = 31) had improved weekly pruritus severity scores from baseline to week 8; percentage and absolute reductions were 49.08% and 1.13 points, respectively (p <.001). Bilastine improved the Dermatology Life Quality Index at weeks 4 and 8 (p <.001) in all disease groups, and the 7-day Urticaria Activity Score in CSU patients (p <.001). Bilastine was well tolerated. Conclusions: Bilastine relieved pruritus associated with urticaria and other skin diseases, with a very good safety profile. [ABSTRACT FROM AUTHOR]

Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria in adults and children aged ≥ 6 years. Pharmacokinetic data for children aged 6-11 years were extracted post hoc from a study in which children (2-11 years) with allergic rhinoconjunctivitis or urticaria received oral bilastine (10 mg/day). Maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC) data were compared with adult pharmacokinetic data from seven clinical studies (bilastine 20 mg/day). Safety data for children aged 6-11 years were extracted post hoc from a phase III randomized controlled trial of children (2-11 years) with allergic rhinoconjunctivitis or chronic urticaria receiving once-daily bilastine 10 mg or placebo for 12 weeks. Exposure and Cmax values were similar for children (6-11 years) and adults: median pediatric/adult ratios for AUC0-24 and Cmax were 0.93 and 0.91, respectively. There was no significant difference in the incidence of treatment-emergent adverse in children (6-11 years) receiving bilastine 10 mg or placebo.Conclusion: Pharmacokinetic and safety analyses in children aged 6-11 years support the suitability of the pediatric dose of bilastine 10 mg and confirm that the safety profiles of bilastine and placebo are similar.What is Known:• Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria in adults (20 mg/day) and children aged ≥ 6 years (10 mg/day).• An ontogenic model based on adult data and pharmacokinetic/pharmacodynamic simulations supported the selection of a bilastine dose of 10 mg/day in children aged 2-11 years. Bilastine 10 mg/day was shown to have a safety profile similar to that of placebo in a large phase III randomized clinical trial in children aged 2-11 years.What is New:• As bilastine is approved in Europe for children aged ≥6 years, the current study reports the results of two post hoc analyses of pharmacokinetic and safety data in children aged 6-11 years.• Analysis of pharmacokinetic and safety data in children aged 6-11 years supports the suitability of the pediatric dose of bilastine 10 mg and confirms that its safety profile is similar to that of placebo. [ABSTRACT FROM AUTHOR]

As well as being expressed as a full-length transcript, the group II metabotropic glutamate receptor 3 (GRM3, mGlu3) gene is expressed as an mRNA isoform which lacks exon 4 (GRM3Δ4) and which is predicted to encode a protein with a novel C terminus (called mGlu3Δ4). This variant may contribute to the mechanism by which GRM3 acts as a schizophrenia risk gene. However, little is known about the properties or function of mGlu3Δ4. Here, using transiently transfected HEK293T/17 cells, we confirm that GRM3Δ4 cDNA is translated, with mGlu3Δ4 existing as a homodimer as well as a monomer, and localizing primarily to cell membranes including the plasma membrane. Co-immunoprecipitation shows that mGlu3Δ4 interacts with canonical mGlu3. mGlu3Δ4 does not bind the mGlu2/3 antagonist [3H]LY341495, but the presence of mGlu3Δ4 reduces binding of [3H]LY341495 to mGlu3, paralleled by a decrease in the abundance of membrane-associated mGlu3. These experiments indicate that mGlu3Δ4 may negatively modulate mGlu3, and thereby impact on the roles of GRM3/mGlu3 in schizophrenia and as a therapeutic target. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown. Here we found that chronic atypical antipsychotics downregulated the transcription of metabotropic glutamate 2 receptor (mGlu2, also known as Grm2), an effect that was associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurred in concert with a serotonin 5-HT2A receptor-dependent upregulation and increased binding of HDAC2 to the mGlu2 promoter. Virally mediated overexpression of HDAC2 in frontal cortex decreased mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevented the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augmented their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target for schizophrenia treatment. [ABSTRACT FROM AUTHOR]

Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT 2A -receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) can form multiprotein complexes (heteromers), which can alter the pharmacology and functions of the constituent receptors. Previous findings demonstrated that the Gq/11-coupled serotonin 5-HT2A receptor and the Gi/o-coupled metabotropic glutamate 2 (mGlu2) receptor-GPCRs that are involved in signaling alterations associated with psychosis-assemble into a heteromeric complex in the mammalian brain. In single-cell experiments with various mutant versions of the mGlu2 receptor, we showed that stimulation of cells expressing mGlu2-5-HT2A heteromers with an mGlu2 agonist led to activation of Gq/11 proteins by the 5-HT2A receptors. For this crosstalk to occur, one of the mGlu2 subunits had to couple to Gi/o proteins, and we determined the relative location of the Gi/o-contacting subunit within the mGlu2 homodimer of the heteromeric complex. Additionally, mGlu2-dependent activation of Gq/11, but not Gi/o, was reduced in the frontal cortex of 5-HT2A knockout mice and was reduced in the frontal cortex of postmortem brains from schizophrenic patients. These findings offer structural insights into this important target in molecular psychiatry., (Copyright © 2016, American Association for the Advancement of Science.)

Serotonin 5-HT(2A) and metabotropic glutamate 2 (mGlu2) are G protein-coupled receptors suspected in the pathophysiology of psychiatric disorders, such as schizophrenia, depression, and suicide. Previous findings demonstrate that mGlu2 mRNA expression is down-regulated in brain cortical regions of 5-HT2A knockout (KO) mice. However, the molecular mechanism responsible for this alteration remains unknown. We show here repressive epigenetic changes at the promoter region of the mGlu2 gene in frontal cortex of 5-HT(2A)-KO mice. Disruption of 5-HT(2A) receptor-dependent signaling in mice was associated with decreased acetylation of histone H3 (H3ac) and H4 (H4ac) and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the mGlu2 promoter, epigenetic changes that correlate with transcriptional repression. Neither methylation of histone H3 at lysine 4 (H3K4me1/2/3) nor tri-methylation of histone H3 at lysine 9 (H3K9me3) was affected. We found that Egr1, a transcription factor in which promoter activity was positively regulated by the 5-HT(2A) receptor agonist 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide, binds less to the mGlu2 promoter in frontal cortex of 5-HT(2A)-KO, compared with wild-type mice. Furthermore, expression of mGlu2 was increased by viral-mediated gene transfer of FLAG-tagged Egr1 in mouse frontal cortex. Together, these observations suggest that 5-HT(2A) receptor-dependent signaling epigenetically affects mGlu2 transcription in mouse frontal cortex.