Facilitators and barriers to implementation of suicide prevention interventions: Scoping review

We know that suicide is preventable, yet hundreds of thousands of people still die due to suicide every year. Many interventions were proven to be effective, and dozens of others showed promising results. However, translating these interventions into new settings brings several challenges. One of the crucial obstacles to success is not anticipating possible barriers to implementation nor enhancing possible benefits of factors facilitating the implementation. While we witnessed great support for suicide prevention activities globally in the past years, implementation barriers and facilitating factors are yet to be comprehensively mapped to help implementation activities worldwide. This scoping review maps current knowledge on facilitators and barriers to the implementation of suicide prevention interventions while using the Consolidated Framework for Implementation Research (CFIR) for classification. We included 64 studies. Barriers and facilitators were most commonly identified in the outer setting CFIR domain, namely in the sub-domain of patient needs and resources, which refers to the way in which these needs and resources are reflected by the reviewed interventions. The second most saturated CFIR domain for facilitators was intervention characteristics, where relative advantage, adaptability and cost of intervention sub-domains were equally represented. These sub-domains refer mostly to how the intervention is perceived by key stakeholders, to what extent it can be tailored to the implementation context and how much it costs. While intervention characteristics domain was the second most common also for barriers, the complexity sub-domain referring to high perceived difficulty of implementation was the most frequently represented. With reference to the results, we recommend adapting interventions to the needs of the target groups. Furthermore, carefully selecting the intervention to suit the target context concerning their adaptability, costs and complexity is vital for a successful implementation. Further implications for practice and research are discussed

Specific Mechanisms underlying Right Heart Failure

AIMS: Research into right ventricular (RV) physiology and identification of pathomechanisms underlying RV failure have been neglected for many years because function of the RV is often considered to be less important for overall hemodynamics and maintenance of blood circulation. In view of this, the present study focuses on identifying specific adaptive mechanisms of the right and left ventricle (LV) during a state of chronic nitric oxide (NO) deficiency, one of the main causes of cardiac failure. NO deficiency was induced in rats by L-NAME feeding over a four weeks period. The cardiac remodeling was then characterized separately for the RV/LV using qRT-PCR, histology, and functional measurements. RESULTS: Only the RV underwent remodeling that corresponded morphologically and functionally with the pattern of dilated cardiomyopathy. Symptoms in the LV were subtle and consisted primarily of moderate hypertrophy. A massive increase in reactive oxygen species (ROS) (+4.5+/-0.8 fold, vs. control) and a higher degree of oxidized tropomyosin (+46+/-4% vs. control) and peroxynitrite (+32+/-2% vs. control) could be identified as the cause of both RV fibrosis and contractile dysfunction. The expression of superoxide dismutase-2 was specifically increased in the LV by 51+/-3% and prevented the ROS increase and the corresponding structural and functional remodeling. INNOVATION: This study identified the inability of the RV to increase its antioxidant capacity as an important risk factor for developing RV failure. CONCLUSION: Unlike the LV, the RV did not display the necessary adaptive mechanisms to cope with increased oxidative stress during a state of chronic NO deficiency

Effects of 3α-amino-5α-pregnan-20-one on GABAA receptor: Synthesis, activity and cytotoxicity

The 3α-hydroxy function has been considered essential for the biological activity of neurosteroids at the GABAA receptor. It was found that 3α-amino-5α-pregnan-20-one (3) increased the binding of [3H]flunitrazepam at the GABAA receptor in the primary culture of cortical neurons. This derivative did not display cytotoxicity at relevant neuroactive concentrations, and its structure enabled us to gain further insight into possible functional group modifications in position 3α. Various synthetic methods were investigated in search for the most suitable synthetic approach

Allopregnanolone and pregnanolone analogues modified in the C ring: Synthesis and activity

El pdf es la versión post-print.(25R)-3β-Hydroxy-5α-spirostan-12-one (hecogenin) and 11α-hydroxypregn-4-ene-3,20-dione (11α-hydroxyprogesterone) were used as starting materials for the synthesis of a series of 11- and 12-substituted derivatives of 5ξ-pregnanolone (3α-hydroxy-5α- pregnan-20-one and 3α-hydroxy-5β-pregnan-20-one), the principal neurosteroid acting via γ-aminobutyric acid (GABA). These analogues were designed to study the structural requirements of the corresponding GABA A receptor. Their biological activity was measured by in vitro test with [3H]flunitrazepam as radioligand in which allopregnanolone and its active analogues stimulated the binding to the GABAA receptor. Analysis of the SAR data suggests dependence of the flunitrazepam binding activity on the hydrophobic-hydrophilic balance of the groups at the C-ring edge rather than on specific interactions between them and the receptor. © 2013 American Chemical Society.This work was supported by Czech Grant 303/12/1464, Research Project of the AS CR RVO 61388963, and the Spanish Grants PI 061212 and PI 10/0453 from the Ministries of Health and of Science and Innovation, Grant 2009/SGR/214 from the Generalitat of Catalunya, and Grant 2006CZ0025 from CSIC.Peer Reviewe

Activity of B-nor analogues of neurosteroids on the GABAA receptor in primary neuronal cultures

A GABAA receptor study of several B-nor analogues of allopregnanolone and pregnanolone has been carried out. B-Norallopregnanolone (i.e., 3α-hydroxy-7-nor-5α-pregnan-20-one) was found comparable to allopregnanolone when measured with labeled TBPS. Analogous results were obtained from their effect on neurons in culture: this time, both 3α-hydroxy-7-nor-5ξ-pregnan-20-ones (5 and 6) were found to stimulate [3H]flunitrazepam binding and GABA-induced 36Cl - influx. These effects were inhibited by GABAA receptor antagonists. Other analogues carrying electronegative substituents (epoxides 9 and 10 and ketone 12) in the B ring were inactive. Similarly, B-normal ketones 17, and 18 and 6-azasteroids 20 and 21 were also inactive. B-Nor analogues 5 and 6 did not induce neurotoxicity at relevant concentrations. A computational analysis of active and inactive neurosteroid analogues allowed the proposal of a 3D pharmacophoric hypothesis of their interaction with the GABAA receptor. © 2006 American Chemical Society.Fil: Suñol, Cristina. Consejo Superior de Investigaciones Científicas; EspañaFil: Garcia, Daniel Asmed. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Superior de Investigaciones Científicas; EspañaFil: Bujons, Jordi. Consejo Superior de Investigaciones Científicas; EspañaFil: Kristofikova, Zdena. Academy of Sciences of the Czech Republic; República ChecaFil: Matyas, Libor. Academy of Sciences of the Czech Republic; República ChecaFil: Babot, Zoila. Consejo Superior de Investigaciones Científicas; EspañaFil: Kasal, Alexander. Academy of Sciences of the Czech Republic; República Chec

Allopregnanolone (3α-Hydroxy-5α-pregnan-20-one) derivatives with a polar chain in position 16α: Synthesis and activity

The lipophilic nature of allopregnanolone prevents its user-friendly application in human medicine. On inspiration by pReviously prepared allopregnanolone with a 16α -bound tetraethylammonium salt, an attempt was made to produce allopregnanolone analogues with polar groups introduced into position 16α with the goal of increasing water solubility, brain accessibility, and potency of neuroactive steroids. The Michael addition to derivatives of pregn-16-en-20-one was the key reaction step. The link between the steroid skeleton and the new side chain was either a methylene group (when diethyl malonate was added) or an oxygen atom (when a hydroxy derivative was added). [35S]TBPS displacement was used to evaluate the products. Several carbamates (but not their parent alcohols) displaced TBPS from the picrotoxin binding site on GABAA receptors. Although none of them was more potent than the above ammonium salt, which stimulated this study, their nonionic nature should not prevent their passage into the brain. © 2009 American Chemical Society.Fil: Slavíková, Barbora. Academy of Sciences of the Czech Republic; República ChecaFil: Krištofíková, Zdena. Prague Psychiatric Centre; República ChecaFil: Chodounská, Hana. Academy of Sciences of the Czech Republic; República ChecaFil: Buděšínský, Miloš. Academy of Sciences of the Czech Republic; República ChecaFil: Duran, Fernando Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Veleiro, Adriana Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Burton, Gerardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Kasal, Alexander. Academy of Sciences of the Czech Republic; República Chec

Allopregnanolone and Pregnanolone Analogues Modified in the C Ring: Synthesis and Activity

(25<i>R</i>)-3β-Hydroxy-5α-spirostan-12-one (hecogenin) and 11α-hydroxypregn-4-ene-3,20-dione (11α-hydroxyprogesterone) were used as starting materials for the synthesis of a series of 11- and 12-substituted derivatives of 5ξ-pregnanolone (3α-hydroxy-5α-pregnan-20-one and 3α-hydroxy-5β-pregnan-20-one), the principal neurosteroid acting via γ-aminobutyric acid (GABA). These analogues were designed to study the structural requirements of the corresponding GABA_A receptor. Their biological activity was measured by in vitro test with [³H]­flunitrazepam as radioligand in which allopregnanolone and its active analogues stimulated the binding to the GABA_A receptor. Analysis of the SAR data suggests dependence of the flunitrazepam binding activity on the hydrophobic–hydrophilic balance of the groups at the C-ring edge rather than on specific interactions between them and the receptor