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1.
Cancer Discov ; 12(11): 2684-2709, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36053276

RESUMO

The chromatin reader eleven-nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line- and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support the clinical translation of this approach. SIGNIFICANCE: AML is a poor-prognosis disease for which new therapeutic approaches are desperately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent efficacy in MLL-rearranged and NPM1-mutated AML, and determined its mechanisms of action. These biological and chemical insights will facilitate both basic research and clinical translation. This article is highlighted in the In This Issue feature, p. 2483.


Assuntos
Leucemia Mieloide Aguda , Lisina , Humanos , Leucemia Mieloide Aguda/genética , Histonas/metabolismo , Cromatina , Proteína de Leucina Linfoide-Mieloide/metabolismo
2.
Angew Chem Int Ed Engl ; 60(43): 23327-23334, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34416073

RESUMO

Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.


Assuntos
Antineoplásicos/farmacologia , Quinase 1 de Adesão Focal/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Dipeptídeos/química , Dipeptídeos/farmacocinética , Dipeptídeos/farmacologia , Quinase 1 de Adesão Focal/metabolismo , Humanos , Camundongos , Estrutura Molecular , Ubiquitina-Proteína Ligases/metabolismo
3.
J Med Chem ; 64(17): 12978-13003, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34432979

RESUMO

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogues with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 month duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.


Assuntos
Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Animais , Desenho de Fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Meia-Vida , Humanos , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Células THP-1
4.
ACS Chem Biol ; 15(9): 2316-2323, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32697072

RESUMO

The Bcl-2 family of proteins, such as Bcl-xL and Bcl-2, play key roles in cancer cell survival. Structural studies of Bcl-xL formed the foundation for the development of the first Bcl-2 family inhibitors and FDA approved drugs. Recently, Proteolysis Targeting Chimeras (PROTACs) that degrade Bcl-xL have been proposed as a therapeutic modality with the potential to enhance potency and reduce toxicity versus antagonists. However, no ternary complex structures of Bcl-xL with a PROTAC and an E3 ligase have been successfully determined to guide this approach. Herein, we report the design, characterization, and X-ray structure of a VHL E3 ligase-recruiting Bcl-xL PROTAC degrader. The 1.9 Å heterotetrameric structure, composed of (ElonginB:ElonginC:VHL):PROTAC:Bcl-xL, reveals an extensive network of neo-interactions, between the E3 ligase and the target protein, and between noncognate parts of the PROTAC and partner proteins. This work illustrates the challenges associated with the rational design of bifunctional molecules where interactions involve composite interfaces.


Assuntos
Benzotiazóis/metabolismo , Isoquinolinas/metabolismo , Oligopeptídeos/metabolismo , Proteólise/efeitos dos fármacos , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Proteína bcl-X/antagonistas & inibidores , Benzotiazóis/química , Benzotiazóis/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Ligação Proteica , Proteína bcl-X/química , Proteína bcl-X/metabolismo
5.
Commun Biol ; 3(1): 140, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198438

RESUMO

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines.


Assuntos
Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Inflamação/prevenção & controle , Leucócitos Mononucleares/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/enzimologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/enzimologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Estabilidade Enzimática , Feminino , Humanos , Inflamação/enzimologia , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Injeções Intravenosas , Leucócitos Mononucleares/enzimologia , Masculino , Proteólise , Ratos Sprague-Dawley , Ratos Wistar , Células THP-1 , Técnicas de Cultura de Tecidos , Ubiquitinação
6.
Drug Discov Today Technol ; 31: 69-80, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31200862

RESUMO

Proteolysis Targeting Chimeras (PROTACs) are a rapidly expanding new therapeutic modality inducing selective protein degradation and offering the potential of a differentiated pharmacological profile across multiple therapeutic areas. As the repertoire of protein targets and E3 ligases available for incorporation into PROTACs continues to grow, understanding the drug- and system-dependent parameters for PROTACs will be critical for achieving tissue/cell specific pharmacology. The review discusses the current knowledge and future direction of in vivo PROTAC study evaluation. The importance of establishing the quantitative relationship between loss of protein target and biological function in vivo, coupled with building mechanistic PK/PD and ultimately PBPK/PD models, is emphasised with the aim to aid translation from preclinical to clinical space.


Assuntos
Proteólise , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Biológicos , Pesquisa Translacional Biomédica
7.
J Pharmacol Exp Ther ; 361(3): 429-440, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28442583

RESUMO

Phosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating cellular survival, development, and function. Expression of the PI3Kδ isoform is largely restricted to leukocytes and it plays a key role in immune cell development and function. Seletalisib is a novel small-molecule inhibitor of PI3Kδ that was evaluated in biochemical assays, cellular assays of adaptive and innate immunity, and an in vivo rat model of inflammation. Our findings show that seletalisib is a potent, ATP-competitive, and selective PI3Kδ inhibitor able to block protein kinase B (AKT) phosphorylation following activation of the B-cell receptor in a B-cell line. Moreover, seletalisib inhibited N-formyl peptide-stimulated but not phorbol myristate acetate-stimulated superoxide release from human neutrophils, consistent with a PI3Kδ-specific activity. No indications of cytotoxicity were observed in peripheral blood mononuclear cells (PBMCs) or other cell types treated with seletalisib. Findings from cellular assays of adaptive immunity demonstrated that seletalisib blocks human T-cell production of several cytokines from activated T-cells. Additionally, seletalisib inhibited B-cell proliferation and cytokine release. In human whole blood assays, seletalisib inhibited CD69 expression upon B-cell activation and anti-IgE-mediated basophil degranulation. Seletalisib showed dose-dependent inhibition in an in vivo rat model of anti-CD3-antibody-induced interleukin 2 release. Collectively, these data characterize seletalisib as a selective PI3Kδ inhibitor and potential therapeutic candidate for the treatment of B-cell malignancies and autoimmune diseases driven by dysregulated proinflammatory cytokine secretion.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Piridinas/química , Piridinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases , Relação Dose-Resposta a Droga , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/enzimologia , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Endogâmicos Lew , Ratos Wistar
8.
Pharm Stat ; 15(3): 277-85, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27028721

RESUMO

Whilst innovative Bayesian approaches are increasingly used in clinical studies, in the preclinical area Bayesian methods appear to be rarely used in the reporting of pharmacology data. This is particularly surprising in the context of regularly repeated in vivo studies where there is a considerable amount of data from historical control groups, which has potential value. This paper describes our experience with introducing Bayesian analysis for such studies using a Bayesian meta-analytic predictive approach. This leads naturally either to an informative prior for a control group as part of a full Bayesian analysis of the next study or using a predictive distribution to replace a control group entirely. We use quality control charts to illustrate study-to-study variation to the scientists and describe informative priors in terms of their approximate effective numbers of animals. We describe two case studies of animal models: the lipopolysaccharide-induced cytokine release model used in inflammation and the novel object recognition model used to screen cognitive enhancers, both of which show the advantage of a Bayesian approach over the standard frequentist analysis. We conclude that using Bayesian methods in stable repeated in vivo studies can result in a more effective use of animals, either by reducing the total number of animals used or by increasing the precision of key treatment differences. This will lead to clearer results and supports the "3Rs initiative" to Refine, Reduce and Replace animals in research. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Teorema de Bayes , Avaliação Pré-Clínica de Medicamentos/métodos , Modelos Animais , Projetos de Pesquisa , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Nootrópicos/farmacologia
9.
Australas Psychiatry ; 24(1): 34-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26246445

RESUMO

OBJECTIVE: The purpose of this research was to examine earliest memories in patients with a mental disorder and their clinical relevance to diagnosis and treatment. METHOD: A semi-structured early memory questionnaire was developed and 50 patients with anxiety, depression or a psychotic disorder were interviewed. A thematic analysis was conducted to extract dominant themes from the qualitative data. RESULTS: Family events, play, and receiving attention were dominant themes of pleasant memories, while unpleasant memories consisted of fear-provoking situations, abuse/violence, and death-related themes. Participants were able to recall the feelings they had experienced at the time of their earliest memories and most participants stated that their first memories had significant impact in their lives. CONCLUSIONS: The findings of this exploratory study suggest that earliest memories may be of clinical significance for diagnostic and therapeutic interventions in psychiatry.


Assuntos
Maus-Tratos Infantis/psicologia , Emoções , Transtornos Mentais/psicologia , Rememoração Mental , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Medo , Feminino , Felicidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Austrália Ocidental
10.
J Transl Med ; 12: 285, 2014 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-25344414

RESUMO

BACKGROUND: Novel molecules that specifically target human TNFα in rheumatoid arthritis pose problems for preclinical assessment of efficacy. In this study collagen antibody-induced arthritis (CAIA) has been induced in human TNFα transgenic mice to provide a novel model that has been optimised for the evaluation of molecules targeting human TNFα. METHODS: Tg1278TNFko mice lack murine TNFα and are heterozygous for multiple copies of the human TNFα transgene that is expressed under normal physiological control. To establish CAIA, a collagen II monoclonal antibody cocktail (CAb) at 2, 4 or 8 mg was injected i.p. on Day 0 followed by a lipopolysaccharide (LPS) boost (10 or 100 µg) i.p. on Day 1 or Day 4. Animals were assessed for arthritis symptoms using a clinical score, cytokine levels (human TNFα, IL-1ß and IL-6) in sera and joints, and histopathology. The dependence of the model on human TNFα was determined by dosing animals with etanercept. RESULTS: Tg1278TNFko animals treated with 2, 4 or 8 mg CAb on Day 0, with 100 µg LPS on Day 4, had more severe arthritis and earlier symptoms than wild type animals at all doses of CAb tested. Subsequently it was found that the transgenic model did not require LPS at all for arthritis development but a lower dose of LPS (10 µg) was found necessary for reproducible and robust disease (close to 100% incidence, well-synchronised, with high arthritis scores). Furthermore the LPS challenge could be brought forward to Day 1 so that its' actions to facilitate disease could be separated temporally from the arthritis phase (beginning about Day 4). Etanercept, administered immediately after the serum spike of cytokines associated with LPS had subsided, was able to dose-dependently inhibit arthritis development and this was associated with a marked protection of the joints histologically on Day 14. Etanercept was also able to reverse the signs of arthritis when given therapeutically allowing animals to be matched for disease burden before dosing begins. CONCLUSIONS: The features of CAIA in Tg1278TNFko animals make the model well-suited to testing the next generation of therapeutics that will target human TNFα in rheumatoid arthritis.


Assuntos
Anticorpos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Colágeno Tipo II/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Artrite Reumatoide/metabolismo , Etanercepte/uso terapêutico , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos
11.
Australas Psychiatry ; 22(1): 66-70, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24288382

RESUMO

OBJECTIVE: To assess the frequency and characteristics of somatoform disorders in patients with chronic pain. METHOD: The study took place in the psychiatric outpatient clinic of a rehabilitation hospital. Participants were interviewed using the World Health Organization Somatoform Disorders Schedule (WHO-SDS) version 2.0. Thirty new and 30 current attendees to the clinic were interviewed following referral by pain medicine specialists. RESULTS: Somatoform disorders were commonly co-morbid with chronic pain in the study population. Persistent somatoform pain disorder (PSPD) was the commonest somatoform disorder. There was a significant difference between women and men suffering from somatic autonomic dysfunction (SAD). CONCLUSIONS: The findings of this study confirm that somatoform disorders are common co-morbid diagnoses in patients with chronic pain. Combining psychological treatments with medication, appropriate physical treatments and attending to social issues, may indeed improve the well-being of such patients.


Assuntos
Dor Crônica/complicações , Transtornos Somatoformes/complicações , Terapia por Acupuntura , Adolescente , Adulto , Doenças do Sistema Nervoso Autônomo/complicações , Dor Crônica/epidemiologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Nível de Saúde , Humanos , Hipocondríase/psicologia , Masculino , Pessoa de Meia-Idade , Neurastenia/psicologia , Tamanho da Amostra , Caracteres Sexuais , Transtornos Somatoformes/epidemiologia , Austrália Ocidental , Adulto Jovem
12.
Am J Pathol ; 182(6): 2071-81, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23602647

RESUMO

IL-17 is argued to play an important role in the multiple sclerosis-like disease experimental autoimmune encephalitis (EAE). We investigated the therapeutic effects of anti-IL-17A in a chronic relapsing EAE ABH mouse model using conventional scoring, quantitative behavioral outcomes, and a novel vascular cell adhesion molecule 1 (VCAM-1)-targeted magnetic resonance imaging (MRI) contrast agent [anti-VCAM-microparticles of iron oxide (MPIO)] to identify conventionally undetectable neuropathology. Mice were administered prophylactic or treatment regimens of anti-IL-17A or IgG and two injections of anti-VCAM-MPIO before undergoing T2*-weighted three-dimensional and gadolinium-diethylenetriamine pentaacetic acid T1-weighted MRI. Rotarod, inverted screen, and open field motor function tests were performed, conventional clinical scores calculated, and central IL-17A mRNA expression quantified during acute disease, remission, and relapse. Prophylactic anti-IL-17A prevents acute disease and relapse and is associated with reduced clinical and functional severity. Treatment regimens delay relapse, improve functional scores, and are associated with reduced VCAM-MPIO lesions during remission. No significant alteration was detectable in levels of gadolinium-diethylenetriamine pentaacetic acid- or VCAM-MPIO-positive lesions during relapse. Prophylactic and treatment anti-IL-17A were therapeutically effective in chronic relapsing EAE, improving clinical and quantifiable functional outcomes. IL-17A expression seems significant during acute disease but less important chronically. Disease-related immunoneuropathology is more sensitively detected using VCAM-MPIO MRI, which may, therefore, be used to monitor therapy meaningfully.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Encefalomielite Autoimune Experimental/terapia , Interleucina-17/antagonistas & inibidores , Molécula 1 de Adesão de Célula Vascular/metabolismo , Doença Aguda , Animais , Encéfalo/metabolismo , Meios de Contraste , Avaliação Pré-Clínica de Medicamentos/métodos , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Gadolínio DTPA , Regulação da Expressão Gênica , Interleucina-17/biossíntese , Interleucina-17/genética , Imageamento por Ressonância Magnética/métodos , Camundongos , Camundongos Biozzi , Atividade Motora , RNA Mensageiro/genética , Indução de Remissão , Prevenção Secundária , Índice de Gravidade de Doença , Resultado do Tratamento
13.
Complement Ther Clin Pract ; 18(4): 216-20, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23059435

RESUMO

AIMS: Aims were to determine the effectiveness of acupuncture and Chinese herbs as treatments for depression, and to assess beliefs, attitudes and treatment experience. METHOD: Participants received acupuncture or acupuncture and Chinese herbs combined for five weeks. Acupuncture was given for 30 min twice a week and herbs taken three times a day. A Beliefs and Attitudes questionnaire was administered at baseline and Treatment Experience questionnaire post treatment. Outcome measure was improvement in depressive symptoms at the end of treatment period. RESULTS: Nineteen participants completed 5 weeks of treatment, 12 in the acupuncture group and 7 in the combined group. Treatment significantly improved depressive symptoms, however, there were no differences between groups. At baseline, participants were positive about the perceived effectiveness of treatment, and treatment experiences were positive. CONCLUSIONS: Acupuncture was effective in reducing depressive symptoms. However, herbs did not have an additional treatment effect. Beliefs and attitudes were positive.


Assuntos
Terapia por Acupuntura/métodos , Atitude Frente a Saúde , Transtorno Depressivo/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Adulto , Austrália , Terapia Combinada , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
14.
Curr Opin Psychiatry ; 24(1): 72-7, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20844434

RESUMO

PURPOSE OF REVIEW: This article aims to summarize recent findings relating to the impact of fire disasters on the mental health of victims, responders, families and communities within the context of the existing literature. RECENT FINDINGS: Recent studies support previous findings that fire disasters are associated with a negative impact on the mental and physical health of victims, their families and professional and voluntary responders to the disasters. These effects can be delayed in onset and can persist over at least several years, although long-term follow-up studies over 20 years or more indicate that the psychological effects on victims are minimal relative to controls by this stage. SUMMARY: Fire disasters, like other natural or man-made disasters, can have significant mental health impact on individuals directly and indirectly affected and on communities caught up in the events.


Assuntos
Desastres , Incêndios , Nível de Saúde , Saúde Mental , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Saúde da Família , Humanos , Doenças Profissionais/epidemiologia , Doenças Profissionais/psicologia , Prevalência , Trabalho de Resgate , Transtornos de Estresse Pós-Traumáticos/etiologia , Sobreviventes/psicologia
15.
Contemp Nurse ; 34(2): 167-76, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20509801

RESUMO

This paper summarises a consultation-liaison nurse's journey as a senior mental health clinician working within the general hospital setting. It begins with a brief history of consultation-liaison nursing (CLN) and covers the CLN experience in both the general hospital and the emergency department showing how the role evolved to become more focused on the needs of the general hospital. It shares some experiences during a stimulating, challenging and rewarding career where clinical supervision is seen as essential not only to reflect on and improve practice but to assist the CL nurse in working through the emotional demands of the role. The paper aims to increase knowledge of the CLN experience and promote interest in this specialist area of mental health nursing which is developing rapidly internationally and in Australia.


Assuntos
Prática Avançada de Enfermagem/organização & administração , Atitude do Pessoal de Saúde , Consultores/psicologia , Enfermeiros Clínicos , Papel do Profissional de Enfermagem/psicologia , Enfermagem Psiquiátrica/organização & administração , Prática Avançada de Enfermagem/educação , Austrália , Competência Clínica , Comorbidade , Serviços de Emergência Psiquiátrica , Necessidades e Demandas de Serviços de Saúde , Hospitais Gerais , Humanos , Transtornos Mentais/complicações , Transtornos Mentais/enfermagem , Transtornos Mentais/psicologia , Enfermeiros Clínicos/educação , Enfermeiros Clínicos/organização & administração , Enfermeiros Clínicos/psicologia , Supervisão de Enfermagem , Relações Médico-Enfermeiro , Enfermagem Psiquiátrica/educação , Reino Unido , Estados Unidos
16.
Curr Opin Psychiatry ; 22(1): 50-4, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19122535

RESUMO

PURPOSE OF REVIEW: Despite the relative frequency with which the diagnosis of adjustment disorder is made, there is a very limited research literature in regard to its cause, epidemiology and treatment. This review summarizes recent papers and findings in relation to this diagnostic category. RECENT FINDINGS: The conceptual underpinnings of the diagnosis adjustment disorder is the subject of ongoing debate as is its differentiation from other psychiatric disorders such as depressive disorders. One group has proposed and tested a diagnostic model of adjustment disorder as a stress-response syndrome, related to posttraumatic stress disorder, which is a distinct psychopathological entity rather than a diagnosis of exclusion. Initial neuroimaging work in adjustment disorder indicates that this may be a helpful approach for increasing understanding of the biology of the disorder. Recent studies support the use of brief psychotherapy in the treatment of adjustment disorder. SUMMARY: Although the studies and articles described in this review raise some interesting questions in relation to the diagnosis, cause, epidemiology and treatment of adjustment disorder, much more research is needed before we can draw some firm conclusions about the need for the redefinition and reclassification of this diagnostic category.


Assuntos
Transtornos de Adaptação/diagnóstico , Transtornos de Adaptação/epidemiologia , Transtornos de Adaptação/etiologia , Transtornos de Adaptação/terapia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Humanos , Modelos Psicológicos
17.
Contemp Nurse ; 30(1): 69-75, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19072192

RESUMO

There is well documented evidence for the increasing and widespread use of complementary and alternative medicine in the treatment of symptoms of both physical and mental disorders within Western populations. This paper aims to provide a focused review of recent literature on the use of one of these therapies, namely aromatherapy, in nursing and mental health care of people suffering from anxiety and depressive disorders. The evidence base for the efficacy of aromatherapy used to treat these conditions remains poor with a particular paucity of methodologically rigorous studies. However, there are some promising results which suggest that further research is warranted to investigate the potential of essential oils in treating anxiety, depression and symptoms of stress. The experimentally designed inhalation studies are of particular importance as both health professionals and consumers demand more accurate and scientifically based information about the effects and safety of essential oils.


Assuntos
Aromaterapia , Ansiedade/terapia , Aromaterapia/efeitos adversos , Aromaterapia/enfermagem , Depressão/terapia , Humanos , Neoplasias/enfermagem , Neoplasias/psicologia , Neoplasias/terapia , Óleos Voláteis
18.
J Leukoc Biol ; 84(4): 1202-12, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18586982

RESUMO

IL-17-producing Th cells (Th17) are a distinct subset of effector cells that bridge the innate and adaptive immune system and are implicated in autoimmune disease processes. CD4(+) splenocytes from DO11.10 mice were activated with OVA peptide(323-339) and maintained under Th17 polarization conditions, resulting in significantly higher proportions of IL-17(+) T cells compared with nonpolarized (Th0) cells. Th17-polarizing conditions significantly increased the proportion of cells expressing the chemokine receptors CCR2, CCR6, and CCR9 when compared with Th0 cells. In contrast, there was a significant decrease in the proportion of cells expressing CXCR3 under Th17-polarizing conditions compared with nonpolarizing conditions. The respective chemokine agonists for CCR2 (CCL2 and CCL12), CCR6 (CCL20), and CCR9 (CCL25) elicited migration and PI-3K-dependent signaling events in Th17-polarized cells, thus indicating that all three receptors were functionally and biochemically responsive. Furthermore, postmigration phenotypic analysis demonstrated that the agonists for CCR2 and CCR6, but not CCR9, stimulated a modest enrichment of IL-17(+) cells compared with the premigration population. Pan-isoform inhibitors of PI-3K/Akt signaling prevented CCR2- and CCR6-mediated, polarized Th17 cell migration in a concentration-dependent manner. The unique chemokine receptor expression pattern of Th17 cells and their corresponding PI-3K-dependent migratory responses are important for understanding the pathogenesis of autoimmune diseases and may provide opportunities for the application of CCR2 and CCR6 antagonists and PI-3K isoform-selective inhibitors in defined inflammatory settings.


Assuntos
Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CCR2/fisiologia , Receptores CCR6/fisiologia , Linfócitos T Auxiliares-Indutores/fisiologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/fisiologia , Movimento Celular , Separação Celular , Citocinas/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinases/imunologia , Receptores CCR2/agonistas , Receptores CCR6/agonistas , Receptores de Quimiocinas/genética , Baço/citologia , Baço/imunologia , Linfócitos T Auxiliares-Indutores/imunologia
19.
J Med Chem ; 50(13): 3101-12, 2007 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-17536796

RESUMO

Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2 receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for recombinant, human CCK2 receptors and high selectivity over CCK1 receptors observed in the initial lead but display more potent inhibition of pentagastrin-stimulated gastric acid secretion in vivo. Moreover, this has largely been achieved without altering their potency at wild-type canine and rat receptors, as judged by their displacement of [125I]-BH-CCK-8S in a radioligand binding assay and by their activity in an isolated, perfused rat stomach bioassay, respectively. 2-(5-Cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro- [1,2,4]oxadiazol-3-yl)-phenyl)-acetamide (47) was identified as the most effective compound stemming from this approach, proving to be a potent inhibitor of pentagastrin-stimulated gastric acid secretion in rats and dogs by intravenous bolus as well as by enteral administration.


Assuntos
Benzodiazepinas/síntese química , Ácido Gástrico/metabolismo , Pentagastrina/farmacologia , Receptor de Colecistocinina B/antagonistas & inibidores , Administração Oral , Animais , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Cães , Mucosa Gástrica/metabolismo , Humanos , Infusões Intravenosas , Injeções Intravenosas , Camundongos , Células NIH 3T3 , Ensaio Radioligante , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade
20.
J Med Chem ; 48(22): 6803-12, 2005 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-16250639

RESUMO

The systematic optimization of the structure of a novel 2,4,5-trisubstituted imidazole-based cholecystokinin-2 (CCK(2)) receptor antagonist afforded analogues with nanomolar receptor affinity. These compounds were now comparable in their potency to the bicyclic heteroaromatic-based compounds 5 (JB93182) and 6 (JB95008), from which the initial examples were designed using a field-point based molecular modeling approach. They were also orally active as judged by their inhibition of pentagastrin stimulated acid secretion in conscious dogs, in contrast to the bicyclic heteroaromatic-based compounds, which were ineffective because of biliary elimination. Increasing the hydrophilicity through replacement of a particular methylene group with an ether oxygen, as in 3-{[5-(adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]amino}benzoic acid (53), had little effect on the receptor affinity but significantly increased the oral potency. Comparison of the plasma pharmacokinetics and the inhibition of pentagastrin-stimulated acid output following bolus intraduodenal administration of both 53 and 6 indicated that 53 was well absorbed, had a longer half-life, and was not subject to the elimination pathways of the earlier series.


Assuntos
Imidazóis/síntese química , Pirróis/síntese química , Receptor de Colecistocinina B/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Córtex Cerebral/metabolismo , Cães , Feminino , Ácido Gástrico/metabolismo , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Infusões Intravenosas , Camundongos , Modelos Moleculares , Pentagastrina/administração & dosagem , Pentagastrina/farmacologia , Pirróis/química , Pirróis/farmacologia , Relação Quantitativa Estrutura-Atividade , Ensaio Radioligante
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