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1.
Cancer Discov ; 12(11): 2684-2709, 2022 11 02.
Article in English | MEDLINE | ID: mdl-36053276

ABSTRACT

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.


Subject(s)
Leukemia, Myeloid, Acute , Lysine , Humans , Leukemia, Myeloid, Acute/genetics , Histones/metabolism , Chromatin , Myeloid-Lymphoid Leukemia Protein/metabolism
2.
Angew Chem Int Ed Engl ; 60(43): 23327-23334, 2021 10 18.
Article in English | MEDLINE | ID: mdl-34416073

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Focal Adhesion Kinase 1/antagonists & inhibitors , Proteolysis/drug effects , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Benzamides/chemistry , Benzamides/pharmacokinetics , Benzamides/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Dipeptides/chemistry , Dipeptides/pharmacokinetics , Dipeptides/pharmacology , Focal Adhesion Kinase 1/metabolism , Humans , Mice , Molecular Structure , Ubiquitin-Protein Ligases/metabolism
3.
J Med Chem ; 64(17): 12978-13003, 2021 09 09.
Article in English | MEDLINE | ID: mdl-34432979

ABSTRACT

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.


Subject(s)
Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , Animals , Drug Design , Gene Expression Regulation/drug effects , Half-Life , Humans , Male , Molecular Structure , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics , THP-1 Cells
4.
ACS Chem Biol ; 15(9): 2316-2323, 2020 09 18.
Article in English | MEDLINE | ID: mdl-32697072

ABSTRACT

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.


Subject(s)
Benzothiazoles/metabolism , Isoquinolines/metabolism , Oligopeptides/metabolism , Proteolysis/drug effects , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , bcl-X Protein/antagonists & inhibitors , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacology , Oligopeptides/chemistry , Oligopeptides/pharmacology , Protein Binding , bcl-X Protein/chemistry , bcl-X Protein/metabolism
5.
Commun Biol ; 3(1): 140, 2020 03 20.
Article in English | MEDLINE | ID: mdl-32198438

ABSTRACT

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.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Drug Design , Inflammation/prevention & control , Leukocytes, Mononuclear/drug effects , Proteasome Endopeptidase Complex/metabolism , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/pharmacokinetics , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/enzymology , Crohn Disease/drug therapy , Crohn Disease/enzymology , Cytokines/metabolism , Dose-Response Relationship, Drug , Enzyme Stability , Female , Humans , Inflammation/enzymology , Inflammation/immunology , Inflammation Mediators/metabolism , Injections, Intravenous , Leukocytes, Mononuclear/enzymology , Male , Proteolysis , Rats, Sprague-Dawley , Rats, Wistar , THP-1 Cells , Tissue Culture Techniques , Ubiquitination
6.
Drug Discov Today Technol ; 31: 69-80, 2019 Apr.
Article in English | MEDLINE | ID: mdl-31200862

ABSTRACT

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.


Subject(s)
Proteolysis , Animals , Drug Evaluation, Preclinical , Humans , Models, Biological , Translational Research, Biomedical
7.
J Pharmacol Exp Ther ; 361(3): 429-440, 2017 06.
Article in English | MEDLINE | ID: mdl-28442583

ABSTRACT

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.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Animals , Cells, Cultured , Class I Phosphatidylinositol 3-Kinases , Dose-Response Relationship, Drug , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/enzymology , Male , Phosphatidylinositol 3-Kinases/metabolism , Rats , Rats, Inbred Lew , Rats, Wistar
8.
Pharm Stat ; 15(3): 277-85, 2016 05.
Article in English | MEDLINE | ID: mdl-27028721

ABSTRACT

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.


Subject(s)
Bayes Theorem , Drug Evaluation, Preclinical/methods , Models, Animal , Research Design , Animals , Cytokines/metabolism , Disease Models, Animal , Inflammation/pathology , Lipopolysaccharides/pharmacology , Nootropic Agents/pharmacology
9.
Australas Psychiatry ; 24(1): 34-8, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26246445

ABSTRACT

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.


Subject(s)
Child Abuse/psychology , Emotions , Mental Disorders/psychology , Mental Recall , Adolescent , Adult , Aged , Child , Child, Preschool , Fear , Female , Happiness , Humans , Infant , Male , Middle Aged , Surveys and Questionnaires , Western Australia
10.
J Transl Med ; 12: 285, 2014 Oct 25.
Article in English | MEDLINE | ID: mdl-25344414

ABSTRACT

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.


Subject(s)
Antibodies/administration & dosage , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Collagen Type II/antagonists & inhibitors , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Arthritis, Rheumatoid/metabolism , Etanercept/therapeutic use , Humans , Mice , Mice, Knockout , Mice, Transgenic
11.
Australas Psychiatry ; 22(1): 66-70, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24288382

ABSTRACT

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.


Subject(s)
Chronic Pain/complications , Somatoform Disorders/complications , Acupuncture Therapy , Adolescent , Adult , Autonomic Nervous System Diseases/complications , Chronic Pain/epidemiology , Diagnostic and Statistical Manual of Mental Disorders , Female , Health Status , Humans , Hypochondriasis/psychology , Male , Middle Aged , Neurasthenia/psychology , Sample Size , Sex Characteristics , Somatoform Disorders/epidemiology , Western Australia , Young Adult
12.
Am J Pathol ; 182(6): 2071-81, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23602647

ABSTRACT

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.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Encephalomyelitis, Autoimmune, Experimental/therapy , Interleukin-17/antagonists & inhibitors , Vascular Cell Adhesion Molecule-1/metabolism , Acute Disease , Animals , Brain/metabolism , Contrast Media , Drug Evaluation, Preclinical/methods , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Gadolinium DTPA , Gene Expression Regulation , Interleukin-17/biosynthesis , Interleukin-17/genetics , Magnetic Resonance Imaging/methods , Mice , Mice, Biozzi , Motor Activity , RNA, Messenger/genetics , Remission Induction , Secondary Prevention , Severity of Illness Index , Treatment Outcome
13.
Complement Ther Clin Pract ; 18(4): 216-20, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23059435

ABSTRACT

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.


Subject(s)
Acupuncture Therapy/methods , Attitude to Health , Depressive Disorder/therapy , Drugs, Chinese Herbal/therapeutic use , Adult , Australia , Combined Modality Therapy , Drugs, Chinese Herbal/administration & dosage , Female , Humans , Male , Middle Aged , Pilot Projects , Surveys and Questionnaires , Treatment Outcome , Young Adult
14.
Curr Opin Psychiatry ; 24(1): 72-7, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20844434

ABSTRACT

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.


Subject(s)
Disasters , Fires , Health Status , Mental Health , Stress Disorders, Post-Traumatic/epidemiology , Family Health , Humans , Occupational Diseases/epidemiology , Occupational Diseases/psychology , Prevalence , Rescue Work , Stress Disorders, Post-Traumatic/etiology , Survivors/psychology
15.
Contemp Nurse ; 34(2): 167-76, 2010.
Article in English | MEDLINE | ID: mdl-20509801

ABSTRACT

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.


Subject(s)
Advanced Practice Nursing/organization & administration , Attitude of Health Personnel , Consultants/psychology , Nurse Clinicians , Nurse's Role/psychology , Psychiatric Nursing/organization & administration , Advanced Practice Nursing/education , Australia , Clinical Competence , Comorbidity , Emergency Services, Psychiatric , Health Services Needs and Demand , Hospitals, General , Humans , Mental Disorders/complications , Mental Disorders/nursing , Mental Disorders/psychology , Nurse Clinicians/education , Nurse Clinicians/organization & administration , Nurse Clinicians/psychology , Nursing, Supervisory , Physician-Nurse Relations , Psychiatric Nursing/education , United Kingdom , United States
16.
Curr Opin Psychiatry ; 22(1): 50-4, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19122535

ABSTRACT

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.


Subject(s)
Adjustment Disorders/diagnosis , Adjustment Disorders/epidemiology , Adjustment Disorders/etiology , Adjustment Disorders/therapy , Diagnostic and Statistical Manual of Mental Disorders , Humans , Models, Psychological
17.
Contemp Nurse ; 30(1): 69-75, 2008 Aug.
Article in English | MEDLINE | ID: mdl-19072192

ABSTRACT

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.


Subject(s)
Aromatherapy , Anxiety/therapy , Aromatherapy/adverse effects , Aromatherapy/nursing , Depression/therapy , Humans , Neoplasms/nursing , Neoplasms/psychology , Neoplasms/therapy , Oils, Volatile
18.
J Leukoc Biol ; 84(4): 1202-12, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18586982

ABSTRACT

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.


Subject(s)
Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptors, CCR2/physiology , Receptors, CCR6/physiology , T-Lymphocytes, Helper-Inducer/physiology , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/physiology , Cell Movement , Cell Separation , Cytokines/metabolism , Gene Expression Profiling , Gene Expression Regulation , Mice , Mice, Inbred BALB C , Phosphatidylinositol 3-Kinases/immunology , Receptors, CCR2/agonists , Receptors, CCR6/agonists , Receptors, Chemokine/genetics , Spleen/cytology , Spleen/immunology , T-Lymphocytes, Helper-Inducer/immunology
19.
J Med Chem ; 50(13): 3101-12, 2007 Jun 28.
Article in English | MEDLINE | ID: mdl-17536796

ABSTRACT

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.


Subject(s)
Benzodiazepines/chemical synthesis , Gastric Acid/metabolism , Pentagastrin/pharmacology , Receptor, Cholecystokinin B/antagonists & inhibitors , Administration, Oral , Animals , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Dogs , Gastric Mucosa/metabolism , Humans , Infusions, Intravenous , Injections, Intravenous , Mice , NIH 3T3 Cells , Radioligand Assay , Rats , Recombinant Proteins/antagonists & inhibitors , Structure-Activity Relationship
20.
J Med Chem ; 48(22): 6803-12, 2005 Nov 03.
Article in English | MEDLINE | ID: mdl-16250639

ABSTRACT

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.


Subject(s)
Imidazoles/chemical synthesis , Pyrroles/chemical synthesis , Receptor, Cholecystokinin B/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cerebral Cortex/metabolism , Dogs , Female , Gastric Acid/metabolism , Imidazoles/chemistry , Imidazoles/pharmacology , In Vitro Techniques , Infusions, Intravenous , Mice , Models, Molecular , Pentagastrin/administration & dosage , Pentagastrin/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Quantitative Structure-Activity Relationship , Radioligand Assay
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