Enhanced cortisol suppression following administration of low-dose dexamethasone in first-episode psychosis patients

OBJECTIVE Impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis and hyper-activity of this system have been described in patients with psychosis. Conversely, some psychiatric disorders such as post-traumatic stress disorder (PTSD) are characterised by HPA hypo-activity, which could be related to prior exposure to trauma. This study examined the cortisol response to the administration of low-dose dexamethasone in first-episode psychosis (FEP) patients and its relationship to childhood trauma. METHOD The low-dose (0.25 mg) Dexamethasone Suppression Test (DST) was performed in 21 neuroleptic-naive or minimally treated FEP patients and 20 healthy control participants. Childhood traumatic events were assessed in all participants using the Childhood Trauma Questionnaire (CTQ) and psychiatric symptoms were assessed in patients using standard rating scales. RESULTS FEP patients reported significantly higher rates of childhood trauma compared to controls (p = 0.001) and exhibited lower basal (a.m.) cortisol (p = 0.04) and an increased rate of cortisol hyper-suppression following dexamethasone administration compared to controls (33% (7/21) vs 5% (1/20), respectively; p = 0.04). There were no significant group differences in mean cortisol decline or percent cortisol suppression following the 0.25 mg DST. This study shows for the first time that a subset of patients experiencing their first episode of psychosis display enhanced cortisol suppression. CONCLUSIONS These findings suggest there may be distinct profiles of HPA axis dysfunction in psychosis which should be further explored.

Pharmacology in one semester [Version 3, Semester 1, 2014]

- For use in Introductory Units/Courses to Biomedical/Science Students - For use with Allied Health Students who are taking pharmacology as a Unit/Course or a part Unit/Course

“Success in (Surviving) Bioscience and Pharmacology” – an eBook to improve the retention of diploma nurses transitioning to a Bachelor of Nursing course

Diploma students transitioning into the NS40 BNursing (BN) course at QUT withdraw from the bioscience and pharmacology units, and leave the university at higher rates than traditional students. The diploma students, entering in second year, have missed out on 2 units of bioscience taught to the traditional students in their first year, and miss out on a 3rd unit of bioscience taught to the traditional students in their 2nd year. Instead the diploma students receive one specialized unit in bioscience only i.e. a bridging unit. As a consequence, the diploma students may not have the depth of bioscience knowledge to be able to successfully study the bridging unit (LSB111) or the pharmacology unit (LSB384). Our plan was to write an eBook which refreshed and reinforced diploma students’ knowledge of bioscience aiming to prepare them with the concepts and terminology, and to build a level of confidence to support their transition to the BN. We have previously developed an intervention associated with reduced attrition of diploma nursing students, and this was our starting point. The study skills part of the initial intervention was addressed in the eBook, by links to the specialist services and resources available from our liaison librarian and academic skills adviser. The introductory bioscience/pharmacology information provided by the previous intervention involved material from standard textbooks. However, we considered this material too difficult for diploma students. Thus, we created simplified diagrams to go with text as part of our eBook. The outcome is an eBook, created and made available to the diploma students via the Community Website: “Surviving Bioscience and Pharmacology”. Using simplified diagrams to illustrate the concise text, definition to explain the concepts, the focus has been on encouraging self-awareness and help-seeking strategies and building students who take responsibility for their learning. All the nursing students in the second semester LSB384 Pharmacology Unit have been surveyed face-to-face to get feedback on their engagement with the eBook resource. The data has not been analysed to date. An important consideration is that the website be evaluated by the diploma students as they come into bioscience in first semester (LSB111), the student population for whom the eBook is primarily intended. To get a good response rate we need to do a face-to-face survey. However, we have not been able to do this, as the co-ordinator of the unit has changed since we started the project, and the present co-ordinator will not allow us access to these students.

Reduced attrition of accelerated nursing students from pharmacology – is it associated with graduation?

In order to reduce the attrition of accelerated nursing students in bioscience/pharmacology, we introduced an innovation to help these students. Although this innovation was associated with reduced attritions from the units in their first year at university, we now show that there was a reduced graduation rate of the accelerated students who survived pharmacology, compared to the traditional students.

The Pharmacology of Oxycodone : Studies In Vitro, In Vivo and In Humans

The antinociceptive properties of oxycodone and its metabolites were studied in models of thermal and mechanical nociception and in the spinal nerve ligation (SNL) model of neuropathic pain in rats. Oxycodone induced potent antinociception after subcutaneous (s.c.) administration in all models of nociception used in rats compared with morphine, methadone and its enantiomers. In the SNL model of neuropathic pain in rats, oxycodone produced dose dependent antinociception after s.c. administration. The antinociceptive effects of s.c. oxycodone were antagonized by naloxone but not by nor-binaltorphimine (Nor-BNI) a selective κ-opioid receptor antagonist indicating that the antinociceptive properties of oxycodone are predominantly μ-opioid receptor-mediated. The antinociceptive activity of oxymorphone, noroxycodone, and noroxymorphone, oxidative metabolites of oxycodone, were studied to determine their role in the oxycodone-induced antinociception in the rat. Of the metabolites of oxycodone s.c. administration of oxymorphone produced potent thermal and mechanical antinociception. Noroxycodone had a poor antinociceptive effect and noroxymorphone was inactive. Oxycodone produced naloxone-reversible antinociception after intrathecal (i.t) administration with a poor potency compared with morphine and oxymorphone. This seems to be related to the low efficacy and potency of oxycodone to stimulate μ-opioid receptor activation in the spinal cord in μ-opioid receptor agonist-stimulated (GTP)γ[S] autoradiography, compared with morphine and oxymorphone. All metabolites studied were more potent than oxycodone after i.t. administration. I.t. noroxymorphone induced a significantly longer lasting antinociceptive effect compared with the other drugs studied. The role of cytochrome P450 (CYP) 2D6-mediated metabolites on the analgesic activity of oxycodone in humans was studied by blocking the CYP2D6-mediated metabolism of oxycodone with paroxetine. Paroxetine co-administration had no effect on the analgesic effect of oxycodone compared with placebo in chronic pain patients, indicating that oxycodone-induced analgesia and adverse-effects are not dependent of the CYP2D6-mediated metabolism in humans. Although oxycodone has many pharmacologically active metabolites, they seem to have an insignificant role in oxycodone-induced antinociception in humans and rats.

Reduced withdrawal and failure rates of accelerated nursing students enrolled in pharmacology is associated with a supportive intervention

Background To reduce nursing shortages, accelerated nursing programs are available for domestic and international students. However, the withdrawal and failure rates from these programs may be different than for the traditional programs. The main aim of our study was to improve the retention and experience of accelerated nursing students. Methods The academic background, age, withdrawal and failure rates of the accelerated and traditional students were determined. Data from 2009 and 2010 were collected prior to intervention. In an attempt to reduce the withdrawal of accelerated students, we set up an intervention, which was available to all students. The assessment of the intervention was a pre-post-test design with non-equivalent groups (the traditional and the accelerated students). The elements of the intervention were a) a formative website activity of some basic concepts in anatomy, physiology and pharmacology, b) a workshop addressing study skills and online resources, and c) resource lectures in anatomy/physiology and microbiology. The formative website and workshop was evaluated using questionnaires. Results The accelerated nursing students were five years older than the traditional students (p < 0.0001). The withdrawal rates from a pharmacology course are higher for accelerated nursing students, than for traditional students who have undertaken first year courses in anatomy and physiology (p = 0.04 in 2010). The withdrawing students were predominantly the domestic students with non-university qualifications or equivalent experience. The failure rates were also higher for this group, compared to the traditional students (p = 0.05 in 2009 and 0.03 in 2010). In contrast, the withdrawal rates for the international and domestic graduate accelerated students were very low. After the intervention, the withdrawal and failure rates in pharmacology for domestic accelerated students with non-university qualifications were not significantly different than those of traditional students. Conclusions The accelerated international and domestic graduate nursing students have low withdrawal rates and high success rates in a pharmacology course. However, domestic students with non-university qualifications have higher withdrawal and failure rates than other nursing students and may be underprepared for university study in pharmacology in nursing programs. The introduction of an intervention was associated with reduced withdrawal and failure rates for these students in the pharmacology course.

Dexamethasone negatively regulates phenobarbitone-activated transcription but synergistically enhances cytoplasmic levels of cytochrome P-450b/e messenger RNA

Dexamethasone has a potentiating effect on phenobarbitone mediated induction of cytochrome P-450b + e mRNAs in adult rat liver. However, the glucocorticoid inhibits phenobarbitone-activated transcription of cytochrome P-450b + e mRNAs by 60-70%. This inhibitory effect is evident in run-off transcription of the endogenous genes as well as in the transcription of an added cloned gene fragment. Dexamethasone inhibits the phenobarbitone-mediated increase in the binding of a transcription factor(s) to the upstream region of the gene as evidenced by gel retardation and Southwestern blot analysis. The glucocorticoid does not stabilize the phenobarbitone-induced polyribosomal cytochrome P-450b + e mRNAs but appears to stabilize the nuclear transcripts. It is proposed that a negative element may mediate the action of dexamethasone at the level of nuclear transcription and stabilization of the nuclear transcript may account for the potentiating effect of the glucocorticoid on phenobarbitone-mediated increase in cytochrome P-450b + e mRNAs in the cytoplasm of the adult rat liver. However, the cytochrome P-450b protein levels are slightly lower in phenobarbitone + dexamethasone treatment than in phenobarbitone-treated liver microsomes.

Pharmacology and pore-forming domains of the cystic fibrosis transmembrane conductance regulator

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel member of the ATP-binding cassette (ABC) superfamily of membrane proteins. CFTR has two homologous halves, each consisting of six transmembrane spanning domains (TM) followed by a nucleotide binding fold, connected by a regulatory (R) domain. This thesis addresses the question of which domains are responsible for Cl^- selectivity, i.e., which domains line the channel pore.

To address this question, novel blockers of CFTR were characterized. CFTR was heterologously expressed in Xenopus oocytes to study the mechanism of block by two closely related arylaminobenzoates, diphenylamine-2-carboxylic acid (DPC) and flufenamic acid (FFA). Block by both is voltage-dependent, with a binding site ≈ 40% through the electric field of the membrane. DPC and FFA can both reach their binding site from either side of the membrane to produce a flickering block of CFTR single channels. In addition, DPC block is influenced by Cl^- concentration, and DPC blocks with a bimolecular forward binding rate and a unimolecular dissociation rate. Therefore, DPC and FFA are open-channel blockers of CFTR, and a residue of CFTR whose mutation affects their binding must line the pore.

Screening of site-directed mutants for altered DPC binding affinity reveals that TM-6 and TM-12 line the pore. Mutation of residue 5341 in TM-6 abolishes most DPC block, greatly reduces single-channel conductance, and alters the direction of current rectification. Additional residues are found in TM-6 (K335) and TM-12 (T1134) whose mutations weaken or strengthen DPC block; other mutations move the DPC binding site from TM-6 to TM-12. The strengthened block and lower conductance due to mutation T1134F is quantitated at the single-channel level. The geometry of DPC and of the residues mutated suggest α-helical structures for TM-6 and TM-12. Evidence is presented that the effects of the mutations are due to direct side-chain interaction, and not to allosteric effects propagated through the protein. Mutations are also made in TM-11, including mutation S1118F, which gives voltage-dependent current relaxations. The results may guide future studies on permeation through ABC transporters and through other Cl^- channels.

Breast cancer therapies in development. A review of their pharmacology and clinical potential.

Although the management of breast cancer has improved over the past few decades, it remains an important challenge for the clinician. Cytotoxic chemotherapy and hormonotherapy, when given in the adjuvant setting, have a definitive though modest impact on the outcome of early-stage breast cancer. In metastatic disease, these therapies help to provide substantial palliation of symptoms but have a limited impact on survival. The discovery of vinorelbine and the taxanes, paclitaxel and docetaxel, certainly represented the most encouraging clinical development of the 1980s in breast cancer therapy. Several other new cytotoxic agents have been recognised for their potential in the treatment of this disorder. Many of them are only in a very early phase of their clinical development and it remains to be proven that they will have a major role in daily practice in the near future.

Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential.

Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO(3)(*-), peroxyl radical, and less efficiently H(2)O(2). By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and/or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds.

Characterization of porous, dexamethasone-releasing polyurethane coatings for glucose sensors.

Commercially available implantable needle-type glucose sensors for diabetes management are robust analytically but can be unreliable clinically primarily due to tissue-sensor interactions. Here, we present the physical, drug release and bioactivity characterization of tubular, porous dexamethasone (Dex)-releasing polyurethane coatings designed to attenuate local inflammation at the tissue-sensor interface. Porous polyurethane coatings were produced by the salt-leaching/gas-foaming method. Scanning electron microscopy and micro-computed tomography (micro-CT) showed controlled porosity and coating thickness. In vitro drug release from coatings monitored over 2 weeks presented an initial fast release followed by a slower release. Total release from coatings was highly dependent on initial drug loading amount. Functional in vitro testing of glucose sensors deployed with porous coatings against glucose standards demonstrated that highly porous coatings minimally affected signal strength and response rate. Bioactivity of the released drug was determined by monitoring Dex-mediated, dose-dependent apoptosis of human peripheral blood derived monocytes in culture. Acute animal studies were used to determine the appropriate Dex payload for the implanted porous coatings. Pilot short-term animal studies showed that Dex released from porous coatings implanted in rat subcutis attenuated the initial inflammatory response to sensor implantation. These results suggest that deploying sensors with the porous, Dex-releasing coatings is a promising strategy to improve glucose sensor performance.

Characterization of porous, dexamethasone-releasing polyurethane coatings for glucose sensors

© 2014 Acta Materialia Inc.Commercially available implantable needle-type glucose sensors for diabetes management are robust analytically but can be unreliable clinically primarily due to tissue-sensor interactions. Here, we present the physical, drug release and bioactivity characterization of tubular, porous dexamethasone (Dex)-releasing polyurethane coatings designed to attenuate local inflammation at the tissue-sensor interface. Porous polyurethane coatings were produced by the salt-leaching/gas-foaming method. Scanning electron microscopy and micro-computed tomography (micro-CT) showed controlled porosity and coating thickness. In vitro drug release from coatings monitored over 2 weeks presented an initial fast release followed by a slower release. Total release from coatings was highly dependent on initial drug loading amount. Functional in vitro testing of glucose sensors deployed with porous coatings against glucose standards demonstrated that highly porous coatings minimally affected signal strength and response rate. Bioactivity of the released drug was determined by monitoring Dex-mediated, dose-dependent apoptosis of human peripheral blood derived monocytes in culture. Acute animal studies were used to determine the appropriate Dex payload for the implanted porous coatings. Pilot short-term animal studies showed that Dex released from porous coatings implanted in rat subcutis attenuated the initial inflammatory response to sensor implantation. These results suggest that deploying sensors with the porous, Dex-releasing coatings is a promising strategy to improve glucose sensor performance.

Improving Indwelling Glucose Sensor Performance: Porous, Dexamethasone-Releasing Coatings that Modulate the Foreign Body Response

Inflammation and the formation of an avascular fibrous capsule have been identified as the key factors controlling the wound healing associated failure of implantable glucose sensors. Our aim is to guide advantageous tissue remodeling around implanted sensor leads by the temporal release of dexamethasone (Dex), a potent anti-inflammatory agent, in combination with the presentation of a stable textured surface.

First, Dex-releasing polyurethane porous coatings of controlled pore size and thickness were fabricated using salt-leaching/gas-foaming technique. Porosity, pore size, thickness, drug release kinetics, drug loading amount, and drug bioactivity were evaluated. In vitro sensor functionality test were performed to determine if Dex-releasing porous coatings interfered with sensor performance (increased signal attenuation and/or response times) compared to bare sensors. Drug release from coatings monitored over two weeks presented an initial fast release followed by a slower release. Total release from coatings was highly dependent on initial drug loading amount. Functional in vitro testing of glucose sensors deployed with porous coatings against glucose standards demonstrated that highly porous coatings minimally affected signal strength and response rate. Bioactivity of the released drug was determined by monitoring Dex-mediated, dose-dependent apoptosis of human peripheral blood derived monocytes in culture.

The tissue modifying effects of Dex-releasing porous coatings were accessed by fully implanting Tygon® tubing in the subcutaneous space of healthy and diabetic rats. Based on encouraging results from these studies, we deployed Dex-releasing porous coatings from the tips of functional sensors in both diabetic and healthy rats. We evaluated if the tissue modifying effects translated into accurate, maintainable and reliable sensor signals in the long-term. Sensor functionality was accessed by continuously monitoring glucose levels and performing acute glucose challenges at specified time points.

Sensors treated with porous Dex-releasing coatings showed diminished inflammation and enhanced vascularization of the tissue surrounding the implants in healthy rats. Functional sensors with Dex-releasing porous coatings showed enhanced sensor sensitivity over a 21-day period when compared to controls. Enhanced sensor sensitivity was accompanied with an increase in sensor signal lag and MARD score. These results indicated that Dex-loaded porous coatings were able to elicit a favorable tissue response, and that such tissue microenvironment could be conducive towards extending the performance window of glucose sensors in vivo.

The diabetic pilot animal study showed differences in wound healing patters between healthy and diabetic subjects. Diabetic rats showed lower levels of inflammation and vascularization of the tissue surrounding implants when compared to their healthy counterparts. Also, functional sensors treated with Dex-releasing porous coatings did not show enhanced sensor sensitivity over a 21-day period. Moreover, increased in sensor signal lag and MARD scores were present in porous coated sensors regardless of Dex-loading when compared to bare implants. These results suggest that the altered wound healing patterns presented in diabetic tissues may lead to premature sensor failure when compared to sensors implanted in healthy rats.

A Pharmacology-Based Enrichment Program for Undergraduates Promotes Interest in Science.

There is a strong need to increase the number of undergraduate students who pursue careers in science to provide the "fuel" that will power a science and technology-driven U.S. economy. Prior research suggests that both evidence-based teaching methods and early undergraduate research experiences may help to increase retention rates in the sciences. In this study, we examined the effect of a program that included 1) a Summer enrichment 2-wk minicourse and 2) an authentic Fall research course, both of which were designed specifically to support students' science motivation. Undergraduates who participated in the pharmacology-based enrichment program significantly improved their knowledge of basic biology and chemistry concepts; reported high levels of science motivation; and were likely to major in a biological, chemical, or biomedical field. Additionally, program participants who decided to major in biology or chemistry were significantly more likely to choose a pharmacology concentration than those majoring in biology or chemistry who did not participate in the enrichment program. Thus, by supporting students' science motivation, we can increase the number of students who are interested in science and science careers.