Psychotropic drugs

19.1 Depression and Antidepressants 19.1.1 Depression 19.1.2 Neurochemistry of Depression and the Monoamine Theory 19.1.3 Antidepressant Indications and Drug Classes 19.1.4 General Considerations with the use of Antidepressants 19.1.5 Tricyclic Antidepressants 19.1.6 Monoamine Oxidase Inhibitors 19.1.7 Selective Serotonin Reuptake Inhibitors 19.1.8 Combined Serotonin and Noradrenaline Reuptake Inhibitors 19.1.9 Long Term Adaptive Changes with Antidepressants 19.2 Psychosis, Schizophrenia, and Antipsychotics 19.2.1 Psychosis and Schizophrenia 19.2.2 Neurochemistry of Psychosis and the Dopamine Theory 19.2.3 Antipsychotic Drug Indications and Drug Classes 19.2.4 Antipsychotic Mechanisms of Action 19.2.5 Typical Antipsychotics (First Generation) 19.2.6 Atypical Antipsychotics (Second Generation) 19.3 Anxiety and Anxiolytics 19.3.1 Fear, Anxiety and Anxiety Disorders 19.3.2 Neurochemistry of Anxiety 19.3.3 Anxiolytic Drug Indications and Drug Classes 19.3.4 Benzodiazepines 19.3.5 Antidepressants 19.3.6 Buspirone

Influence of cytochrome P-450 inhibitors on the inhalative uptake of methyl chloride and methylene chloride in male B6C3F1 mice

Dichloromethane (DCM) is thought to be metabolized in vivo by two independent pathways: a glutathione (GSH) dependent pathway that yields CO2 and a cytochrome P-450 mediated one that yields both CO and CO2 (Gargas et al 1986). With a physiologically based pharmacokinetic (PB-PK) model, Andersen et al (1987) calculate the quantitative parameters for both metabolic pathways. Using the kinetic parameters thus obtained and the results of two carcinogenicity studies with rodents (Serota et al 1986; NTP 1985), the authors then estimate the tumour risk for humans.

Applying an equity lens to tobacco-control policies and their uptake in six western-european countries

We identified policies that may be effective in reducing smoking among socioeconomically disadvantaged groups, and examined trends in their level of application between 1985 and 2000 in six western-European countries (Sweden, Finland, the United Kingdom, the Netherlands, Germany, and Spain). We located studies from literature searches in major databases, and acquired policy data from international data banks and questionnaires distributed to tobacco policy organisations/researchers. Advertising bans, smoking bans in workplaces, removing barriers to smoking cessation therapies, and increasing the cost of cigarettes have the potential to reduce socioeconomic inequalities in smoking. Between 1985 and 2000, tobacco control policies in most countries have become more targeted to decrease the smoking behaviour of low-socioeconomic groups. Despite this, many national tobacco-control strategies in western-European countries still fall short of a comprehensive policy approach to addressing smoking inequalities.

Water uptake of aerosols with a focus on seeded aerosols and instrumentation techniques

This thesis focuses on the volatile and hygroscopic properties of mixed aerosol species. In particular, the influence organic species of varying solubility have upon seed aerosols. Aerosol studies were conducted at the Paul Scherrer Institut Laboratory for Atmospheric Chemistry (PSI-LAC, Villigen, Switzerland) and at the Queensland University of Technology International Laboratory for Air Quality and Health (QUT-ILAQH, Brisbane, Australia). The primary measurement tool employed in this program was the Volatilisation and Hygroscopicity Tandem Differential Mobility Analyser (VHTDMA - Johnson et al. 2004). This system was initially developed at QUT within the ILAQH and was completely re-developed as part of this project (see Section 1.4 for a description of this process). The new VHTDMA was deployed to the PSI-LAC where an analysis of the volatile and hygroscopic properties of ammonium sulphate seeds coated with organic species formed from the photo-oxidation of á-pinene was conducted. This investigation was driven by a desire to understand the influence of atmospherically prevalent organics upon water uptake by material with cloud forming capabilities. Of particular note from this campaign were observed influences of partially soluble organic coatings upon inorganic ammonium sulphate seeds above and below their deliquescence relative humidity (DRH). Above the DRH of the seed increasing the volume fraction of the organic component was shown to reduce the water uptake of the mixed particle. Below the DRH the organic was shown to activate the water uptake of the seed. This was the first time this effect had been observed for á-pinene derived SOA. In contrast with the simulated aerosols generated at the PSI-LAC a case study of the volatile and hygroscopic properties of diesel emissions was undertaken. During this stage of the project ternary nucleation was shown, for the first time, to be one of the processes involved in formation of diesel particulate matter. Furthermore, these particles were shown to be coated with a volatile hydrophobic material which prevented the water uptake of the highly hygroscopic material below. This result was a first and indicated that previous studies into the hygroscopicity of diesel emission had erroneously reported the particles to be hydrophobic. Both of these results contradict the previously upheld Zdanovksii-Stokes-Robinson (ZSR) additive rule for water uptake by mixed species. This is an important contribution as it adds to the weight of evidence that limits the validity of this rule.

Uptake of an OHS code of practice by Australian construction firms

The Australian construction industry is moving towards the implementation of a voluntary code of practice (VCP) for occupational health and safety (OHS). The evidence suggests that highly-visible clients and project management firms, in addition to their subcontractors, will embrace such a code, while smaller firms not operating in high-profile contracting regimes may prove reticent. This paper incorporates qualitative data from a research project commissioned by Engineers Australia and supported by the Australian Contractors’ Association, Property Council of Australia, Royal Australian Institute of Architects, Association of Consulting Engineers Australia, Australian Procurement and Construction Council, Master Builders Australia and the Australian CRC for Construction Innovation. The paper aims to understand the factors that facilitate or prevent the uptake of the proposed VCP by smaller firms, together with pathways to adoption.

Uptake of an OHS code of practice by construction firms : barriers and enablers in an Australian industry

The Australian construction industry, reflecting a global trend, is moving towards the implementation of a voluntary code of practice (hereafter VCP) for occupational health and safety. The evidence suggests that highlyvisible clients and project management firms, in addition to their subcontractors, look set to embrace such a code. However, smaller firms not operating in high-profile contracting regimes may prove reticent to adopt a VCP. This paper incorporates qualitative data from a high-profile research project commissioned by Engineers Australia and supported by the Australian Contractors’ Association, Property Council of Australia, Royal Australian Institute of Architects, Association of Consulting Engineers Australia, Australian Procurement and Construction Council, Master Builders Australia and the Australian CRC for Construction Innovation. The paper aims to understand the factors that facilitate or prevent the uptake of the VCP by smaller firms, together with pathways to the adoption of a VCP by industry.

A model for the uptake of E-business by building small and medium enterprises

The adoption of e-business by Small and Medium Enterprises (SMEs) in construction lags from other service and product businesses within the building sector. This paper develops a model to facilitate the uptake of electronic business, especially in relation to SMEs within the Australian construction sector. Ebusiness is defined here as “the undertaking of business-related transactions, communications and information exchanges utilising electronic medium and environment”, the elicited model highlights significant changes needed including skills development, social, economic and cultural issues. The model highlights barriers for SMEs to migrate towards e-transactions, e-bidding, e-tendering and ecollaboration and provides learning and skills development components. The model is derived from case study fieldwork and is to inform diffusion and awareness models for best practice. Empirical techniques included ‘focus group’ interviews and one to one ‘interviews’. Data was transcribed and analysed using cluster analyses. Preliminary results reveal that current models for e-business adoption are not effective within the construction context as they have emerged from other service and product industries - such as retail or tourism. These generic models have largely ignored the nature of the construction industry, and some modifications appears to be required. This paper proposes an alternative adoption model which is more sensitive to the nature of the industry – particularly for e-business uptake in building SME’s.

Electronic Tendering : Guidelines and Recommendations for Successful Implementation and Uptake

This publication, summarising outcomes of an investigation into eTendering as a part of a CRC Construction Innovation research project, presents guidelines and recommendations to be considered when implementing eTendering systems, procedures and policies.

The PG500 series : novel heparan sulfate mimetics as potent angiogenesis and heparanase inhibitors for cancer therapy

Heparan sulfate mimetics, which we have called the PG500 series, have been developed to target the inhibition of both angiogenesis and heparanase activity. This series extends the technology underpinning PI-88, a mixture of highly sulfated oligosaccharides which reached Phase III clinical development for hepatocellular carcinoma. Advances in the chemistry of the PG500 series provide numerous advantages over PI-88. These new compounds are fully sulfated, single entity oligosaccharides attached to a lipophilic moiety, which have been optimized for drug development. The rational design of these compounds has led to vast improvements in potency compared to PI-88, based on in vitro angiogenesis assays and in vivo tumor models. Based on these and other data, PG545 has been selected as the lead clinical candidate for oncology and is currently undergoing formal preclinical development as a novel treatment for advanced cancer.

Modulation of the SHBG signalling axis

Sex hormone-binding globulin (SHBG) is a homodimeric plasma glycoprotein that is the major sex steroid carrier-protein in the bloodstream and functions also as a key regulator of steroid bioavailability within target tissues, such as the prostate. Additionally, SHBG binds to prostatic cell membranes via the putative and unidentified SHBG receptor (RSHBG), activating a signal transduction pathway implicated in stimulating both proliferation and expression of prostate specific antigen (PSA) in prostate cell lines in vitro. A yeast-two hybrid assay suggested an interaction between SHBG and kallikrein-related protease (KLK) 4, which is a serine protease implicated in the progression of prostate cancer. The potential interaction between these two proteins was investigated in this PhD thesis to determine whether SHBG is a proteolytic substrate of KLK4 and other members of the KLK family including KLK3/PSA, KLK7 and KLK14. Furthermore, the effects from SHBG proteolytic degradation on SHBG-regulated steroid bioavailability and the activation of the putative RSHBG signal transduction pathway were examined in the LNCaP prostate cancer cell line. SHBG was found to be a proteolytic substrate of the trypsin-like KLK4 and KLK14 in vitro, yielding several proteolysis fragments. Both chymotrypsin-like PSA and KLK7 displayed insignificant proteolytic activity against SHBG. The kinetic parameters of SHBG proteolysis by KLK4 and KLK14 demonstrate a strong enzyme-substrate binding capacity, possessing a Km of 1.2 ± 0.7 µM and 2.1 ± 0.6 µM respectively. The catalytic efficiencies (kcat/Km) of KLK4 and KLK14 proteolysis of SHBG were 1.6 x 104 M-1s-1 and 3.8 x 104 M-1s-1 respectively, which were comparable to parameters previously reported for peptide substrates. N-terminal sequencing of the fragments revealed cleavage near the junction of the N- and C-terminal laminin globulin-like (G-like) domains of SHBG, resulting in the division of the two globulins and ultimately the full degradation of these fragments by KLK4 and KLK14 over time. Proteolytic fragments that may retain steroid binding were rapidly degraded by both proteases, while fragments containing residues beyond the steroid binding pocket were less degraded over the same period of time. Degradation of SHBG was inhibited by the divalent metal cations calcium and zinc for KLK4, and calcium, zinc and magnesium for KLK14. The human secreted serine protease inhibitors (serpins), α1-antitrypsin and α2-antiplasmin, inhibited KLK4 and KLK14 proteolysis of SHBG; α1-antichymotrypsin inhibited KLK4 but not KLK14 activity. The inhibition by these serpins was comparable and in some cases more effective than general trypsin protease inhibitors such as aprotinin and phenylmethanesulfonyl fluoride (PMSF). The binding of 5α-dihydrotestosterone (DHT) to SHBG modulated interactions with KLK4 and KLK14. Steroid-free SHBG was more readily digested by both enzymes than DHT-bound SHBG. Moreover, a binding interaction exists between SHBG and pro-KLK4 and pro-KLK14, with DHT strengthening the binding to pro-KLK4 only. The inhibition of androgen uptake by cultured prostate cancer cells, mediated by SHBG steroid-binding, was examined to assess whether SHBG proteolysis by KLK4 and KLK14 modulated this process. Proteolytic digestion eliminated the ability of SHBG to inhibit the uptake of DHT from conditioned media into LNCaP cells. Therefore, the proteolysis of SHBG by KLK4 and KLK14 increased steroid bioavailability in vitro, leading to an increased uptake of androgens by prostate cancer cells. Interestingly, different transcriptional responses of PSA and KLK2, which are androgen-regulated genes, to DHT-bounsd SHBG treatment were observed between low and high passage number LNCaP cells (lpLNCaP and hpLNCaP respectively). HpLNCaP cells treated with DHT-bound SHBG demonstrated a significant synergistic upregulation of PSA and KLK2 above DHT or SHBG treatment alone, which is similar to previously reported downstream responses from RSHBG-mediated signaling activation. As this result was not seen in lpLNCaP cells, only hpLNCaP cells were further investigated to examine the modulation of potential RSHBG activity by KLK4 and KLK14 proteolysis of SHBG. Contrary to reported results, no increase in intracellular cAMP was observed in hpLNCaP cells when treated with SHBG in the presence and absence of either DHT or estradiol. As a result, the modulation of RSHBG-mediated signaling activation could not be determined. Finally, the identification of the RSHBG from both breast (MCF-7) and prostate cancer (LNCaP) cell lines was attempted. Fluorescently labeled peptides corresponding to the putative receptor binding domain (RBD) of SHBG were shown to be internalized by MCF-7 cells. Crosslinking of the RBD peptide to the cell surfaces of both MCF-7 and LNCaP cells, demonstrated the interaction of the peptide with several targets. These targets were then captured using RBD peptides synthesized onto a hydrophilic scaffold and analysed by mass spectrometry. The samples captured by the RBD peptide returned statistically significantly matches for cytokeratin 8, 18 and 19 as well as microtubule-actin crosslinking factor 1, which may indicate a novel interaction between SHBG and these proteins, but ultimately failed to detect a membrane receptor potentially responsible for the putative RSHBG-mediated signaling. This PhD project has reported the proteolytic processing of SHBG by two members of the kallikrein family, KLK4 and KLK14. The effect of SHBG proteolysis by KLK4 and KLK14 on RSHBG-mediated signaling activation was unable to be determined as the reported signal transduction pathway was not activated after treatment with SHBG, in combination with either DHT or estradiol. However, the digestion of SHBG by these two proteases positively regulated androgen bioavailability to prostate cancer cells in vitro. The increased uptake of androgens is deleterious in prostate cancer due to the promotion of proliferation, metastasis, invasion and the inhibition of apoptosis. The increased bioavailability of androgens, from SHBG proteolysis by KLK4 and KLK14, may therefore promote both carcinogenesis and progression of prostate cancer. Finally, this information may contribute to the development of therapeutic treatment strategies for prostate cancer by inhibiting the proteolysis of SHBG, by KLK4 and KLK14, to prevent the increased uptake of androgens by hormone-dependent cancerous tissues.

Electromyographic activity in lower limb muscles is temporally associated with the slow phase of oxygen uptake during cycling

Although the "slow" phase of pulmonary oxygen uptake (Vo2) appears to represent energetic processes in contracting muscle, electromyographic evidence tends not to support this. The present study assessed normalized integrated electromyographic (NIEMG) activity in eight muscles that act about the hip, knee and ankle during 8 min of moderate (ventilatory threshold) cycling in six male cyclists. (Vo2) was measured breath by breath during four repeated trials at each of the two intensities. Moderate and very heavy exercise followed a 4-min period of light exercise (50 W). During moderate exercise the slow (Vo2) phase was absent and NIEMG in all muscles did not increase after the first minute of exercise. During very heavy exercise, the slow phase emerged (time delay=58 ± 16 s) and increased progressively (time constant=120 ± 35 s) to an amplitude (0.83 ± 0.16 L/min) that was approximately 21% of the total (Vo2) response. This slow (Vo2) phase coincided with a significant increase in NIEMG in most muscles, and differences in NIEMG activities between the two intensities revealed "slow" muscle activation profiles that differed between muscles in terms of the onset, amplitude and shape of these profiles. This supports the hypothesis that the slow (Vo2) phase is a function of these different slow muscle activation profiles.