Yes / Background: Prescribing drugs for psychosis (antipsychotics) is challenging due to high rates of poor treatment outcomes, which are in part explained by an individual’s genetics. Pharmacogenomic (PGx) testing can help clinicians tailor the choice or dose of psychosis drugs to an individual’s genetics, particularly psychosis drugs with known variable response due to CYP2D6 gene variants (‘CYP2D6-PGx antipsychotics’). Aims: This study aims to investigate differences between demographic groups prescribed ‘CYP2D6-PGx antipsychotics’ and estimate the proportion of patients eligible for PGx testing based on current pharmacogenomics guidance. Methods: A cross-sectional study took place extracting data from 243 patients’ medical records to explore psychosis drug prescribing, including drug transitions. Demographic data such as age, sex, ethnicity, and clinical sub-team were collected and summarised. Descriptive statistics explored the proportion of ‘CYP2D6-PGx antipsychotic’ prescribing and the nature of transitions. We used logistic regression analysis to investigate associations between demographic variables and prescription of ‘CYP2D6-PGx antipsychotic’ versus ‘non-CYP2D6-PGx antipsychotic’. Results: Two-thirds (164) of patients had been prescribed a ‘CYP2D6-PGx antipsychotic’ (aripiprazole, risperidone, haloperidol or zuclopenthixol). Over a fifth (23%) of patients would have met the suggested criteria for PGx testing, following two psychosis drug trials. There were no statistically significant differences between age, sex, or ethnicity in the likelihood of being prescribed a ‘CYP2D6-PGx antipsychotic’. Conclusions: This study demonstrated high rates of prescribing ‘CYP2D6-PGx-antipsychotics’ in an EIP cohort, providing / This research was supported by the National Institute for Health and Care Research (NIHR) Yorkshire and Humber Patient Safety Translational Research Centre (NIHR Yorkshire and Humber PSTRC). This research has been funded through a scholarship from the Bradford District Care NHS Foundation Trust in partnership with the University of Bradford.

Millions of people in the US currently suffer from chronic pain but available therapeutics do not provide effective chronic pain treatment. Opiate therapy is still the gold standard for chronic pain management with detrimental side effects, such as tolerance, addiction, constipation, and respiratory depression that limit their therapeutic potential. Opiates exert their positive and negative effects by activating the μ opioid receptor (MOR). Conversely, the κ opioid receptor (KOR) has been shown to modulate the tolerance and addiction produced by MOR agonists and is also involved in mood modulation (anxiety and depression). Therefore, blocking KOR activation results in positive effects against opiate side effects and stress-related depression. Dynorphin A (Dyn A) is the endogenous opioid peptide for the KOR. Structure-activity relationship (SAR) studies were carried out to develop a KOR selective antagonist based on the Dyn A structure. A minimum Dyn A pharmacophore with improved stability, no cell toxicity, and antagonist activity was discovered. Peptidomimetic enkephalin analogues previously developed in our group as MOR and δ opioid receptor (DOR) agonists have shown multifunctional activity, with MOR/DOR agonist and KOR antagonist activities. To our knowledge, this finding is first of its class for the opioid receptors. Novel design and synthesis of KOR selective ligands based on our multifunctional enkephalin analogues was done. Successful peptide synthesis resulted in analogues with high stability in rat plasma and no cell toxicity.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Psychiatry Melbourne, 2005 / Sexual dysfunction is a common side effect of treatment with antidepressants, particularly those with a serotonergic action. The problem has significant implications for a patient’s quality of life and their compliance with medication. Given the often longterm nature of depressive disorders and their treatment this side effect poses a potential management challenge and may have serious prognostic implications. There are currently few evidence-based treatment strategies for the management of antidepressant induced sexual dysfunction. This study was conducted to evaluate the usefulness of granisetron, a serotonin type-3 receptor antagonist, in the treatment of women experiencing sexual dysfunction due to serotonergic antidepressants. Twelve women with antidepressant induced sexual dysfunction were assigned to receive either granisetron (N=5) or placebo (N=7) in a 14-day randomised, double blind, placebo controlled drug trial. Two subjects in the granisetron group did not complete the study. Each subject’s sexual functioning was assessed at baseline, day 7 and day 14 using both the Arizona Sexual Experience Scale and the Feiger Sexual Function and Satisfaction Questionnaire. No statistical differences were measured either at baseline or at endpoint between the granisetron and placebo groups. The study did not produce evidence supporting the usefulness of granisetron as an adjunctive medication in women with antidepressant induced sexual dysfunction. Furthermore, this finding does not suggest a primary role for the serotonin type-3 receptor in the pathogenesis of this side effect.

Immunological stressors, in the form of clinical and sub-clinical disease are currently controlled using both prophylactic antibiotics in-feed, and therapeutic antibiotic treatment. Respiratory disease, primarily Actinobacillus pleuropneumoniae (App) infection, is recognised as a major factor causing reduced productivity in pigs. This thesis reports investigations into the use of novel immunomodulators in particular Interleukin 4 (IL-4) and Interleukin 1 receptor antagonist (IL-1ra) as alternatives to antibiotics to treat App infection. Immunological and molecular biological assays were used to investigate and accumulate data. An in vitro study undertaken to find potential anti-inflammatory substances, revealed that Interleukin 8 (IL-8) mRNA production stimulated by PMA or LPS in whole pigs' blood was suppressed by IL-4. IL-1ra also suppressed stimulated IL-8 mRNA production by heat killed App bacteria (KB) in vitro. An acute LPS challenge in pigs in vivo however, showed no variation in illness or weight loss between pigs treated prophylactically with anti-inflammatory substance (IL-4 and IL-1ra) and saline treated pigs. The use of plasmids as a delivery system for anti-inflammatory substance did not show promise since it did not enhance growth or prolong the expression of the substances in the pigs. However, in the chronic App challenge model IL-4 and IL-1ra administered prophylactically in vivo showed an ability to improve growth. The therapeutic administration of IL-4 and IL-1ra to App challenged pigs showed no difference in pigs' growth, regardless of the treatment or control administered. To conclude, IL-4 and IL-1ra showed promise when administered prophylactically and improved growth and abrogated disease under conditions of App challenge. However when IL-4 and IL-1ra where administered therapeutically they did not perform as well. Moreover these compounds have potential as a commercial application to reduce the growth reduction caused by disease such as App.

Interleukin-1 (IL-1) is a prototypic multifunctional cytokine. IL-1 family include interleukin-1 a (IL-1 a), interleukin-1b (IL-1 b) and interleukin-1 receptor antagonist (IL-1 Ra). IL-1 b is the archetypeal pleiotropic cytokine which have been produced by many cells and exerting its biological effects on almost all cell types. IL-1 b is the most potent of known agents that are gastric cytoprotective, antiulcer, antisecretory and an inhibitor of gastric emptying. IL-1 Ra competes with IL-1 b for cell surface receptor occupancy. Host genetic factors that affect interleukin-1 (IL-1) have been reported to influence the susceptibility of Caucasians to gastric cancer. Whether Asians have the same genetic susceptibility remains unclear. In this study, the genetic associations of IL-1B and IL-1RN polymorphisms with gastric cancer and duodenal ulcer in Taiwan were evaluated. Genomic DNA from 140 unrelated Taiwanese patients with gastric adenocarcinoma, 94 with duodenal ulcer and 165 ethically matched healthy controls was typed for polymorphisms at positions ¡V31, -511, and +3954 in the IL-1B gene, and the variable number of tandem repeats polymorphisms in intron 2 of the IL-1RN gene. The allele frequencies of IL-1RN 2R in gastric cancer cases were much higher than those in healthy controls (9% vs. 3%, p = 0.781). The allele frequencies of IL-1B ¡V31, IL-1B ¡V511 and IL-1B +3954 did not differ. An increased risk of the development of intestinal type gastric carcinoma was found in IL-1RN 2R carriers with an odds ratio (OR) of 4.06 (95% confidence interval [CI]: 1.68 ¡V 9.79, p-value=0.085). And another increased risk of the development of diffuse type gastric carcinoma was found in IL-1RN 2R carriers with an odds ratio (OR) of 3.15 (95% confidence interval [CI]: 1.16 ¡V 8.56, p-value=0.061). A significant association was found in IL-1RN 2R/4R genotype and the risk of the development of duodenal ulcer, with an odds ratio (OR) of 2.57 (95% CI: 1.03 ¡V 6.38, p = 0.292). No significant relationship was noted in duodenal ulcer patients with IL-1B genotype examed in this study. Additionally, a synergistic interaction between blood type A and IL-1 RN 2R carriers existed in gastric cancer patients (OR= 4.51; 95% CI: 1.20 ¡V 16.88, p-value=0.516). The synergistic interaction was even stronger between blood type O and IL-1 RN 2R carriers of duodenal ulcer patients (OR= 10.3; 95% CI: 2.10 ¡V 50.61, p-value=0.160). In conclusion, the genetic polymorphisms of IL-1RN 2R and blood type A are associated with the development of gastric cancer. The genetic polymorphisms of IL-1RN 2R and blood type O are associated with the development of duodenal ulcer.

The endocannabinoid system is a novel pharmacological target in the treatment of metabolic syndrome. Antagonism of the endocannabinoid-1 receptor (CB1R) leads to a transient reduction in food intake, a sustained decrease in body weight and an improvement in metabolic parameters in animal models of obesity. Skeletal muscle is the primary tissue involved in glucose uptake in response to insulin, and insulin sensitivity of skeletal muscle is vital to the maintenance of whole-body euglycemia. Little is known regarding the effects of CB1R antagonism on skeletal muscle glucose transport activity. The purpose of this dissertation was to test the hypothesis that antagonism of the CB1R activates signaling molecules of the insulin signaling pathway to increase glucose transport activity in normal and insulin-resistant skeletal muscle, thereby improving whole-body glucose tolerance. CB1R antagonism with SR141716 directly enhanced basal and insulin-stimulated glucose transport activity in skeletal muscle from lean and obese Zucker while activation of the CB1R with ACEA, decreased glucose transport activity. Key proteins associated with regulation of glucose transport activity were not altered by either CB1R agonism (ACEA) or antagonism (SR141716). Chronic CB1R antagonist treatment (10 mg/kg SR141716 i.p. / 14 days) also enhanced insulin-stimulated glucose transport activity in skeletal muscle of both lean and obese animals, again with no alteration in relevant signaling factors. Plasma free fatty acids (FFAs) were decreased in chronically-treated lean and obese animals and whole-body insulin sensitivity was improved in obese Zucker rats. The enhanced insulin sensitivity seen in chronically-treated obese animals was associated with a dramatic reduction in insulin secretion following a glucose challenge. Acute CB1R antagonism in obese animals also elicited a reduction in insulin secretion following a glucose challenge; however, with no improvement of whole-body insulin sensitivity. Acute CB1R antagonist treatment did not alter skeletal muscle glucose transport activity or circulating FFAs for any animals. These data suggest that although CB1R antagonism directly enhances basal and insulin stimulated glucose transport in skeletal muscle of lean and obese rats, direct action on the skeletal muscle is not responsible for the improvement in insulin-stimulated glucose transport activity and whole-body insulin sensitivity seen in chronically-treated obese animals.

Immunological stressors, in the form of clinical and sub-clinical disease are currently controlled using both prophylactic antibiotics in-feed, and therapeutic antibiotic treatment. Respiratory disease, primarily Actinobacillus pleuropneumoniae (App) infection, is recognised as a major factor causing reduced productivity in pigs. This thesis reports investigations into the use of novel immunomodulators in particular Interleukin 4 (IL-4) and Interleukin 1 receptor antagonist (IL-1ra) as alternatives to antibiotics to treat App infection. Immunological and molecular biological assays were used to investigate and accumulate data. An in vitro study undertaken to find potential anti-inflammatory substances, revealed that Interleukin 8 (IL-8) mRNA production stimulated by PMA or LPS in whole pigs' blood was suppressed by IL-4. IL-1ra also suppressed stimulated IL-8 mRNA production by heat killed App bacteria (KB) in vitro. An acute LPS challenge in pigs in vivo however, showed no variation in illness or weight loss between pigs treated prophylactically with anti-inflammatory substance (IL-4 and IL-1ra) and saline treated pigs. The use of plasmids as a delivery system for anti-inflammatory substance did not show promise since it did not enhance growth or prolong the expression of the substances in the pigs. However, in the chronic App challenge model IL-4 and IL-1ra administered prophylactically in vivo showed an ability to improve growth. The therapeutic administration of IL-4 and IL-1ra to App challenged pigs showed no difference in pigs' growth, regardless of the treatment or control administered. To conclude, IL-4 and IL-1ra showed promise when administered prophylactically and improved growth and abrogated disease under conditions of App challenge. However when IL-4 and IL-1ra where administered therapeutically they did not perform as well. Moreover these compounds have potential as a commercial application to reduce the growth reduction caused by disease such as App.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22042号 / 医博第4527号 / 新制||医||1039(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 佐藤 俊哉, 教授 湊谷 謙司, 教授 稲垣 暢也 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Montelukast (ML) is primarily an antagonist of type 1 cysteinyl leukotriene receptors (CysLT1R), an activity which underpins its therapeutic efficacy in bronchial asthma. However, ML has also been reported to be useful in the treatment of acute and chronic inflammatory disorders of both infective and non-infective origin in which CysLTs are unlikely to be the predominant mediators of harmful inflammatory responses. These include conditions such as chronic obstructive pulmonary disease and cystic fibrosis in which the neutrophil is believed to be the primary offender, suggesting that ML may possess neutrophil-targeted, CysLT1R-independent mechanisms of anti-inflammatory activity. Accordingly, the laboratory research presented in this thesis was designed with the primary objectives of characterizing possible CysLT1R-dependent and – independent neutrophil-targeted anti-inflammatory activities of ML in vitro, and consisted of 3 phases. These were investigation of: i) the effects of the CysLTs, LTC4 and LTD4 (in the absence and presence of ML) on mobilization of intracellular Ca2+ stores, generation of reactive oxygen species (ROS) and release of primary and secondary granule proteinases; ii) the effects of ML on a series of pro-inflammatory activities of neutrophils following activation of the cells with the chemoattractants FMLP and platelet-activating factor (PAF); and iii) the interactive, anti-inflammatory effects on neutrophils of ML in combination with the long-acting beta-2 agonist, formoterol. In addition to the aforementioned activities, measurement of the production and expression of CR3, as well as generation of inositol triphosphate (IP3), cyclic AMP, and activities of the enzymes cAMP- and cGMP-phosphodiesterases (PDEs) in isolated neutrophil cytosol and membrane fractions, were also included. The following assays were used: i) chemiluminescence procedures for the detection of ROS; ii) a colourimetric procedure for the detection of elastase; iii) ELISA procedures for the detection of the matrix metalloproteinases (MMPs) 8- and -9, LTB4, and cyclic AMP; iv) fura-2-based spectrofluorimetry and a radiometric procedure for monitoring cytosolic Ca2+ fluxes; v) flow cytometry for CR3; and vi) radioassays for IP3 and activity of cAMP- and cGMP-PDEs. Exposure of neutrophils to LTD4, but not LTC4, activated a very modest and transient increase in cytosolic Ca2+, but failed to initiate the generation of ROS or release of elastase or MMP-8. However, brief pre-treatment with either LTC4 or LTD4 sensitized the cells for increased production of ROS and release of granule proteinases following activation with FMLP, which was partially attenuated by inclusion of ML. In the second part of the study, pre-treatment of neutrophils with ML, at therapeutically relevant concentrations, resulted in dose-related inhibition of the FMLP- or PAF-activated generation of ROS and LTB4, as well as the release of elastase, with the former being unaffected by an inhibitor of 5-lipoxygenase (MK886), compatible with a CysLT1R-independent mechanism of anti-inflammatory activity. From a mechanistic perspective, these interactions of ML with neutrophils were associated with accelerated clearance of Ca2+ from the cytosol of the cells which could not be attributed to inhibition of production of IP3, but was, however, associated with increased levels of cAMP, apparently as a consequence of non- specific inhibition of cyclic nucleotide phosphodiesterases. In the third part of the study, combining ML with formoterol caused (in most cases) additive inhibitory effects on the generation of ROS and LTB4, release of granule proteinases, as well as expression of CR3, which again were associated with elevations in cAMP and interference with Ca2+ mobilization. In conclusion, ML appears to attenuate neutrophil activation by CysLT1R-dependent and –independent mechanisms. In the case of the former by interfering with the modest sensitizing (priming) interactions of LTC4 and LTD4 with neutrophils, and in the latter by inhibition of PDEs, leading a to sustained elevation in cAMP, resulting in rapid clearance of Ca2+ from the cytosol and decreased uptake of the cation from the extracellular milieu. / Thesis (PhD)--University of Pretoria, 2011. / Immunology / Unrestricted

Several trials have reported rapid antidepressant response from the anesthetic drug ketamine although the mechanism behind this effect is not fully understood. Research has focused mainly on ketamine’s action in the brain, including its effects on chemical balance, connections between brain cells and networks, and cognition. Trials with psychedelic drugs have had similar antidepressant results as ketamine, and the quality of the subjective psychedelic experience seems to mediate antidepressant action. Ketamine causes similar alterations of consciousness, which have been viewed as side effects. This thesis examines whether ketamine works in a similar way as psychedelics, where the ketamine-induced dissociative-like experience has a relationship to antidepressant response. Leading theories of depression and ketamine’s action in the brain are presented, and eight studies examining the relationship between ketamine-induced subjective experience and antidepressant response are reviewed. Three included studies found a relationship between psychedelic- and dissociative-like symptoms and reduction in depression, while five did not. The supposed relationship between psychedelic- and dissociative-like symptoms and antidepressant action has not been adequately explored and needs further examination in clinical trials.