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Item Open Access 3,4-Methylenedioxymethamphetamine (MDMA) induced hyperthermia - the role of pro-inflammatory cytokines(Bentham Open, 2011) Salem, A.; Gordon, J.; Hutchinson, M.; Irvine, R.Item Metadata only 5-HT₁B receptor modulation of the serotonin transporter in vivo: studies using KO mice(Pergamon-Elsevier Science Ltd, 2014) Montanez, S.; Munn, J.; Owens, W.; Horton, R.; Daws, L.Item Metadata only 5-hydroxymethyl-furfural and structurally related compounds block the ion conductance in human aquaporin-1 channels, and slow cancer cell migration and invasion(American Society for Pharmacology and Experimental Therapeutics, 2020) Chow, P.H.; Kourghi, M.; Pei, J.V.; Nourmohammadi, S.; Yool, A.J.Aquaporin-1 (AQP1) dual water and ion channels enhance migration and invasion when upregulated in leading edges of certain classes of cancer cells. Work here identifies structurally-related furan compounds as novel inhibitors of AQP1 ion channels. 5-Hydroxymethyl-2-furfural (5HMF), a component of natural medicinal honeys, and three structurally-related compounds nitrofuroic acid (5NFA), acetoxymethylfuraldehyde (5AMF), and methylnitrofuroate (M5NF), were analyzed for effects on water and ion channel activities of human AQP1 channels expressed in Xenopus oocytes. Two-electrode voltage clamp showed dose-dependent block of the AQP1 ion current by 5HMF (IC50 0.43 mM ), 5NFA (IC50 1.2 mM), 5AMF (IC50 ~3 mM), but no inhibition by M5NF. In silico docking predicted the active ligands interacted with glycine 165, located in loop D gating domains surrounding the intracellular vestibule of the tetrameric central pore. Water fluxes through separate intrasubunit pores were unaltered by the furan compounds (at concentrations up to 5mM). Effects on cell migration, invasion and cytoskeletal organization in vitro were tested in high AQP1-expressing cancer lines, HT29 and MDA, and low AQP1-expressing SW480. 5HMF, 5NFA and 5AMF selectively impaired cell motility in the AQP1-enriched cell lines. In contrast M5NF immobilized all the cancer lines by disrupting actin cytoskeleton. No reduction in cell viability was observed at doses that were effective in blocking motility. These results define furans as a new class of AQP1 ion channel inhibitors for basic research, and potential lead compounds for development of therapeutic agents targeting aquaporin channel activity. SIGNIFICANCE STATEMENT: 5-hydroxymethyl furfural (5HMT), a component of natural medicinal honeys, blocks the ion conductance but not the water flux through human Aquaporin-1 (AQP1) channels, and impairs AQP1-dependent cell migration and invasiveness in cancer cell lines. Analyses of 5HMT and structural analogs demonstrate a structure-activity relationship for furan compounds, supported by in silico docking modeling. This work identifies new low-cost pharmacological antagonists for AQP1 available to researchers internationally. Furans merit consideration as a new class of therapeutic agents for controlling cancer metastasis.Item Metadata only 5-hydroxytryptamine-induced contraction of the marmoset aorta is mediated by a 5-HT-1 like receptor.(BLACKWELL SCIENCE, 1998) Dyer, S.; de la Lande, I.; Frewin, D.; Head, R.1. 5-Hydroxytryptamine (5-HT) exerts both contractile and relaxant effects in the marmoset isolated aorta, actions that are unaffected by the 5-HT[sub 2] antagonist ketanserin. The aim of the present study was to define the receptors mediating the contractile activity of 5-HT in the marmoset aorta. 2. Contractile responses were elicited in aortic rings that were either: (i) precontracted submaximally with the thromboxane A[sub 2] agonist U44069 in order to amplify the responses; or (ii) exposed to N[sup ω]-nitro-L-arginine (100 µmol/L) plus LY53857 (0.1 µmol/L; a 5-HT[sub 2] receptor antagonist shown previously to inhibit relaxation). The effect of 5-HT on adenosine 3',5'-cyclic monophosphate (cAMP) formation was also investigated. 3. The effects of agonists and antagonists comprised: (i) agonist potencies in the order 5-carboxamidotryptamine > 5-HT > sumatriptan > 8-hydroxy-2-(di-n-propylamino)tetralin; (ii) inhibition of contractile action of 5-HT by the 5-HT[sub 1D] antagonist GR 127935; (iii) a contractile response to methysergide; (iv) a lack of effect of tropisetron, an antagonist of 5-HT[sub 3] and 5-HT[sub 4] receptors; and (v) inhibition of forskolin-stimulated cAMP formation by 5-HT (in the presence of LY 53857), indicative of negative coupling to adenylate cyclase. 4. The above effects fulfil the criteria for a 5-HT[sub 1]-like receptor. In view of the previous finding that this contractile response is insensitive to ketanserin, it is concluded that the contractile effects of 5-HT in the marmoset aorta are mediated exclusively by a 5-HT[sub 1]-like receptor.Item Metadata only A Bayesian approach for population pharmacokinetic modelling of sirolimus(Blackwell Publishing Ltd, 2006) Dansirikul, C.; Morris, R.; Tett, S.; Duffull, S.Aims
To explore a Bayesian approach for the pharmacokinetic analysis of sirolimus concentration data arising from therapeutic drug monitoring (poorly informative concentration-time point design), and to explore possible covariate relationships for sirolimus pharmacokinetics.Methods
Sirolimus concentration-time data were available as part of routine clinical care from 25 kidney transplant recipients. Most samples were taken at or near the trough time point at steady state. The data were analyzed using a fully conditional Bayesian approach with PKBUGS (v 1.1)/WinBUGS (v 1.3). Features of the data included noncompliance and missing concentration measurements below the limit of sensitivity of the assay. Informative priors were used.Results
A two-compartment model with proportional residual error provided the best fit to the data (consisting of 315 sirolimus concentration-time points). The typical value for the apparent clearance (CL/F ) was 12.5 l h(-1) at the median age of 44 years. Apparent CL was found to be inversely related to age with a posterior probability of a clinically significant effect of 0.734.Conclusions
A population pharmacokinetic model was developed for sirolimus using a novel approach. Bayesian modelling with informative priors allowed interpretation of a significant covariate relationship, even using poorly informative data.Item Metadata only A brief pictorial and historical introduction to guaiacum – from a putative cure for syphilis to an actual screening method for colorectal cancer(Wiley, 2017) Eppenberger, P.; Galassi, F.; Rühli, F.Abstract not availableItem Metadata only A case study of real-time monitoring of solid-state phase transformations in acoustically levitated particles using near infrared and Raman spectroscopy(Elsevier, 2013) Rehder, S.; Wu, J.X.; Laackmann, J.; Moritz, H.-U.; Rantanen, J.; Rades, T.; Leopold, C.S.The objective of this study was to monitor the amorphous-to-crystalline solid-state phase transformation kinetics of the model drug ibuprofen with spectroscopic methods during acoustic levitation. Chemical and physical information was obtained by real-time near infrared (NIRS) and Raman spectroscopy measurements. The recrystallisation kinetic parameters (overall recrystallisation rate constant β and the time needed to reach 50% of the equilibrated level t(50)), were determined using a multivariate curve resolution approach. The acoustic levitation device coupled with non-invasive spectroscopy enabled monitoring of the recrystallisation process of the difficult-to-handle (adhesive) amorphous sample. The application of multivariate curve resolution enabled isolation of the underlying pure spectra, which corresponded well with the reference spectra of amorphous and crystalline ibuprofen. The recrystallisation kinetic parameters were estimated from the recrystallisation profiles. While the empirical recrystallisation rate constant determined by NIR and Raman spectroscopy were comparable, the lag time for recrystallisation was significantly lower with Raman spectroscopy as compared to NIRS. This observation was explained by the high energy density of the Raman laser beam, which might have led to local heating effects of the sample and thus reduced the recrystallisation onset time. It was concluded that acoustic levitation with NIR and Raman spectroscopy combined with multivariate curve resolution allowed direct determination of the recrystallisation kinetics of amorphous drugs and thus is a promising technique for monitoring solid-state phase transformations of adhesive small-sized samples during the early phase of drug development.Item Metadata only A comparison of antagonist-precipitated withdrawal under anesthesia to standard inpatient withdrawal as a precursor to maintenance naltrexone treatment in heroin users: outcomes at 6 and 12 months(Elsevier Sci Ireland Ltd, 2002) McGregor, C.; Ali, R.; White, J.; Thomas, P.; Gowing, L.To compare two methods of heroin withdrawal, 51 heroin users were randomised to undergo a 1 day precipitated withdrawal procedure using naloxone under anaesthetic. About 50 participants were randomised to receive the current standard inpatient withdrawal treatment using clonidine plus symptomatic medication. Following withdrawal, both groups were offered 9 months of naltrexone treatment and supportive counselling. Outcome measures were: commencement of naltrexone, retention in treatment and heroin use at 6 and 12 months. Significantly more of the precipitated withdrawal group completed withdrawal, commenced naltrexone and stayed in treatment for the first 3 months. Overall, there was a significant reduction in both self-reported heroin use and morphine concentration in hair over the 12 month study period, with participants in the precipitated withdrawal group showing significantly lower morphine concentration at 6 months. Being younger and having a lower level of dependence were predictors of abstinence at 6 and 12 months. The advantage of precipitated withdrawal under anesthesia did not persist beyond 3 months with respect to retention in naltrexone treatment or beyond 6 months with respect to heroin use. Long-term follow-up is crucial in assessing the effects of treatment interventions for heroin dependence.Item Metadata only A comparison of folic acid and 5-methyltetrahydrofolate for prevention of DNA damage and cell death in human lymphocytes in vitro(Oxford Univ Press, 2003) Wang, X.; Fenech, M.Folic acid (FA), the most oxidized and stable form of folate, is commonly used as a dietary supplement and in culture media. FA must be reduced and methylated to become the metabolically active form found in blood and utilized by tissues, i.e. 5-methyltetrahydrofolate (5-MeTHF). 5-MeTHF is the methyl group donor required for the conversion of homocysteine to methionine catalyzed by vitamin B(12)-dependent methionine synthase. It is hypothesized that 5-MeTHF may be more effective than FA in reducing spontaneous DNA damage and improving cell proliferation because, unlike FA, it can donate a methyl group for methionine synthesis, which is required for cell division via polyamine production and for maintenance methylation of DNA after its conversion to S-adenosylmethionine. We aimed to determine whether FA and 5-MeTHF differed in their capacity to prevent genetic damage and cell proliferation of human lymphocytes in vitro. Lymphocytes from eight female volunteers (40-48 years) were cultured in RPMI 1640 medium containing 12-120 nM FA or 5-MeTHF for 9 days. Mitogenesis was stimulated with phytohemagglutinin and the medium changed on days 3 and 6. Cytokinesis was inhibited by adding cytochalasin B on day 8 and cells were harvested and transferred to microscope slides on day 9. Chromosome damage, cell death and cytostasis was measured using the cytokinesis-block micronucleus assay in its comprehensive mode. The results showed that the frequency of micronucleated binucleate cells was significantly lower at 120 nM FA compared with 120 nM 5-MeTHF (P < 0.05), however, at 12 nM concentration both forms of folate were associated with increased frequency of micronuclei and nuclear buds relative to 120 nM (P < 0.05). Apoptosis tended to be significantly higher in 5-MeTHF cultures compared with FA cultures, however, necrosis and nuclear division were similar between cultures. We conclude that 5-MeTHF is not more efficient than FA in preventing human lymphocyte genomic instability in this in vitro system. Further research is needed to clarify the role of choline and methionine concentration and the importance of the reduced folate carrier and the folate receptor in determining the relative bioavailability of 5-MeTHF and FA with regard to genome stability.Item Metadata only A comparison of folic acid deficiency-induced genomic instability in lymphocytes of breast cancer patients and normal non-cancer controls from a Chinese population in Yunnan(Oxford Univ Press, 2006) Wang, X.; Wu, X.; Liang, Z.; Huang, Y.; Fenech, M.; Xue, J.We hypothesized that the genomic response to folate deficiency might be different between breast cancer cases and healthy subjects. To test this hypothesis, we performed a comprehensive study on the genotoxic and cytotoxic effects of in vitro folic acid (FA) deficiency on primary human lymphocytes from 19 breast cancer patients and 20 age-matched healthy females from Yunnan, China using the cytokinesis-block micronucleus assay. Lymphocytes from the volunteers were cultured in RPMI1640 medium containing 30, 120 or 240 nM FA for 9 days. The results showed that 30 nM FA was associated with increased frequencies of micronucleated binucleated cell (MNed BNC), nucleoplasmic bridges (NPB), nuclear buds (BUD), apoptosis (APO) and necrosis (NEC) relative to 120 and 240 nM FA (P<0.001) in lymphocytes of case and control groups in vitro, however there were no significant differences between the 120 and 240 nM FA within each sampling group. The case group showed significantly higher frequencies of MNed BNC than control at 120 and 240 nM FA (P<0.05-0.001) but not at 30 nM FA (P=0.052). NEC was significantly higher in breast cancer group than control at all concentrations of FA (P<0.005). FA concentration explained 60, 39, 39, 52 and 71% of the variance of MNed BNC, NPB, BUD, APO and NEC, respectively compared with breast cancer status which only explained 6 and 7% of the variance of MNed BNC and NEC(Two way ANOVA, P<0.0001). Difference of difference analysis showed that breast cancer cases were not abnormally sensitive to the genome-damaging effect of folate deficiency. We concluded that (i) increased concentrations of FA abolished the genome-damaging effect of FA deficiency in lymphocytes of both breast cancer patients and controls to a similar extent and (ii) FA concentration is much more important than breast cancer status in determining genomic instability and cell death.Item Metadata only A comparison of patterns of spontaneous adverse drug reaction reporting with St. John's Wort and fluoxetine during the period 2000-2013(Wiley-Blackwell, 2015) Hoban, C.; Byard, R.; Musgrave, I.Herbal medicines are perceived to be safe by the general public and medical practitioners, despite abundant evidence from clinical trials and case reports that show herbal preparations can have significant adverse effects. The overall impact of adverse events to herbal medicines in Australia is currently unknown. Post marketing surveillance of medications through spontaneous adverse drug reaction (ADR) reports to the Therapeutic Goods Administration (TGA) is one way to estimate this risk. The patterns of spontaneously reported ADRs provide insight to herbal dangers, especially when compared with patterns of a mechanistically similar conventional drug. The study compared the pattern of spontaneously reported ADRs to St. John's Wort (Hypericum perforatum), a common herbal treatment for depression which contains selective serotonin reuptake inhibitors (SSRI), to fluoxetine, a commonly prescribed synthetic SSRI antidepressant. Spontaneous ADR reports sent to the TGA between 2000-2013 for St. John's Wort (n = 84) and fluoxetine (n = 447) were obtained and analysed. The demographic information, types of interaction, severity of the ADR, and the body systems affected (using the Anatomical Therapeutic Chemical classification system) were recorded for individual ADR cases. The majority of spontaneously reported ADRs for St. John's Wort and fluoxetine were concerning females aged 26-50 years (28.6%, 22.8%). The organ systems affected by ADRs to St John's Wort and fluoxetine have a similar profile, with the majority of cases affecting the central nervous system (45.2%, 61.7%). This result demonstrates that herbal preparations can result in ADRs similar to those of prescription medications.Item Metadata only A comparison of two formulations of intradermal capsaicin as models of neuropathic pain in healthy volunteers(Blackwell Publishing Ltd, 2009) Gustafsson, H.; Akesson, J.; Lau, C.; Williams, D.; Miller, L.; Yap, S.; Rolan, P.AIMS: To compare the dose–response relationships of two formulations [Tween- or hydroxypropyl-b cyclodextrin (HP-b-CD)-based] of intradermal capsaicin in healthy volunteers and to assess the effect of potential covariates of response. One, 10, 30 and 100 mg in 10ml were compared for the outcomes of flare, spontaneous pain, mechanical allodynia and hyperalgesia in eight healthy men and eight healthy women. RESULTS: The formulations produced comparable responses at doses 1, 10 and 30 mg, but in all parameters the response was less at 100 mg with the Tween formulation.Mean area for hyperalgesia was 9 cm2 [95% confidence interval (CI) 5, 13] higher with the HP-b-CD formulation. Flare area was 5 cm2 (95% CI 8, 13) greater with the HP-b-CD formulation. There was a significant difference between pain responses from the injection site on the upper forearm compared with the lower forearm on all four pain assessments. In contrast, significant differences were seen in pain response between nondominant and dominant arm for flare, allodynia and hyperalgesia but not for spontaneous pain. A significant difference in sex was seen only for hyperalgesia. The nominal 100-mg dose of the Tween formulation contained only 39% of label strength in the aqueous phase, which may explain the lower pharmacodynamic response. CONCLUSION: The formulations are comparable over the dose range 1–30 mg. The significantly lower pain response at the 100 mg dose in the Tween compared with the HP-b-CD formulation is likely to be due to limitations in solubility at the 100 mg level. Given the greater ease of formulation and the superior dose–response relationship, the HP-b-CD formulation is preferable for use in the model in future studies.Item Metadata only A Comprehensive Insight Towards Pharmaceutical Aspects of Graphene Nanosheets(Bentham Science Publishers Ltd., 2020) Emadi, F.; Emadi, A.; Gholami, A.Graphene Derivatives (GDs) have captured the interest and imagination of pharmaceutical scientists. This review exclusively provides pharmacokinetics and pharmacodynamics information with a particular focus on biopharmaceuticals. GDs can be used as multipurpose pharmaceutical delivery systems due to their ultra-high surface area, flexibility, and fast mobility of charge carriers. Improved effects, targeted delivery to tissues, controlled release profiles, visualization of biodistribution and clearance, and overcoming drug resistance are examples of the benefits of GDs. This review focuses on the application of GDs for the delivery of biopharmaceuticals. Also, the pharmacokinetic properties and the advantage of using GDs in pharmaceutics will be reviewed to achieve a comprehensive understanding about the GDs in pharmaceutical sciences.Item Metadata only A concept of welfare based on reward evaluating mechanisms in the brain: Anticipatory behaviour as an indicator for the state of reward systems(Elsevier Science BV, 2001) Spruijt, B.; Van den Bos, R.; Buisman-Pijlman, F.In this review we attempt to link the efficiency by which animals behave (economy of animal behaviour) to a neuronal substrate and subjective states to arrive at a definition of animal welfare which broadens the scope of its study. Welfare is defined as the balance between positive (reward, satisfaction) and negative (stress) experiences or affective states. The state of this balance may range from positive (good welfare) to negative (poor welfare). These affective states are momentary or transient states which occur against the background of and are integrated with the state of this balancing system. As will be argued the efficiency in behaviour requires that, for instance, satisfaction is like a moving target: reward provides the necessary feedback to guide behaviour; it is a not steady-state which can be maintained for long. This balancing system is reflected in the brain by the concerted action of opioid and mesolimbic dopaminergic systems. The state of this system reflects the coping capacity of the animal and is determined by previous events. In other words, this integrative approach of behavioural biology and neurobiology aims at understanding how the coping capacity of animals may be affected and measured. We argue that this balancing system underlies the economy of behaviour. Furthermore we argue that among other techniques anticipation in Pavlovian conditioning is an easy and useful tool to assess the state of this balancing system: for estimating the state of an animal in terms of welfare we focus on the conditions when an animal is facing a challenge.Item Metadata only A cost-effectiveness analysis of heroin detoxification methods in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD)(Pergamon-Elsevier Science Ltd, 2006) Shanahan, M.; Doran, C.; Digiusto, E.; Bell, J.; Lintzeris, N.; White, J.; Ali, R.; Saunders, J.; Mattick, R.; Gilmour, S.Abstract This economic evaluation was part of the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD) project. Data from four trials of heroin detoxification methods, involving 365 participants, were pooled to enable a comprehensive comparison of the cost-effectiveness of five inpatient and outpatient detoxification methods. This study took the perspective of the treatment provider in assessing resource use and costs. Two short-term outcome measures were used—achievement of an initial 7-day period of abstinence, and entry into ongoing post-detoxification treatment. The mean costs of the various detoxification methods ranged widely, from AUD $491 (buprenorphine-based outpatient); to AUD $605 for conventional outpatient; AUD $1404 for conventional inpatient; AUD $1990 for rapid detoxification under sedation; and to AUD $2689 for anaesthesia per episode. An incremental cost-effectiveness analysis was carried out using conventional outpatient detoxification as the base comparator. The buprenorphine-based outpatient detoxification method was found to be the most cost-effective method overall, and rapid opioid detoxification under sedation was the most cost-effective inpatient methodItem Metadata only A cross-country comparison of rivaroxaban spontaneous adverse event reports and concomitant medicine use with the potential to increase the risk of harm(Springer, 2014) McDonald, C.; Kalisch Ellett, L.; Barratt, J.; Caughey, G.Concerns with the safety profiles of the newer anticoagulants have been raised because of differences in treatment populations between pre-marketing studies (randomized controlled trials) and clinical practice. Little is known about the potential safety issues and the reporting in spontaneous adverse event databases associated with rivaroxaban.To analyse spontaneous adverse event reports associated with the oral anticoagulant rivaroxaban from Australia, Canada and the USA; and to examine concomitant medicine use that may increase the risk of adverse events.Spontaneous adverse event report databases from Australia, Canada and the USA were examined for all reports of adverse events associated with rivaroxaban and concomitant medicines from 1 August 2005 to 31 March 2013. Disproportionality analysis (the proportional reporting ratio [PRR] and reporting odds ratio [ROR]) was conducted for quantitative detection of signals, using the US database.There were 244 spontaneous adverse event reports associated with rivaroxaban from Australia, 536 from Canada and 1,638 from the USA. Reporting of haemorrhage (any type) was common, ranging from 30.7% for Australia to 37.5% for Canada. Gastrointestinal haemorrhage was the most commonly reported haemorrhage, accounting for 13.9% of Australian, 16.4% of Canadian and 11.1% of US adverse event reports. Positive signals were confirmed in the US data (haemorrhage [any type] PRR 11.93, χ (2) 4,414.78 and ROR 13.41, 95% confidence interval [CI] 12.13-14.81; gastrointestinal haemorrhage PRR 12.52, χ (2) 2,018.48 and ROR 13.15, 95% CI 11.36-15.21). Reporting of concomitant use of medicines with the potential to increase bleeding risk ranged from 63.7% in Australia to 89.2% in Canada.A large proportion of adverse event reports for rivaroxaban were associated with use of concomitant medicines, which may have increased the risk of adverse events-in particular, haemorrhage. Increased awareness of a patient's comorbidity and associated medicine use is needed when rivaroxaban is used in clinical practice.Item Open Access A high-throughput screening assay for eukaryotic elongation factor 2 kinase inhibitors(Elsevier, 2016) Xiao, T.; Liu, R.; Proud, C.; Wang, M.Eukaryotic elongation factor 2 kinase (eEF2K) inhibitors may aid in the development of new therapeutic agents to combat cancer. Purified human eEF2K was obtained from an Escherichia coli expression system and a luminescence-based high-throughput screening (HTS) assay was developed using MH-1 peptide as the substrate. The luminescent readouts correlated with the amount of adenosine triphosphate remaining in the kinase reaction. This method was applied to a large-scale screening campaign against a diverse compound library and subsequent confirmation studies. Nine initial hits showing inhibitory activities on eEF2K were identified from 56,000 synthetic compounds during the HTS campaign, of which, five were chosen to test their effects in cancer cell lines.Item Metadata only A lifetime passion for micronucleus cytome assays - Reflections from Down Under(Elsevier Science BV, 2009) Fenech, M.A brief account of an improbable career in the field of genetic toxicology is given, extending from my early years in Malta through a life-changing decision to study in Australia (Down Under). I describe the circumstances that led to the discovery of the cytokinesis-block micronucleus (CBMN) assay and its evolution into a cytome assay of chromosome breakage and loss (micronuclei), asymmetrical chromosome rearrangements or telomere end fusions (nucleoplasmic bridges), gene amplification (nuclear buds), cell death (necrosis, apoptosis) and cytostasis (nuclear division index). This paper also describes the role of my laboratory in the beginning of the HUMN project, its achievements, and the applications of CBMN cytome assays in the fields of radiation biology, genetic toxicology, epidemiology, biodosimetry and genome health nutrigenomics, leading to the Genome Health Clinic concept. Along the way I mention my encounters with some of the influential people in the field of mutagenesis who provided me with the motivation and guidance needed to realise these achievements. I hope this account provides some inspiration to the next generation of scientists who may be fortunate to see the realisation of the application of the principles of mutagenesis in health optimisation or disease prevention and eventually in mainstream medicine.Item Metadata only A model-based evaluation of single metrics for discriminating changes in rheumatoid arthritis disease activity(Wiley-Blackwell, 2016) Wojciechowski, J.; Wiese, M.; Proudman, S.; Foster, D.; Upton, R.Aims: Composite indices for quantifying rheumatoid arthritis (RA) disease activity such as the 28‐joint disease activity score (DAS28) are comprised of single parameters (‘metrics’) in various combinations. Population modelling methods were used to evaluate single metrics for their ability to reflect changes in disease activity with a view to understanding and improving composite indices. Methods: A total of 11 single metrics of RA disease activity (tender and swollen joint counts, acute phase reactants and global health, pain and physical function assessments) were obtained from 203 patients with recent onset RA. Participants received combination disease‐modifying anti‐rheumatic drugs (DMARDs) according to a treat‐to‐target approach with a pre‐defined protocol for treatment intensification. Models describing each metric's magnitude and variability of change from baseline to a single ‘treated’ state in the population were developed using nonmem®. Measures that displayed uniformly large changes between states across the population were ranked higher in terms of discriminatory capacity. Results: Joint counts demonstrated a greater ability to discriminate changes in RA disease activity than others. Correlations between metrics demonstrated that erythrocyte sedimentation rate (ESR) had limited relationships with others for baseline scores and changes in RA disease activity (r generally < 0.2). However it appeared to be important in describing changes for those individuals where ESR levels were initially elevated. Conclusion: It appears unlikely that a single group of metrics may be suitable to capture disease activity changes across all RA patients and defining the most appropriate metric(s) for individual patients will be an important area of future research.Item Metadata only A new simple diagnostic assay for the identification of the major CYP2D6 genotypes by DNA sequencing analysis(Dustri-Verlag Dr Karl Feistle, 2004) James, H.; Coller, J.; Gillis, D.; Bahnisch, J.; Sallustio, B.; Somogyi, A.AIM: To establish a method suitable for diagnostic genotyping of CYP2D6 alleles by DNA sequencing. METHODS: Initial PCR reactions were performed to specifically amplify exons 3, 4, 5 and 6 of the CYP2D6 gene using primers previously published. New primers were used to identify *2, *3, *4, *6, *7, *8, *9 and *41 in 2 sequencing reactions. Additional primers were designed for reverse sequencing in samples with 1 or 3 b.p. deletions. Previously published assays were used to detect *5, *10 and *16 alleles to complete genotype assignment. RESULTS: We reliably detected the nonfunctional alleles, *3, *4, *6, *7 and *8, which are associated with the poor metabolizer phenotype, and 2 important alleles associated with decreased enzyme activity, *9 and *41. Observed allele frequencies were comparable to those found previously in Caucasian populations. CONCLUSION: CYP2D6 genotype has been shown in previous clinical studies to be a good predictor of CYP2D6 phenotype and, therefore, related to therapeutic response and the risk of drug toxicity. This genotyping method is simple and reliable, and, therefore, can be routinely performed on an isolated patient sample, providing a relatively quick turnaround time needed for clinical practice. In addition, the simultaneous drawing of blood with the commencement of drug therapy will allow dosage adjustment on the basis of the CYP2D6 genotype to reduce the risk of adverse drug reactions.