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1.
Article in English | MEDLINE | ID: mdl-36653062

ABSTRACT

INTRODUCTION: Evaluate the prevalence of, and factors associated with, diabetes in people with severe mental illness (SMI) attending the Collaborative Centre for Cardiometabolic Health in Psychosis (ccCHiP) tertiary referral clinics. RESEARCH DESIGN AND METHODS: Adult patients attending an initial ccCHiP clinic consultation (2014-2019) were studied. Diabetes was defined by an hemoglobin A1c of ≥6.5%, fasting blood glucose of ≥7.0 mmol/L, or a self-reported diagnosis of diabetes and prescription of antihyperglycemic medication. RESULTS: Over 5 years, 1402 individuals attended a baseline consultation. Mean age of 43.9±12.8 years, 63.1% male and 63.5% had a diagnosis of schizophrenia. Prevalence of diabetes was 23.0% (n=322); an additional 19.5% fulfilled criteria for pre-diabetes. Of those with diabetes, 15.8% were newly diagnosed. Of those with pre-existing diabetes, 84.5% were receiving treatment with antihyperglycemic medication. Over 94% of individuals with diabetes had dyslipidemia; half were current smokers; and 46.4% reported sedentary behavior. On multivariate analysis, diabetes was associated with older age, Aboriginal, Indian or Middle Eastern maternal ethnicity, elevated waist-to-height ratio, family history of diabetes and use of antipsychotic medication. CONCLUSION: Prevalence of diabetes mellitus in this multiethnic cohort with SMI is significantly higher than the Australian population. Targeted interventions via an assertive integrated approach are required to optimize cardiometabolic health in this population.


Subject(s)
Cardiovascular Diseases , Diabetes Mellitus , Mental Disorders , Adult , Humans , Male , Middle Aged , Female , Outpatients , Prevalence , Australia , Diabetes Mellitus/epidemiology , Mental Disorders/complications , Mental Disorders/epidemiology , Cardiovascular Diseases/epidemiology , Hypoglycemic Agents/therapeutic use
2.
Curr Diab Rep ; 18(3): 14, 2018 02 19.
Article in English | MEDLINE | ID: mdl-29457196

ABSTRACT

PURPOSE OF REVIEW: The purposes of this review are to identify population characteristics of important risk factors for the development and progression of diabetic kidney disease (DKD) in the United States and to discuss barriers and opportunities to improve awareness, management, and outcomes in patients with DKD. RECENT FINDINGS: The major risk factors for the development and progression of DKD include hyperglycemia, hypertension, and albuminuria. DKD disproportionately affects minorities and individuals with low educational and socioeconomic status. Barriers to effective management of DKD include the following: (a) limited patient and healthcare provider awareness of DKD, (b) lack of timely referrals of patients to a nephrologist, (c) low patient healthcare literacy, and (d) insufficient access to healthcare and health insurance. Increased patient and physician awareness of DKD has been shown to enhance patient outcomes. Multifactorial and multidisciplinary interventions targeting multiple risk factors and patient/physician education may provide better outcomes in patients with DKD.


Subject(s)
Diabetic Nephropathies/epidemiology , Diabetic Nephropathies/etiology , Disease Progression , Humans , Risk Factors , United States/epidemiology
3.
Bioorg Med Chem Lett ; 21(6): 1876-9, 2011 Mar 15.
Article in English | MEDLINE | ID: mdl-21316235

ABSTRACT

A series of quinoline derivatives was synthesized as potential bioisosteric replacements for the benzothiadiazine moiety of earlier Hepatitis C NS5B polymerase inhibitors. Several of these compounds exhibited potent activity in enzymatic and replicon assays.


Subject(s)
Benzothiadiazines/pharmacology , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Benzothiadiazines/chemistry , Hepacivirus/enzymology , Hepacivirus/physiology , Protease Inhibitors/chemistry , Virus Replication
4.
J Med Chem ; 52(6): 1659-69, 2009 Mar 26.
Article in English | MEDLINE | ID: mdl-19226162

ABSTRACT

The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.


Subject(s)
Benzothiadiazines/chemical synthesis , Benzothiadiazines/pharmacology , DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Animals , Benzothiadiazines/pharmacokinetics , Biological Availability , Enzyme Inhibitors/pharmacokinetics , Half-Life , Humans , Magnetic Resonance Spectroscopy , Rats , Spectrometry, Mass, Electrospray Ionization
5.
Bioorg Med Chem Lett ; 18(14): 3887-90, 2008 Jul 15.
Article in English | MEDLINE | ID: mdl-18599294

ABSTRACT

4,4-Dialkyl-1-hydroxy-3-oxo-3.4-dihydronaphthalene-3-yl benzothiadiazine derivatives were synthesized and evaluated as inhibitors of genotypes 1a and 1b HCV NS5B polymerase. A number of these compounds exhibited potent activity against genotypes 1a and 1b HCV polymerase in both enzymatic and cell culture activities. A representative compound also showed favorable pharmacokinetics in the rat.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Area Under Curve , Chemistry, Pharmaceutical/methods , Drug Design , Genotype , Infusions, Intravenous , Inhibitory Concentration 50 , Models, Chemical , Rats , Viral Nonstructural Proteins/genetics
6.
Bioorg Med Chem Lett ; 18(2): 568-70, 2008 Jan 15.
Article in English | MEDLINE | ID: mdl-18068361

ABSTRACT

A series of gem-dialkyl naphthalenone derivatives with varied alkyl substitutions were synthesized and evaluated according to their structure-activity relationship. This investigation led to the discovery of potent inhibitors of the hepatitis C virus at low nanomolar concentrations in both enzymatic and cell-based HCV genotype 1a assays.


Subject(s)
DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Naphthalenes/pharmacology , Genotype , Hepacivirus/genetics , Structure-Activity Relationship
7.
Antimicrob Agents Chemother ; 51(12): 4290-6, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17908950

ABSTRACT

A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.


Subject(s)
Antiviral Agents/pharmacokinetics , Benzothiadiazines/pharmacokinetics , Cyclic S-Oxides/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Hepacivirus/enzymology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Benzothiadiazines/chemistry , Benzothiadiazines/therapeutic use , Biological Availability , Cyclic S-Oxides/chemistry , Cyclic S-Oxides/therapeutic use , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Genotype , Haplorhini , Hepacivirus/drug effects , Hepacivirus/genetics , Hepatitis C/blood , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Molecular Structure , Pan troglodytes , Phenotype , RNA, Viral/blood , RNA-Dependent RNA Polymerase/genetics , Rats , Viral Load , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/genetics
8.
Anal Biochem ; 368(2): 156-67, 2007 Sep 15.
Article in English | MEDLINE | ID: mdl-17644059

ABSTRACT

Maturation of the hepatitis C virus (HCV) polyprotein occurs by a series of proteolytic processes catalyzed by host cell proteases and the virally encoded proteases NS2 and NS3. Although several peptidomimetic inhibitors of NS3 protease have been published, only a few small molecule inhibitors have been reported. In an effort to improve screening efficiency by minimizing the spectral interference of various test compounds, a substrate that contains the longer wavelength fluorescence resonance energy transfer (FRET) pair, TAMRA/QSY-7, was devised. For the optimized substrate T-Abu-Q, with sequence Ac-Asp-Glu-Lys(TAMRA)-Glu-Glu-Abu-Psi(COO)Ala-Ser-Lys(QSY-7)-amide, the kinetic parameters with HCV NS3 protease are K(m)=30 microM, k(cat)=0.6s(-1), and k(cat)/K(m)=20,100s(-1)M(-1). We show that this substrate is suitable for inhibitor analysis and mechanistic studies so long as the substrate concentration is low enough (0.5 microM) to avoid complications from high inner filter effects. The substrate is especially useful with ultra-high-density screening formats, such as microarrayed compound screening technology, because there is less spectral interference from the compounds being tested than with more traditional (EDANS/DABCYL) FRET protease substrates. The merits of the new substrate, as well as potential applications of this FRET pair to other protease substrates, are discussed.


Subject(s)
Fluorescence Resonance Energy Transfer , Oligopeptides/chemistry , Viral Nonstructural Proteins/chemistry , Dose-Response Relationship, Drug , Fluorescent Dyes/chemistry , Hydrolysis , Kinetics , Oligopeptides/chemical synthesis , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Rhodamines/chemistry , Sensitivity and Specificity , Substrate Specificity , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism
9.
J Virol Methods ; 145(2): 137-45, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17604129

ABSTRACT

Hepatitis C virus (HCV) replicon-based shuttle vectors that permit phenotypes of NS5B polymerase genes from a large number of patient isolates to be rapidly assessed when transiently expressed in cultured cells were designed. When used to test responses to an inhibitor of HCV RNA-dependent RNA polymerase, IC(50) values for inhibition covered a several hundred-fold range among 47 patient samples tested. This observation highlights the variability that can be found by testing isolates derived from HCV-infected subjects. Partial suppression with a polymerase inhibitor of the most sensitive species permitted detection of minor quasispecies that were 7-200-fold more resistant than the bulk population in approximately half of the samples. Sequence analysis showed a wide range of amino acid changes not detected by conventional selection methods using laboratory-derived strains. This approach provides a means to assess variation in antiviral efficacy, and to predict possible responses in a clinical setting.


Subject(s)
Genetic Vectors , Hepacivirus/genetics , Hepatitis C/virology , RNA-Dependent RNA Polymerase/genetics , Replicon , Viral Nonstructural Proteins/genetics , Antiviral Agents/pharmacology , Drug Resistance, Viral , Enzyme Inhibitors/pharmacology , Gene Expression Regulation, Viral , Genotype , Hepacivirus/drug effects , Hepacivirus/enzymology , Hepacivirus/isolation & purification , Humans , Phenotype , Plasmids , RNA, Viral/isolation & purification , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/isolation & purification , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/isolation & purification
11.
Antiviral Res ; 73(1): 40-9, 2007 Jan.
Article in English | MEDLINE | ID: mdl-16914212

ABSTRACT

A transient subgenomic replicon-based shuttle vector system has been developed to investigate how genetic heterogeneity affects HCV replication efficiency. Individual NS5A or NS5B genes or cassettes containing both NS5A and NS5B genes were amplified from "quasispecies" pools derived from HCV genotype 1a or 1b patient sera using RT-PCR and cloned into their respective shuttle vectors. All shuttle vectors containing NS5A or NS5A-5B genes were constructed with the S2204I "adaptive" mutation because replicons lacking the S2204I mutation replicated poorly. Gene sequences of the quasispecies pools within either genotype 1a or 1b patient samples ranged from 94 to 95% in identity. The replication capacity of 1b shuttle vectors containing patient-derived NS5A or NS5B genes averaged 67 and 75%, respectively, relative to the laboratory-optimized 1b replicon. In contrast, the replication efficiencies of both 1a and 1b shuttle vectors containing patient-derived NS5A-5B gene cassettes averaged around 2% relative to the respective laboratory-optimized replicon. All patient-derived replicons were tested in a transient assay for their sensitivity to either interferon-alpha (IFN-alpha) or to the polymerase inhibitor A-782759. Despite the differences in replication efficiency, IC(50) values measured for most of the patient-derived replicons were equivalent to the respective values measured in the control laboratory strain replicons. These results demonstrate that patient sequence heterogeneity affects replication efficiency whenever patient-derived NS5A-5B genes are inserted into the laboratory-optimized replicon. The findings also demonstrate the utility of the shuttle vector system to test patient-derived gene sequences for sensitivity to IFN-alpha and to small molecule inhibitors.


Subject(s)
Hepacivirus/physiology , Hepatitis C/virology , Recombinant Fusion Proteins/genetics , Viral Nonstructural Proteins/genetics , Virus Replication , Cell Line, Tumor , Genetic Vectors , Genotype , Hepacivirus/genetics , Hepacivirus/metabolism , Humans , Recombinant Fusion Proteins/metabolism , Replicon , Viral Nonstructural Proteins/metabolism
14.
Bioorg Med Chem Lett ; 15(6): 1577-82, 2005 Mar 15.
Article in English | MEDLINE | ID: mdl-15745800

ABSTRACT

N-1-Alkylamino and N-1-alkyloxy-4-hydroxyquinolon-3-yl benzothiadiazines were synthesized and evaluated as inhibitors of genotype 1 HCV polymerase. The N-1-alkyloxy derivatives were not potent inhibitors, however N-1-alkylamino derivatives displayed comparable potency to carbon analogs. Analogs with aliphatic substituents were significantly more potent than those with benzylic substituents against genotype 1a polymerase. The most potent inhibitors contained small alkyl or carbocyclic substituents and exhibited IC50's of 50-100 and 200-400 nM against genotype 1b and 1a HCV polymerase, respectively.


Subject(s)
Benzothiadiazines/chemical synthesis , Benzothiadiazines/pharmacology , Hepacivirus/enzymology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Models, Chemical , Molecular Structure , Structure-Activity Relationship
15.
Antiviral Res ; 64(1): 35-45, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15451177

ABSTRACT

Retroviral integrases catalyze two of the steps of insertion of proviral DNA into the host genomic DNA. Inhibitors that target the second step, strand transfer into the host DNA, have been demonstrated to have antiviral activity in cell culture. We describe two classes of HIV-1 integrase inhibitors that block strand transfer, one based on a naphthamidine core and one on a benzimidazole core. While the naphthamidine compounds showed some propensity to interact with the DNA substrate, both classes were shown to bind directly to integrase. The naphthamidine compounds showed activity in cell culture, and a direct effect on integrase was indicated by an increase in 2-LTR products in the presence of a naphthamidine compound. These two classes of compounds represent potential starting points for the development of new classes of integrase inhibitors.


Subject(s)
Benzimidazoles/pharmacology , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , HIV-1/enzymology , Naphthalenes/pharmacology , Base Sequence , Benzimidazoles/chemistry , Cell Line , DNA, Viral/genetics , Genes, Viral , HIV Integrase/chemistry , HIV Integrase/genetics , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/classification , HIV-1/genetics , Humans , In Vitro Techniques , Molecular Structure , Naphthalenes/chemistry , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism
16.
J Biomol Screen ; 8(3): 273-82, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12857381

ABSTRACT

Microarrayed compound screening format (muARCS) is a novel high-throughput screening technology that uses agarose matrices to integrate various biochemical or biological reagents in the assay. To evaluate the feasibility of using the muARCS technology for nucleic acid polymerization assays, the authors developed HIV reverse transcription (RT) and E1-dependent human papillomavirus (HPV) replication assays in this format. HIV RT is an RNA-dependent DNA polymerase, whereas HPV E1 is a DNA helicase. To ensure the efficient capture of the nucleic acid polymerization reaction and to minimize the nonspecific binding, the authors used a SAM(2) biotin capture membrane in the assay. In both studies, the nucleic acid substrate was biotinylated on one end and was bound to the SAM(2) membrane. A low melting-point agarose gel containing the rest of the reaction components was first placed on a polystyrene sheet spotted with compounds to allow passive diffusion of the compounds into the gel. The gel was removed from the compound sheet and applied to the SAM(2) membrane with the immobilized nucleic acid template to initiate the polymerization. After the incubation, the membrane was washed with a high-salt buffer and exposed for imaging. Potential inhibitors can be seen as white spots on a dark background. The sensitivity for the known inhibitors appears to be comparable in muARCS as in a traditional 96-well plate assay. The methodology described in this paper further expands the applications of muARCS technology.


Subject(s)
Biotin/pharmacology , Oligonucleotide Array Sequence Analysis/methods , Alkynes , Anti-HIV Agents/pharmacology , Benzoxazines , Biotin/chemistry , Biotinylation , Cyclopropanes , DNA/chemistry , Dose-Response Relationship, Drug , HIV Reverse Transcriptase/genetics , Inhibitory Concentration 50 , Nevirapine/pharmacology , Nucleic Acids/chemistry , Oxazines/pharmacology , Plasmids/metabolism , RNA/chemistry , RNA-Directed DNA Polymerase/chemistry , Sensitivity and Specificity , Templates, Genetic
17.
J Biomol Screen ; 7(3): 259-66, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12097188

ABSTRACT

A novel high-throughput strand transfer assay has been developed, using Microarray Compound Screening (microARCS) technology, to identify inhibitors of human immunodeficiency virus (HIV) integrase. This technology utilizes agarose matrices to introduce a majority of the reagents throughout the assay. Integration of biotinylated donor DNA with fluorescein isothiocyanate (FITC)-labeled target DNA occurs on a SAM membrane in the presence of integrase. An anti-FITC antibody conjugated to alkaline phosphatase (AP) was used to do an enzyme-linked immunosorbent assay with the SAM. An agarose gel containing AttoPhos, a substrate of AP, was used for detection of the integrase reactions on the SAM. For detection, the AttoPhos gel was separated from the SAM after incubation and then the gel was imaged using an Eagle Eye II closed-circuit device camera system. Potential integrase inhibitors appear as dark spots on the gel image. A library of approximately 250,000 compounds was screened using this HIV integrase strand transfer assay in microARCS format. Compounds from different structural classes were identified in this assay as novel integrase inhibitors.


Subject(s)
HIV Integrase Inhibitors/analysis , HIV Integrase/drug effects , HIV Integrase Inhibitors/pharmacology
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