Increased Prevalence of Albuminuria in HIV-Infected Adults with Diabetes

HIV and type 2 diabetes are known risk factors for albuminuria, but no previous reports have characterized albuminuria in HIV-infected patients with diabetes.We performed a cross-sectional study including 73 HIV-infected adults with type 2 diabetes, 82 HIV-infected non-diabetics, and 61 diabetic control subjects without HIV. Serum creatinine >1.5 mg/dL was exclusionary. Albuminuria was defined as urinary albumin/creatinine ratio >30 mg/g.The prevalence of albuminuria was significantly increased among HIV-infected diabetics (34% vs. 13% of HIV non-diabetic vs. 16% diabetic control, p = 0.005). HIV status and diabetes remained significant predictors of albuminuria after adjusting for age, race, BMI, and blood pressure. Albumin/creatinine ratio correlated significantly with HIV viral load (r = 0.28, p = 0.0005) and HIV-infected subjects with albuminuria had significantly greater cumulative exposure to abacavir (p = 0.01). In an adjusted multivariate regression analysis of HIV-infected subjects, the diagnosis of diabetes (p = 0.003), higher HIV viral load (p = 0.03) and cumulative exposure to abacavir (p = 0.0009) were significant independent predictors of albuminuria.HIV and diabetes appear to have additive effects on albuminuria which is also independently associated with increased exposure to abacavir and HIV viral load. Future research on the persistence, progression and management of albuminuria in this unique at-risk population is needed

Lack of consistency in the relationship between asymptomatic DVT detected by venography and symptomatic VTE in thromboprophylaxis trials

Asymptomatic deep-vein thrombosis (DVT) detected by mandatory venography, a surrogate outcome, comprises most of the efficacy outcome events in recent thromboprophylaxis trials. The validity of this surrogate to estimate trade-off between thrombotic and bleeding events in these clinical trials requires a consistent relationship between asymptomatic DVT and symptomatic venous thromboembolism (VTE). In this systematic review of high quality VTE prevention trials, we examined the consistency of the ratios of asymptomatic DVT to symptomatic VTE across a broad range of indications. Studies were identified from citations listed in the chapters on VTE prevention in the antithrombotic guidelines by the American College of Chest Physicians, 2012. A study was eligible if it: 1) was a randomised trial comparing an anticoagulant with standard of care; 2) included at least 500 participants; 3) reported asymptomatic or all DVT rates; and 4) reported symptomatic VTE rates. Of the 26 eligible trials, 19 trials were conducted in orthopaedic patients, five in general surgery patients and two in general medical patients. The overall median rates (ranges) for asymptomatic DVT and symptomatic VTE were 9.11 % (0.75 to 54.87 %) and 0.49 % (0.00 to 3.10 %), respectively. The median ratio was 14.53, with a wide range (2.75 to 103.86). Wide variability in the ratios persisted despite indication- and anticoagulant-specific analyses. In VTE prevention trials of alternative anticoagulants, the wide variability in the ratios of asymptomatic DVT to symptomatic VTE precludes judging the trade-off between thrombotic and bleeding events on the basis of composite outcomes dominated by venographic DV

Synthesis, in vitro characterization, and radiolabeling of reboxetine analogs as potential PET radioligands for imaging the norepinephrine transporter

Six new ( S, S)-enantiomers of reboxetine derivatives were synthesized and their binding affinities were determined via competition binding assays in cells expressing the human norepinephrine transporter (NET), serotonin transporter (SERT) or dopamine transporter (DAT). All six compounds prepared exhibit high affinity for the NET ( K i ⩽ 2 nM) and selectivity versus the SERT and DAT. Radiolabeling methods were also developed to prepare these ligands in moderate to high radiochemical yield with high radiochemical purity via O- or S-methylation with [ 11C]CH 3I, or O-alkylation with [ 18F]fluoroethyl brosylate or [ 18F]fluoropropyl brosylate, and their log P 7.4 was measured. These new C-11- and F-18-labeled tracers will be utilized in comparative microPET studies to evaluate their potential as PET radioligands for imaging brain NET in nonhuman primates

Synthesis, Radiosynthesis, and Biological Evaluation of Carbon-11 and Fluorine-18 Labeled Reboxetine Analogs: Potential Positron Emission Tomography Radioligands for in Vivo Imaging of the Norepinephrine Transporter

Reboxetine analogs with methyl and fluoroalkyl substituents at position 2 of the phenoxy ring 1–4 were synthesized. In vitro competition binding demonstrated that 1–4 have a high affinity for the norepinephrine transporter (NET) with K i ’s = 1.02, 3.14, 3.68, and 0.30 nM (vs [ 3 H]nisoxetine), respectively. MicroPET imaging in rhesus monkeys showed that the relative regional distribution of [ 11 C] 1 and [ 11 C] 4 is consistent with distribution of the NET in the brain, while [ 18 F] 2 and [ 18 F] 3 showed only slight regional differentiation in brain uptake. Especially, the highest ratios of uptake of [ 11 C] 1 in NET-rich regions to that in caudate were obtained at 1.30–1.45 at 45 min, and remained relatively constant over 85 min. Pretreatment of the monkey with the selective NET inhibitor, desipramine, decreased the specific binding for both [ 11 C] 1 and [ 11 C] 4 . PET imaging in awake monkeys suggested that anesthesia influenced the binding potential of [ 11 C] 1 and [ 11 C] 4 at the NET

Synthesis and biological evaluation of 2 beta ,3 alpha -(substituted phenyl)nortropanes as potential norepinephrine transporter imaging agents

A series of 2 beta ,3 alpha -(substituted phenyl)nortropanes was synthesized and evaluated in vitro for human monoamine transporters. All compounds studied in this series exhibited nanomolar potency for the norepinephrine transporter (NET). Radiolabeling and nonhuman primate microPET brain imaging studies were performed with the most promising compound, [ super(11)C] 1, to determine its utility as a NET imaging agent. Despite high in vitro affinity for the human NET, the high uptake of [ super(11)C] 1 in the caudate and putamen excludes its use as an in vivo PET imaging agent for the NET

Ligand-based design of [18F]OXD-2314 for PET imaging in non-Alzheimer’s disease tauopathies

Abstract Positron emission tomography (PET) imaging of tau aggregation in Alzheimer’s disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [3H]OXD-2115, and in silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies