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Background. The MERIT (Maraviroc versus Efavirenz in Treatment-Naive Patients) study compared maraviroc and efavirenz, both with zidovudine-lamivudine, in antiretroviral-naive patients with R5 human immunodeficiency virus type 1 (HIV-1) infection. Methods. Patients screened for R5 HIV-1 were randomized to receive efavirenz (600 mg once daily) or maraviroc (300 mg once or twice daily) with zidovudine-lamivudine. Coprimary end points were proportions of patients with a viral load <400 and <50 copies/mL at week 48; the noninferiority of maraviroc was assessed. Results. The once-daily maraviroc arm was discontinued for not meeting prespecified noninferiority criteria. In the primary 48-week analysis (n=721), maraviroc was noninferior for <400 copies/mL (70.6% for maraviroc vs 73.1% for efavirenz) but not for <50 copies/mL (65.3% vs 69.3%) at a threshold of −10%. More maraviroc patients discontinued for lack of efficacy (11.9% vs 4.2%), but fewer discontinued for adverse events (4.2% vs 13.6%). In a post hoc reanalysis excluding 107 patients (15%) with non-R5 screening virus by the current, more sensitive tropism assay, the lower bound of the 1-sided 97.5% confidence interval for the difference between treatment groups was above −10% for each end point. Conclusions. Twice-daily maraviroc was not noninferior to efavirenz at <50 copies/mL in the primary analysis. However, 15% of patients would have been ineligible for inclusion by a more sensitive screening assay. Their retrospective exclusion resulted in similar response rates in both arms Trial registration. ClinicalTrials.gov identifier: (NCT00098293).

The CCR5 coreceptor may be a therapeutic target to block HIV infection. HIV-1–infected patients who had received previous antiretroviral treatment were enrolled in one of two phase 3, placebo-controlled, double-blind international studies of treatment with maraviroc (a CCR5 antagonist). Maraviroc significantly lowered the HIV-1 viral load and increased the CD4 cell count at 48 weeks. The CCR5 coreceptor may be a therapeutic target to block HIV infection. In two studies, maraviroc (a CCR5 antagonist) significantly lowered the HIV-1 viral load and increased the CD4 cell count at 48 weeks. For the past decade, treatment of human immunodeficiency virus type 1 (HIV-1) has consisted of a multiple-drug regimen targeting one or more of three HIV-1 proteins: reverse transcriptase, protease, and the glycoprotein envelope subunit gp41. 1 Although these antiretroviral combinations are successful in suppressing viral replication and delaying disease progression, drug resistance and toxic effects may occur. 2 – 4 There is therefore a need for better-tolerated, convenient antiretroviral agents with reduced toxicity and activity against multidrug-resistant viruses. Agents with novel mechanisms of action provide options for patients with drug-resistant virus. 4 CC chemokine receptor 5 (CCR5) is an attractive therapeutic target, since people . . .

Among patients with impaired glucose tolerance, the short-acting insulin secretagogue nateglinide did not reduce the incidence of diabetes over the course of 5 years. Nateglinide also did not reduce the risk of cardiovascular events. Therefore, nateglinide does not have a place in the management of impaired glucose tolerance. Among patients with impaired glucose tolerance, the short-acting insulin secretagogue nateglinide did not reduce the incidence of diabetes over the course of 5 years. Nateglinide also did not reduce the risk of cardiovascular events. Persons with impaired glucose tolerance are at increased risk for type 2 diabetes mellitus and cardiovascular disease 1 – 3 ; therefore, treatments that might reduce the incidence of diabetes and associated cardiovascular disease and death are potentially important. 3 The risk of diabetes is reduced with lifestyle interventions that involve increasing physical activity and reducing weight 4 – 6 and with metformin, 6 acarbose, 7 or rosiglitazone 8 therapy, but no trials to date have been powered to consider cardiovascular outcomes. Among persons with type 2 diabetes, reducing glycemia results in a small reduction in the risk of major macrovascular events. 9 Glucose levels after a glucose challenge, . . .

Background. There is a need to prevent or minimize bone loss associated with antiretroviral treatment (ART) initiation. We compared maraviroc (MVC)- to tenofovir disoproxil fumarate (TDF)–containing ART. Methods. This was a double-blind, placebo-controlled trial. ART-naive subjects with human immunodeficiency virus type 1 RNA load (viral load [VL]) >1000 copies/mL and R5 tropism were randomized to MVC 150 mg or TDF 300 mg once daily (1:1), stratified by VL <100 000 or ≥100 000 copies/mL and age <30 or ≥30 years. All subjects received darunavir 800 mg, ritonavir 100 mg, and emtricitabine 200 mg daily. Dual-energy X-ray absorptiometry scanning was done at baseline and week 48. The primary endpoint was percentage change in total hip bone mineral density (BMD) from baseline to week 48 in the as-treated population. Results. We enrolled 262 subjects. A total of 259 subjects (130 MVC, 129 TDF) contributed to the analyses (91% male; median age, 33 years; 45% white, 30% black, 22% Hispanic). Baseline median VL was 4.5 log10 copies/mL and CD4 count was 390 cells/μL. The decline in hip BMD (n = 115 for MVC, n = 109 for TDF) at week 48 was less with MVC (median [Q1, Q3] of −1.51% [−2.93%, −0.11%] vs −2.40% [−4.30%, −1.32%] for TDF (P<.001). Lumbar spine BMD decline was also less with MVC (median −0.88% vs −2.35%; P<.001). Similar proportions of subjects in both arms achieved VL ≤50 copies/mL in as-treated and ITT analyses. Conclusions. MVC was associated with less bone loss at the hip and lumbar spine compared with TDF. MVC may be an option to attenuate ART-associated bone loss. Clinical Trials Registration. NCT01400412.

Background. Maraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis. Methods. Phase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat. Results. Among 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations. Conclusions. MVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis. Clinical Trials Registration. NCT01505114.

In this large clinical trial, the angiotensin-receptor blocker valsartan reduced the risk of diabetes in patients with impaired glucose tolerance. However, the effect was small, and there was no reduction in the rate of cardiovascular events. Thus, impaired glucose tolerance is probably best managed with lifestyle intervention. In this large clinical trial, the angiotensin-receptor blocker valsartan reduced the risk of diabetes in patients with impaired glucose tolerance. However, the effect was small, and there was no reduction in the rate of cardiovascular events. Patients with impaired glucose tolerance have an increased risk of type 2 diabetes mellitus and cardiovascular disease. 1 – 3 Interventions that might reduce the incidence of diabetes and associated rates of death and complications from cardiovascular causes in such patients are therefore of importance. 3 Several trials have shown that lifestyle modification, including increased physical activity and weight loss, reduces the risk of diabetes, although these trials did not evaluate cardiovascular outcomes. 3 – 8 Certain drugs, including metformin, acarbose, and rosiglitazone, also reduce the incidence of diabetes, although their effect on cardiovascular events is uncertain. 6 , 9 , 10 Another pharmacologic approach to reducing the . . .

Funding Information: This research was funded by the Brazilian agencies Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the European Community’s Seventh Framework Program (FP7/2007-2013) under grant agreement nº 226716 (ELISA) and Fundação para a Ciência e a Tecnologia (FCT) CEFITEC (UID/00068). In this work, we provide results from a joint experimental and theoretical study of the vibronic features of cyclohexane (C6H12) in the photon energy range of 6.8–10.8 eV (182–115 nm). The high-resolution vacuum ultraviolet (VUV) photoabsorption measurements, together with quantum chemical calculations at the time-dependent density functional theory (TDDFT) level, have helped to assign the major electronic excitations to mixed valence–Rydberg and Rydberg transitions. The C6H12 photoabsorption spectrum shows fine structure which has been assigned to CH2 scissoring, ′3(1), CH2 rocking, ′4(1), C–C stretching, ′5(1), and CCC bending/CC torsion, ′24(), modes. Molecular structure calculations at the DFT level for the neutral and cationic electronic ground-states have shown the relevant structural changes that are operative in the higher-lying electronic states. Photolysis lifetimes in the Earth’s atmosphere are shown to be irrelevant, while the main atmospheric sink mechanism is the reaction with the •OH radical. Potential energy curves have been obtained at the TDDFT level of theory, showing the relevance of interchange character mainly involving the CH2 scissoring, ′3(1), and CH2 rocking, ′4(1), modes, while Jahn–Teller distortion yields weak vibronic coupling involving the non-totally symmetric CCC bending/CC torsion, ′24(), mode.

The bifunctional catalyst Ru/H was prepared by equal volume impregnation method and applied to the study of the kinetics of benzene hydroalkylation reaction. The reaction order of 1 for benzene and 1.94 for H.sub.2 ( [Formula omitted]) was obtained by fitting the kinetic experimental data first. Then a kinetic model conforming to the Eley-Rideal (E-R) mechanism was developed based on the types of adsorbates on different active centers of the solid catalyst, and the main mechanism was that the benzene in the adsorbed state was partially hydrogenated to produce cyclohexene, which was not desorbed from the active centers. Some of it was further hydrogenated to produce cyclohexane, and some was alkylated with benzene in the bulk phase to produce cyclohexylbenzene. The reaction rate control step was the alkylation of benzene and cyclohexene. The model parameters were calculated using a genetic algorithm. The model was tested to be able to describe the reaction mechanism of benzene hydroalkylation well and to provide guidance for process optimization.

Transmembrane anion transporters (anionophores) have potential for new modes of biological activity, including therapeutic applications. In particular they might replace the activity of defective anion channels in conditions such as cystic fibrosis. However, data on the biological effects of anionophores are scarce, and it remains uncertain whether such molecules are fundamentally toxic. Here, we report a biological study of an extensive series of powerful anion carriers. Fifteen anionophores were assayed in single cells by monitoring anion transport in real time through fluorescence emission from halide-sensitive yellow fluorescent protein. A bis-( p -nitrophenyl)ureidodecalin shows especially promising activity, including deliverability, potency and persistence. Electrophysiological tests show strong effects in epithelia, close to those of natural anion channels. Toxicity assays yield negative results in three cell lines, suggesting that promotion of anion transport may not be deleterious to cells. We therefore conclude that synthetic anion carriers are realistic candidates for further investigation as treatments for cystic fibrosis. Synthetic anion transporters that replace the activity of defective anion channels have been proposed as treatments for cystic fibrosis; however, it remains uncertain whether such molecules are fundamentally toxic. A series of bis- and tris-(thio)ureas capable of transporting anions have now been tested in cells expressing halide-sensitive yellow fluorescent protein. One bis-urea compound proved especially effective while showing almost no toxicity.

BackgroundMaraviroc, a CCR5 antagonist, is active against R5 but not X4 or dual- or mixed-tropic strains of human immunodeficiency virus type 1 (HIV-1). A phase 2b study was conducted to determine the safety and efficacy of maraviroc in combination with optimized background therapy in treatment-experienced patients infected with dual- or mixed-tropic HIV-1 MethodsTreatment-experienced patients with an HIV-1 RNA level ⩾5000 copies/mL who had received ⩾3 classes of drugs and/or were infected with virus resistant to 2 drug classes and were infected with non-R5 HIV-1 were randomized to receive optimized background therapy plus maraviroc (once or twice daily) or placebo. The primary end point was change in HIV-1 RNA level from baseline to 24 weeks ResultsAmong 167 patients infected with dual- or mixed-tropic HIV-1, baseline mean HIV-1 RNA levels were >5 log10 copies/mL and median CD4+ cell counts were <50 cells/μL. From baseline to 24 weeks, patients who received placebo demonstrated a mean decrease in HIV-1 RNA levels of 0.97 log10 copies/mL, compared with mean decreases of 0.91 and 1.20 log10 copies/mL for those who received maraviroc once (P=.83) or twice (P=.38) daily, respectively. Mean increases in CD4+ cell counts from baseline were 36 cells/μL for patients who received placebo, 60 cells/μL among patients who received maraviroc once daily, and 62 cells/μL among patients who received maraviroc twice daily. The incidences of serious adverse events were similar among groups ConclusionsIn this exploratory study involving extensively treatment-experienced patients with advanced, non-R5 HIV-1 infection, neither superiority nor noninferiority was statistically demonstrated for either maraviroc dosage compared with placebo at 24 weeks of treatment Trial registrationClinicaltrials.gov identifier NCT00098748