Long-term effectiveness of recommended boosted protease inhibitor-based antiretroviral therapy in Europe.

OBJECTIVES: The aim of the study was to evaluate the long-term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)-, darunavir/ritonavir (DRV/r)-, and lopinavir/ritonavir (LPV/r)-containing regimens. METHODS: Data were analysed for 5678 EuroSIDA-enrolled patients starting a DRV/r-, ATZ/r- or LPV/r-containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART-naïve subjects (8%) at ritonavir-boosted protease inhibitor (PI/r) initiation; (2) ART-experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV-1 RNA copies/mL; and (3) ART-experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL ≥24 weeks after PI/r initiation. Kaplan-Meier and multivariable Cox models were used to compare risks of failure by PI/r-based regimen. The main analysis was performed with intention-to-treat (ITT) ignoring treatment switches. RESULTS: The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log-rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART-naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment-experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r-based ART. CONCLUSIONS: Although confounding by indication and calendar year cannot be completely ruled out, in ART-experienced subjects the long-term effectiveness of DRV/r-containing regimens appears to be greater than that of ATZ/r and LPV/r.

Incidence of cancer and overall risk of mortality in individuals treated with raltegravir-based and non-raltegravir-based combination antiretroviral therapy regimens.

OBJECTIVES: There are currently few data on the long-term risk of cancer and death in individuals taking raltegravir (RAL). The aim of this analysis was to evaluate whether there is evidence for an association. METHODS: The EuroSIDA cohort was divided into three groups: those starting RAL-based combination antiretroviral therapy (cART) on or after 21 December 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between 1 January 2005 and 20 December 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007. Baseline characteristics were compared using logistic regression. The incidences of newly diagnosed malignancies and death were compared using Poisson regression. RESULTS: The RAL cohort included 1470 individuals [with 4058 person-years of follow-up (PYFU)] compared with 3787 (4472 PYFU) and 4467 (10 691 PYFU) in the HIST and CONC cohorts, respectively. The prevalence of non-AIDS-related malignancies prior to baseline tended to be higher in the RAL cohort vs. the HIST cohort [adjusted odds ratio (aOR) 1.31; 95% confidence interval (CI) 0.95-1.80] and vs. the CONC cohort (aOR 1.89; 95% CI 1.37-2.61). In intention-to-treat (ITT) analysis (events: RAL, 50; HIST, 45; CONC, 127), the incidence of all new malignancies was 1.11 (95% CI 0.84-1.46) per 100 PYFU in the RAL cohort vs. 1.20 (95% CI 0.90-1.61) and 0.83 (95% CI 0.70-0.99) in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies [adjusted rate ratio (RR) 0.73; 95% CI 0.47-1.14 for RALvs. HIST; RR 0.95; 95% CI 0.65-1.39 for RALvs. CONC] or mortality (adjusted RR 0.87; 95% CI 0.53-1.43 for RALvs. HIST; RR 1.14; 95% CI 0.76-1.72 for RALvs. CONC). CONCLUSIONS: We found no evidence for an oncogenic risk or poorer survival associated with using RAL compared with control groups.

Tunable beam steering enabled by graphene metamaterials.

We demonstrate tunable mid-infrared (MIR) beam steering devices based on multilayer graphene-dielectric metamaterials. The effective refractive index of such metamaterials can be manipulated by changing the chemical potential of each graphene layer. This can arbitrarily tailor the spatial distribution of the phase of the transmitted beam, providing mechanisms for active beam steering. Three different beam steerer (BS) designs are discussed: a graded-index (GRIN) graphene-based metamaterial block, an array of metallic waveguides filled with graphene-dielectric metamaterial and an array of planar waveguides created in a graphene-dielectric metamaterial block with a specific spatial profile of graphene sheets doping. The performances of the BSs are numerically analyzed, showing the tunability of the proposed designs for a wide range of output angles (up to approximately 70°). The proposed graphene-based tunable beam steering can be used in tunable transmitter/receiver modules for infrared imaging and sensing.

Effects of selective catechol-O-methyltransferase inhibitors on single-trial passive avoidance retention in male rats.

The effects of new selective catechol-O-methyltransferase (COMT) inhibitors entacapone (mainly peripheral effect) and tolcapone (acting also in the brain) on normal and impaired cognitive functions were studied in aversively motivated inhibitory avoidance using a single-trial passive avoidance paradigm in young adult rats. Passive avoidance retention latency was shortened by either scopolamine (1.0 mg/kg) or bilateral lesions to nucleus basalis magnocellularis (NBM) caused by infusions of ethylcholine aziridinium (AF64A). Entacapone (30 mg/kg) administered once before training or before the retention test, 24 h after training, prevented the effect of scopolamine but did not alter extinction in these rats. However, entacapone (30 mg/kg) prolonged lag time when given during the extinction process to intact rats after training. Tolcapone administered once before training (10 mg/kg) counteracted the effect of scopolamine. It prolonged retention latency of the intact rats when given after training (10 mg/kg). Tolcapone (3 mg/kg) also prolonged lag time when given during extinction to rats bearing NBM lesions. The effect of scopolamine on extinction and retrieval was not prevented by tolcapone. Only entacapone improved memory storage. Collectively, the present results indicate that COMT inhibitors prolong retention latencies in a single-trial passive avoidance test assessed at several memory phases.

Tolcapone, an inhibitor of catechol O-methyltransferase, counteracts memory deficits caused by bilateral cholinotoxin lesions of the basal nuclei of Meynert.

Repeated administration of tolcapone, an inhibitor of catechol-O-methyltransferase, was able to partially restore the memory deficits caused by bilateral cholinotoxin (AF64A) lesions in the basal magnocellular nuclei of Meynert. The 2-week tolcapone treatment (3 mg kg-1, once a day) was started 24 h before toxin infusion and the last injection was given 24 h before the first avoidance test. The beneficial action of tolcapone may be related to antioxidant properties of nitrocatechols.

[The effect of nooglutil and piracetam on different forms of operant learning]. / Vliianie noogliutila i piratsetama na raznye formy operantnogo obucheniia.

We studied effects of a new drug with nootropic action nooglutil (N-(5-hydroxynicotinoil)-L-glutaminic acid, OHK-10) on initial stages of different forms of operant behaviour in rats, namely avoidance learning in Shuttle box, in Skinner box and on T-maze reflex with water reward. Comparing dates resulted from these three methods permitted evaluation of effects of the drugs on learning. Both drugs had no effects on avoidance response in shuttle box and T-maze reflex with water reward. Nooglutil enhanced escape and avoidance responses meanwhile piracetam improved only escape response.

[The nooglutil correction of functional disorders of the central nervous system caused by prenatal alcoholization in rats]. / Korrektsiia noogliutilom narushenii funktsii tsentral'noi nervnoi sistemy, vyzvannykh prenatal'noi alkogolizatsiei u krys.

Administration of ethanol (5 g/kg/day, per os) to the pregnant rats evoked delayed impairments of the learning and memory in the offspring. Prenatal alcoholization of the animals attenuated the habituation of the exploration behavior in open field, impaired acquisition and retention of active avoidance in a shuttle box, increased slow activity of the EEG spectrum power, disturbed the function of the serotoninergic system in the brain cortex and of the dopaminergic system in the hippocamp. The new nootropic drug nooglutyl (N-5/hydroxynicotinoyl/-L-glutamic acid) administered in a dose of 25 mg/kg/day from the 8th to the 20th day of life prevented the above-mentioned delayed disturbances of higher integrative functions and biochemical processes in rat brain.

[A new substance with nootropic activity--N-5(hydroxynicotinoyl)-L-glutamic acid]. / Novoe veshchestvo s nootropnoi aktivnost'iu--N-5(okinikotinoil)-L-glutaminovaia kislota.

The psychopharmacological activity of a new compound--ONK-10--N-5(hydroxynicotinoyl)-L-glutamic acid was studied. It was shown in experiments on mice and rats that the compound possesses the pronounced antiamnestic and antihypoxic effects, does not disturb the conditioned reflex activity and the orientation behavior, has no anxiolytic activity and anticonvulsant properties, causes no disorder of movement coordination, is low toxic. ONK-10 is superior by its antiamnestic and antihypoxic effects to piracetam, meclophenoxat, demanol aceglumate and is not inferior to aniracetam.

[The psychotropic properties of bonnecor and ethacizine]. / Issledovanie psikhotropnykh svoistv bonnekora i étatsizina.

The comparative study of the psychotropic activity of new acyl derivatives of dibenzazepine and phenothiazine--bonnecor (chlorhydrate 3-carbethoxyamino-5(dimethylaminoacetyl) dibenzazepine and ethacizine (chlorhydrate 2-carbethoxyamino-10-(beta-diethyl-aminopropionyl)phenothiazine)--in the experiments on small laboratory animals showed the presence of the antidepressive, anxiolytic, antiamnesic and antihypoxic effects. The drugs exerted the psychotropic effects at administration in the doses exceeding those which influence the cardiovascular system. By the degree of the anxiolytic action bonnecor and ethacizine are inferior to diazepam, are as potent as trioxasine and are superior to meprobamat. The noted psychotropic action by its character and degree can serve as a beneficial supplement to the spectrum of the pharmacological activity of the studied compounds.

[Dissociation of the anti-amnesic and antihypoxic effects of nootropic and antihypoxic preparations]. / Dissotsiatsiia antiamnesticheskogo i protivogipoksicheskogo éffektov u nootropnykh i protivogipoksicheskikh preparatov.

In experimental studies on mice it was shown that piracetam, Cleregil, centrophenoxine, pyritinol possessed the most pronounced anti-amnestic activity. A close effect was noted with Euclidan, 3-hydroxypyridine and ionol. GABAergic agents (sodium oxybutyrate, phenibut, pantogam), gutimine, nicotinoyl-GABA eliminated amnesia to a lesser extent. The antihypoxic effect on the model of hypobaric hypoxia was exerted by typical antihypoxic agents (gutimine, sodium oxybutyrate, 3-hydroxypyridine). The antihypoxic activity of nootropic drugs (centrophenoxine, pyritinol, phenibut) could be determined only at a significant increase of doses. No interrelationship and the presence of dissociation in manifestation of anti-amnestic and antihypoxic effects were revealed.