We present measurements of J/ψ yields in d+Au collisions at sqrt[s_{NN}]=200  GeV recorded by the PHENIX experiment and compare them with yields in p+p collisions at the same energy per nucleon-nucleon collision. The measurements cover a large kinematic range in J/ψ rapidity (-2.2<y<2.4) with high statistical precision and are compared with two theoretical models: one with nuclear shadowing combined with final state breakup and one with coherent gluon saturation effects. In order to remove model dependent systematic uncertainties we also compare the data to a simple geometric model. The forward rapidity data are inconsistent with nuclear modifications that are linear or exponential in the density weighted longitudinal thickness, such as those from the final state breakup of the bound state.

This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.

Early prediction of human pharmacokinetics (PK) and drug-drug interactions (DDI) in drug discovery and development allows for more informed decision making. Physiologically based pharmacokinetic (PBPK) modelling can be used to answer a number of questions throughout the process of drug discovery and development and is thus becoming a very popular tool. PBPK models provide the opportunity to integrate key input parameters from different sources to not only estimate PK parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. Using examples from the literature and our own company, we have shown how PBPK techniques can be utilized through the stages of drug discovery and development to increase efficiency, reduce the need for animal studies, replace clinical trials and to increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however, some limitations need to be addressed to realize its application and utility more broadly.

The production of e;{+}e;{-} pairs for m_{e;{+}e;{-}}<0.3 GeV/c;{2} and 1<p_{T}<5 GeV/c is measured in p+p and Au+Au collisions at sqrt[s_{NN}]=200 GeV. An enhanced yield above hadronic sources is observed. Treating the excess as photon internal conversions, the invariant yield of direct photons is deduced. In central Au+Au collisions, the excess of the direct photon yield over p+p is exponential in transverse momentum, with an inverse slope T=221+/-19;{stat}+/-19;{syst} MeV. Hydrodynamical models with initial temperatures ranging from T_{init} approximately 300-600 MeV at times of approximately 0.6-0.15 fm/c after the collision are in qualitative agreement with the data. Lattice QCD predicts a phase transition to quark gluon plasma at approximately 170 MeV.

Bose-Einstein correlations of charged kaons are used to probe Au+Au collisions at sqrt[s_{NN}]=200 GeV and are compared to charged pion probes, which have a larger hadronic scattering cross section. Three-dimensional Gaussian source radii are extracted, along with a one-dimensional kaon emission source function. The centrality dependences of the three Gaussian radii are well described by a single linear function of N_{part};{1/3} with a zero intercept. Imaging analysis shows a deviation from a Gaussian tail at r greater, similar10 fm, although the bulk emission at lower radius is well described by a Gaussian. The presence of a non-Gaussian tail in the kaon source reaffirms that the particle emission region in a heavy-ion collision is extended, and that similar measurements with pions are not solely due to the decay of long-lived resonances.

The momentum distribution of electrons from semileptonic decays of charm and bottom quarks for midrapidity |y|<0.35 in p+p collisions at square root of s=200 GeV is measured by the PHENIX experiment at the Relativistic Heavy Ion Collider over the transverse momentum range 2<pT<7 GeV/c. The ratio of the yield of electrons from bottom to that from charm is presented. The ratio is determined using partial D/D-->e(+/-)K(-/+)X (K unidentified) reconstruction. It is found that the yield of electrons from bottom becomes significant above 4 GeV/c in pT. A fixed-order-plus-next-to-leading-log perturbative quantum chromodynamics calculation agrees with the data within the theoretical and experimental uncertainties. The extracted total bottom production cross section at this energy is sigma(bb)=3.2(-1.1)(+1.2)(stat)(-1.3)(+1.4)(syst)mub.

PURPOSE: Preliminary evidence has suggested a synergistic interaction between pregabalin and sildenafil for the treatment of neuropathic pain. The focus of this study was to determine the influence of sildenafil on the pharmacokinetics (PK) of pregabalin with the objective of informing the design of a quantitative pharmacodynamic (PD) study. METHODS: The pharmacokinetics were determined in rats following 2-hr intravenous infusions of pregabalin at doses of 4 mg/kg/hr and 10 mg/kg/hr with and without a sildenafil bolus (2.2 mg) and steady state infusion (12 mg/kg/hr for 6 h). This PK model was utilized in a preclinical trial simulation with the aim of selecting the optimal sampling strategy to characterize the PK-PD profile in a future study. Eight logistically feasible PK sampling strategies were simulated in NONMEM and examined through trial simulation techniques. RESULTS: A two-compartment population PK model best described pregabalin pharmacokinetics. Significant model covariates included either a binary effect of sildenafil administration (30.2% decrease in clearance) or a concentration-dependent effect due to sildenafil's active metabolite. CONCLUSIONS: Analysis of simulations indicated that three post-PD samples had the best cost/benefit ratio by providing a significant increase in the precision (and minor improvement in bias) of both PK and PD parameters compared with no PK sampling.

The double helicity asymmetry in neutral pion production for p_{T}=1 to 12 GeV/c was measured with the PHENIX experiment to access the gluon-spin contribution, DeltaG, to the proton spin. Measured asymmetries are consistent with zero, and at a theory scale of mu;{2}=4 GeV2 a next to leading order QCD analysis gives DeltaG;{[0.02,0.3]}=0.2, with a constraint of -0.7<DeltaG;{[0.02,0.3]}<0.5 at Deltachi;{2}=9 ( approximately 3sigma) for the sampled gluon momentum fraction (x) range, 0.02 to 0.3. The results are obtained using predictions for the measured asymmetries generated from four representative fits to polarized deep inelastic scattering data. We also consider the dependence of the DeltaG constraint on the choice of the theoretical scale, a dominant uncertainty in these predictions.

For Au+Au collisions at 200 GeV, we measure neutral pion production with good statistics for transverse momentum, p_{T}, up to 20 GeV/c. A fivefold suppression is found, which is essentially constant for 5<p_{T}<20 GeV/c. Experimental uncertainties are small enough to constrain any model-dependent parametrization for the transport coefficient of the medium, e.g., q[over ;] in the parton quenching model. The spectral shape is similar for all collision classes, and the suppression does not saturate in Au+Au collisions.

Neutral pion transverse momentum (p_{T}) spectra at midrapidity (|y| less, similar0.35) were measured in Cu+Cu collisions at sqrt[s_{NN}]=22.4, 62.4, and 200 GeV. Relative to pi;{0} yields in p+p collisions scaled by the number of inelastic nucleon-nucleon collisions (N_{coll}) the pi;{0} yields for p_{T} greater, similar2 GeV/c in central Cu+Cu collisions are suppressed at 62.4 and 200 GeV whereas an enhancement is observed at 22.4 GeV. A comparison with a jet-quenching model suggests that final state parton energy loss dominates in central Cu+Cu collisions at 62.4 and 200 GeV, while the enhancement at 22.4 GeV is consistent with nuclear modifications in the initial state alone.