Brief inductions in episodic past or future thinking: effects on episodic detail and problem-solving.

Episodic specificity inductions, involving brief training in recollecting episodic details, have been shown to improve subsequent performance on tasks involving remembering the past, imagining the future and problem solving. The current study examined if specificity inductions targeting self-referential past or future episodic thinking would have dissociable effects on generating past and future episodic detail and problem solving. Sixty-three participants were randomised to either a past self-referential or future self-referential episodic induction. All participants also completed a control task. Participants randomised to the self-referential future thinking induction generated more episodic details on past and future narrative tasks compared to a control task, whereas participants randomised to a self-referential past thinking induction showed similar performance to the control task. When examining within-group performance of participants randomised to the past or future induction, we found some evidence of dissociable effects of inductions on narrative generation tasks, but not on problem solving outcomes. Our findings suggest that self-referential inductions may be useful for increasing episodic specificity, but that the temporal distance and direction of the induction matters. We discuss our results in the context of the potential clinical utility of this approach for populations vulnerable to autobiographical memory disruption.

GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers.

BACKGROUND: Potassium-channels in the carotid body and the brainstem are important regulators of ventilation. The BKCa-channel contains response elements for CO, O2, and CO2. Its block increases carotid body signalling, phrenic nerve activity, and respiratory drive. GAL-021, a new BKCa-channel blocker, increases minute ventilation in rats and non-human primates. This study assessed the single-dose safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of GAL-021 in healthy volunteers. METHODS: Thirty subjects participated in a nine-period, randomized, double-blinded, placebo-controlled, crossover, ascending dose, first-in-human study with i.v. infusions of 0.1-0.96 mg kg(-1) h(-1) for 1 h and intermediate doses up to 4 h. RESULTS: Adverse event rates were generally similar among dose levels and between placebo- and GAL-021-treated subjects. At higher GAL-021 doses, a mild/moderate burning sensation at the infusion site occurred during the infusion. No clinically significant changes in vital signs or clinical chemistries were noted. Minute ventilation increased (AUE0-1 h ≈ 16%, P<0.05) and end-tidal carbon dioxide ([Formula: see text]) decreased (AUE0-1 h ≈ 6%, P<0.05) during the first hour at 0.96 mg kg(-1) h(-1) with 1/2-maximal [Formula: see text] and [Formula: see text]-change occurring by 7.5 min. Drug concentration rose rapidly during the infusion and decreased rapidly initially (distribution t1/2 of 30 min) and then more slowly (terminal t1/2 of 5.6 h). CONCLUSIONS: GAL-021 was safe and generally well tolerated with adverse events comparable with placebo except for an infusion site burning sensation. GAL-021 stimulated ventilation at the highest doses suggesting that greater infusion rates may be required for maximum PD effects. GAL-021 had PK characteristics consistent with an acute care medication.

Imaging of glioma tumor with endogenous fluorescence tomography.

Tomographic imaging of a glioma tumor with endogenous fluorescence is demonstrated using a noncontact single-photon counting fan-beam acquisition system interfaced with microCT imaging. The fluorescence from protoporphyrin IX (PpIX) was found to be detectable, and allowed imaging of the tumor from within the cranium, even though the tumor presence was not visible in the microCT image. The combination of single-photon counting detection and normalized fluorescence to transmission detection at each channel allowed robust imaging of the signal. This demonstrated use of endogenous fluorescence stimulation from aminolevulinic acid (ALA) and provides the first in vivo demonstration of deep tissue tomographic imaging with protoporphyrin IX.

Subsurface diffuse optical tomography can localize absorber and fluorescent objects but recovered image sensitivity is nonlinear with depth.

Subsurface tomography with diffuse light has been investigated with a noncontact approach to characterize the performance of absorption and fluorescence imaging. Using both simulations and experiments, the reconstruction of local subsurface heterogeneity is demonstrated, but the recovery of target size and fluorophore concentration is not linear when changes in depth occur, whereas the mean position of the object for experimental fluorescent and absorber targets is accurate to within 0.5 and 1.45 mm when located within the first 10 mm below the surface. Improvements in the linearity of the response with depth appear to remain challenging and may ultimately limit the approach to detection rather than characterization applications. However, increases in tissue curvature and/or the addition of prior information are expected to improve the linearity of the response. The potential for this type of imaging technique to serve as a surgical guide is highlighted.

The novel, orally active, delta opioid RWJ-394674 is biotransformed to the potent mu opioid RWJ-413216.

Although the mu opioid receptor is the primary target of marketed opioid analgesics, several studies suggest the advantageous effect of combinations of mu and delta opioids. The novel compound RWJ-394674 [N,N-diethyl-4-[(8-phenethyl-8-azabicyclo]3.2.1]oct-3-ylidene)-phenylmethyl]-benzamide]; bound with high affinity to the delta opioid receptor (0.2 nM) and with weaker affinity to the mu opioid receptor (72 nM). 5'-O-(3-[(35)S]-thio)triphosphate binding assay demonstrated its delta agonist function. Surprisingly given this pharmacologic profile, RWJ-394674 exhibited potent oral antinociception (ED(50) = 10.5 micromol/kg or 5 mg/kg) in the mouse hot-plate (48 degrees C) test and produced a moderate Straub tail. Antagonist studies in the more stringent 55 degrees C hot-plate test demonstrated the antinociception produced by RWJ-394674 to be sensitive to the nonselective opioid antagonist naloxone as well as to the delta- and mu-selective antagonists, naltrindole and beta-funaltrexamine, respectively. In vitro studies demonstrated that RWJ-394674 was metabolized by hepatic microsomes to its N-desethyl analog, RWJ-413216 [N-ethyl-4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-phenylmethyl]-benzamide], which, in contrast to RWJ-394674, had a high affinity for the mu rather than the delta opioid receptor and was an agonist at both. Pharmacokinetic studies in the rat revealed that oral administration of RWJ-394674 rapidly gave rise to detectable plasma levels of RWJ-413216, which reached levels equivalent to those of RWJ-394674 by 1 h. RWJ-413216 itself demonstrated a potent oral antinociceptive effect. Thus, RWJ-394674 is a delta opioid receptor agonist that appears to augment its antinociceptive effect through biotransformation to a novel mu opioid receptor-selective agonist.

Solid-phase Mannich condensation of amines, aldehydes, and alkynes: investigation of diverse aldehyde inputs.

Terminal alkynes, secondary amines, and aldehydes undergo "solid-phase Mannich condensation". A set of diverse aldehyde inputs was examined. Aliphatic, aralkyl, aryl, and heteroaryl carboxaldehydes give good yields of Mannich adduct of high purity. Benzaldehydes containing electron-donating substituents that decrease the electrophilicity of the carbonyl center, or heteroaryl aldehydes that are similarly deactivated by resonance effects, do not undergo reaction.

Aminopyrazoles with high affinity for the human neuropeptide Y5 receptor.

1,3-Disubstituted-5-aminopyrazoles were prepared based on a lead compound found through high-throughput screening of our corporate compound library in an assay measuring affinity for the human neuropeptide Y5 receptor. The target compounds were prepared by cyclization of alpha-cyanoketones with appropriate hydrazines, followed by reduction and coupling to various sulfonamido-carboxylic acids. Several of these arylpyrazoles (e.g., 19 and 45) displayed high affinity for the human NPY Y5 receptor (<20nM IC(50)s).

N-acylated alpha-(3-pyridylmethyl)-beta-aminotetralin antagoinists of the human neuropeptide Y Y5 receptor.

Alpha-(3-Pyridylmethyl)-beta-aminotetralins were acylated with amino-piperidinyl and-pyrrolidinyl acetic acids, and with (aminomethyl)cyclohexanecarboxylic acid. Reaction with acyl chlorides, chloroformates, and isocyanates gave amides 8e, carbamates 9, and ureas 10, which bound to the Y5 receptor with nanomolar affinity. Congeners 11a and 11d containing a terminal benzimidazolone group were shown to be functional Y5 antagonists.

N-(sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines: potent antagonists of human neuropeptide Y Y5 receptor.

[3a,4,5,9b-Tetrahydro-1H-benzo[e]indol-2-yl]amines were prepared via reductive amination and concomitant cyclization of alpha-cyanomethyl-beta-aminotetralins. N-acylation with omega-sulfonamido-carboxylic acids and subsequent reduction afforded a series of N-(sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines, which bound to the human neuropeptide Y Y5 receptor with nanomolar affinity.

Multi-component methodologies in solid-phase organic synthesis.

Solid-phase organic synthesis, particularly when used in conjunction with combinatorial techniques, is emerging as a revolutionary technology in chemistry. Multi-component reaction systems are particularly valued because several elements of diversity can be introduced in a single transformation thereby expanding the diversity of compound libraries. A variety of multi-component reactions have been successfully adapted for solid-phase technology as described in this review.

Biapenem American Cyanamid Co.

Biapenem is an injectable carbapenem antibiotic with activity against a broad spectrum of bacteria [155679]. It has been submitted for marketing approval in Japan by Lederle Japan, a joint venture between Cyanamid and Takeda. Biapenem is in phase III trials in Germany, South Africa, Spain, Australia and New Zealand for skin infections, and phase I trials in the UK and the US.

Nonsymmetrically substituted cyclic urea HIV protease inhibitors.

A series of nonsymmetrically substituted cyclic ureacarboxamides was synthesized and evaluated for antiviral activity as a function of the inhibition of HIV-protease. Selected protease inhibitors were also evaluated for oral bioavailability. The synthesis, pharmacology, quantitative structure-activity relationship (QSAR), and pharmacokinetics for the series will be discussed.

Dual-action penems and carbapenems.

Two new series of dual-action antibacterial agents were synthesized in which penems and carbapenems were linked at the 2'-position to quinolones through either an ester or a carbamate moiety. Potent, broad-spectrum antibacterial activity was observed for both classes of compounds, indicative of a dual-mode of action.