Pharmacology of DB844, an orally active aza analogue of pafuramidine, in a monkey model of second stage human African trypanosomiasis

Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead compound, N-methoxy-6-{5-[4-(N-methoxyamidino) phenyl]-furan-2-yl}-nicotinamidine (DB844), was evaluated in a vervet monkey model of second stage HAT, following promising results in mice. DB844 was administered orally to vervet monkeys, beginning 28 days post infection (DPI) with Trypanosoma brucei rhodesiense KETRI 2537. DB844 was absorbed and converted to the active metabolite 6-[5-(4-phenylamidinophenyl)-furanyl-2-yl]-nicotinamide (DB820), exhibiting plasma C(max) values of 430 and 190 nM for DB844 and DB820, respectively, after the 14th dose at 6 mg/kg qd. A 100-fold reduction in blood trypanosome counts was observed within 24 h of the third dose and, at the end of treatment evaluation performed four days post the last drug dose, trypanosomes were not detected in the blood or cerebrospinal fluid of any monkey. However, some animals relapsed during the 300 days of post treatment monitoring, resulting in a cure rate of 3/8 (37.5%) and 3/7 (42.9%) for the 5 mg/kg×10 days and the 6 mg/kg×14 days dose regimens respectively. These DB844 efficacy data were an improvement compared with pentamidine and pafuramidine both of which were previously shown to be non-curative in this model of CNS stage HAT. These data show that synthesis of novel diamidines with improved activity against CNS-stage HAT was possible

Acute inhibition of MEK suppresses congenital melanocytic nevus syndrome in a murine model driven by activated NRAS and Wnt signaling

Congenital melanocytic nevus (CMN) syndrome is the association of pigmented melanocytic nevi with extra-cutaneous features, classically melanotic cells within the central nervous system, most frequently caused by a mutation of NRAS codon 61. This condition is currently untreatable and carries a significant risk of melanoma within the skin, brain, or leptomeninges. We have previously proposed a key role for Wnt signaling in the formation of melanocytic nevi, suggesting that activated Wnt signaling may be synergistic with activated NRAS in the pathogenesis of CMN syndrome. Some familial pre-disposition suggests a germ-line contribution to CMN syndrome, as does variability of neurological phenotypes in individuals with similar cutaneous phenotypes. Accordingly, we performed exome sequencing of germ-line DNA from patients with CMN to reveal rare or undescribed Wnt-signaling alterations. A murine model harboring activated NRASQ61K and Wnt signaling in melanocytes exhibited striking features of CMN syndrome, in particular neurological involvement. In the first model of treatment for this condition, these congenital, and previously assumed permanent, features were profoundly suppressed by acute post-natal treatment with a MEK inhibitor. These data suggest that activated NRAS and aberrant Wnt signaling conspire to drive CMN syndrome. Post-natal MEK inhibition is a potential candidate therapy for patients with this debilitating condition

Preliminary performance measurements of bolometers for the Planck high-frequency instrument

We report on the characterization of bolometers fabricated at the Jet Propulsion Laboratory for the High Frequency Instrument (HFI) of the joint ESA/NASA Herschel/Planck mission to be launched in 2007. The HFI is a multicolor focal plane which consists of 48 bolometers operated at 100mK. Each bolometer is mounted to a feedhorn-filter assembly which defines one of six frequency bands centered between 100-857GHz. Four detectors in each of six bands are coupled to both linear polarizations and thus measure the total intensity. In addition, eight detectors in each of 3 bands (143, 217, and 353GHz) couple only to a single linear polarization and thus provide measurements of the Stokes parameters, Q and U, as well the total intensity. The detectors are required to achieve a Noise Equivalent Power (NEP) at or below the background limit ∼ 10^(-17)W/√Hz for the telescope and time constants of a few ms, short enough to resolve point sources as the 5 to 9 arc-minute beams move across the sky in great circles at 1 rpm. The bolometers are tested at 100mK in a commercial dilution refrigerator with a custom built thermal control system to regulate the heat sink with precision < 100nK/√Hz. The 100mK tests include dark electrical characterization of the load curves, optical and electrical measurement of the thermal time constants and measurement of the noise spectral density from 0.01 to 10Hz for up to 24 bolometers simultaneously

High-spin and low-spin iron(II) complexes with facially-coordinated borohydride ligands

Rare examples of monometallic high-spin and low-spin L_3Fe(H_3BH) complexes have been characterized, where the two L_3 ligands are [Tp^(Ph2)] and [PhBP3] ([Tp^(Ph2)] = [HB(3,5-Ph_2pz)_3]− and [PhBP_3] = [PhB(CH_2PPh_2)_3]−). The structures are reported wherein the borohydride ligand is facially coordinated to the iron center in each complex. Density functional methods have been employed to explain the bonding in these unusual iron(II) centers. Despite the differences in spin states, short Fe–B distances are observed in both complexes and there is significant theoretical evidence to support a substantial bonding interaction between the iron and boron nuclei. In light of this interaction, we suggest that these complexes can be described as (L_3)Fe(η^4-H_3BH) complexes

Ethical and compliance-competence evaluation: a key element of sound corporate governance

Motivated by the ongoing post-Enron refocusing on corporate governance and the shift by the Financial Services Authority (FSA) in the UK to promoting compliance- competence within the financial services sector, this paper demonstrates how template analysis can be used as a tool for evaluating compliance-competence. Focusing on the ethical dimension of compliance-competence, we illustrate how this can be subjectively appraised. We propose that this evaluation technique could be utilised as a starting point in informing senior management of corporate governance issues and be used to monitor and demonstrate key compliance and ethical aspects of an institution to external stakeholders and regulators

Medial prefrontal cortex lesions impair decision-making on a rodent gambling task: Reversal by D1 receptor antagonist administration

Decision-making is a complex cognitive process that is impaired in a number of psychiatric disorders. In the laboratory, decision-making is frequently assessed using “gambling” tasks that are designed to simulate real-life decisions in terms of uncertainty, reward and punishment. Here, we investigate whether lesions of the medial prefrontal cortex (PFC) cause impairments in decision-making using a rodent gambling task (rGT). In this task, rats have to decide between 1 of 4 possible options: 2 options are considered “advantageous” and lead to greater net rewards (food pellets) than the other 2 “disadvantageous” options. Once rats attained stable levels of performance on the rGT they underwent sham or excitoxic lesions of the medial PFC and were allowed to recover for 1 week. Following recovery, rats were retrained for 5 days and then the effects of a dopamine D1-like receptor antagonist (SCH23390) or a D2-like receptor antagonist (haloperidol) on performance were assessed. Lesioned rats exhibited impaired decision-making: they made fewer advantageous choices and chose the most optimal choice less frequently than did sham-operated rats. Administration of SCH23390 (0.03 mg/kg), but not haloperidol (0.015–0.03 mg/kg) attenuated the lesion-induced decision-making deficit. These results indicate that the medial PFC is important for decision-making and that excessive signaling at D1 receptors may contribute to decision-making impairments

Population Uncertainty in Model Ecosystem: Analysis by Stochastic Differential Equation

Perturbation experiments are carried out by contact process and its mean-field version. Here, the mortality rate is increased or decreased suddenly. It is known that the fluctuation enhancement (FE) occurs after the perturbation, where FE means a population uncertainty. In the present paper, we develop a new theory of stochastic differential equation. The agreement between the theory and the mean-field simulation is almost perfect. This theory enables us to find much stronger FE than reported previously. We discuss the population uncertainty in the recovering process of endangered species.Comment: 16 pages, 4 figure, submitted to J. Phys. Soc. Jp

Keck Interferometer Nuller Data Reduction and On-Sky Performance

We describe the Keck Interferometer nuller theory of operation, data reduction, and on-sky performance, particularly as it applies to the nuller exozodiacal dust key science program that was carried out between 2008 February and 2009 January. We review the nuller implementation, including the detailed phasor processing involved in implementing the null-peak mode used for science data and the sequencing used for science observing. We then describe the Level 1 reduction to convert the instrument telemetry streams to raw null leakages, and the Level 2 reduction to provide calibrated null leakages. The Level 1 reduction uses conservative, primarily linear processing, implemented consistently for science and calibrator stars. The Level 2 processing is more flexible, and uses diameters for the calibrator stars measured contemporaneously with the interferometer’s K-band cophasing system in order to provide the requisite accuracy. Using the key science data set of 462 total scans, we assess the instrument performance for sensitivity and systematic error. At 2.0 Jy we achieve a photometrically-limited null leakage uncertainty of 0.25% rms per 10 minutes of integration time in our broadband channel. From analysis of the Level 2 reductions, we estimate a systematic noise floor for bright stars of ~0.2% rms null leakage uncertainty per observing cluster in the broadband channel. A similar analysis is performed for the narrowband channels. We also provide additional information needed for science reduction, including details on the instrument beam pattern and the basic astrophysical response of the system, and references to the data reduction and modeling tools

Altered morphine glucuronide and bile acid disposition in patients with nonalcoholic steatohepatitis

The functional impact of altered drug transport protein expression on the systemic pharmacokinetics of morphine, hepatically-derived morphine glucuronide (morphine-3- and morphine-6-glucuronide), and fasting bile acids was evaluated in patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH) compared to healthy subjects. The maximum concentration (Cmax) and area under the concentration-time curve (AUC0-last) of morphine glucuronide in serum were increased in NASH patients (343 vs. 225nM and 58.8 vs. 37.2μM*min, respectively; P≤0.005); morphine pharmacokinetics did not differ between groups. Linear regression analyses detected an association of NASH severity with increased morphine glucuronide Cmax and AUC0-last (P<0.001). Fasting serum glycocholate, taurocholate and total bile acid concentrations were associated with NASH severity (P<0.006). Increased hepatic basolateral efflux of morphine glucuronide and bile acids is consistent with altered hepatic transport protein expression in patients with NASH and may partially explain differences in efficacy and/or toxicity of some highly transported anionic drugs/metabolites in this patient population

Pharmacology of DB844, an Orally Active aza Analogue of Pafuramidine, in a Monkey Model of Second Stage Human African Trypanosomiasis

Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead compound, N-methoxy-6-{5-[4-(N-methoxyamidino) phenyl]-furan-2-yl}-nicotinamidine (DB844), was evaluated in a vervet monkey model of second stage HAT, following promising results in mice. DB844 was administered orally to vervet monkeys, beginning 28 days post infection (DPI) with Trypanosoma brucei rhodesiense KETRI 2537. DB844 was absorbed and converted to the active metabolite 6-[5-(4-phenylamidinophenyl)-furanyl-2-y​l]-nicotinamide(DB820), exhibiting plasma Cmax values of 430 and 190 nM for DB844 and DB820, respectively, after the 14th dose at 6 mg/kg qd. A 100-fold reduction in blood trypanosome counts was observed within 24 h of the third dose and, at the end of treatment evaluation performed four days post the last drug dose, trypanosomes were not detected in the blood or cerebrospinal fluid of any monkey. However, some animals relapsed during the 300 days of post treatment monitoring, resulting in a cure rate of 3/8 (37.5%) and 3/7 (42.9%) for the 5 mg/kg×10 days and the 6 mg/kg×14 days dose regimens respectively. These DB844 efficacy data were an improvement compared with pentamidine and pafuramidine both of which were previously shown to be non-curative in this model of CNS stage HAT. These data show that synthesis of novel diamidines with improved activity against CNS-stage HAT was possible.This investigation received financial support from the Bill and Melinda Gates Foundation through the Consortium for Parasitic Drug Development