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Knockout mice lacking the adenosine A(2A) receptor are less sensitive to nociceptive stimuli, and this may be due to the presence of pronociceptive A(2A) receptors on sensory nerves. In support of this hypothesis, we have recently shown that in A(2A) receptor knockout mice there are marked reductions in the changes of two markers of spinal cord neuronal activity, [(3)H]MK801 binding to NMDA receptors and uptake of [(14)C]-2-deoxyglucose, in response to formalin injection. We now report that following a more prolonged inflammatory stimulus, consisting of intraplantar injections of PGE(2) and paw pressure, there was in contrast an increase in [(3)H]MK801 binding and [(14)C]-2-deoxyglucose uptake in the spinal cords of the A(2A) receptor knockout mice which was much greater than in the wild-type mice. This increase suggests that when there is a pronounced inflammatory component to the stimulus, loss of inhibitory A(2A) receptors on inflammatory cells outweighs the loss of pronociceptive A(2A) receptors on peripheral nerves so that overall there is an increase in nociceptive signalling. This implies that although A(2A) antagonists have antinociceptive effects they may have only limited use as analgesics in chronic inflammatory pain., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To assess five different methods of signal-to-noise ratio (SNR) measurement for partially parallel imaging (PPI) acquisitions., Methods: Measurements were performed on a spherical phantom and three volunteers using a multichannel head coil a clinical 3T MRI system to produce echo planar, fast spin echo, gradient echo, and balanced steady state free precession image acquisitions. Two different PPI acquisitions, generalized autocalibrating partially parallel acquisition algorithm and modified sensitivity encoding with acceleration factors (R) of 2-4, were evaluated and compared to nonaccelerated acquisitions. Five standard SNR measurement techniques were investigated and Bland-Altman analysis was used to determine agreement between the various SNR methods. The estimated g-factor values, associated with each method of SNR calculation and PPI reconstruction method, were also subjected to assessments that considered the effects on SNR due to reconstruction method, phase encoding direction, and R-value., Results: Only two SNR measurement methods produced g-factors in agreement with theoretical expectations (g ≥ 1). Bland-Altman tests demonstrated that these two methods also gave the most similar results relative to the other three measurements. R-value was the only factor of the three we considered that showed significant influence on SNR changes., Conclusions: Non-signal methods used in SNR evaluation do not produce results consistent with expectations in the investigated PPI protocols. Two of the methods studied provided the most accurate and useful results. Of these two methods, it is recommended, when evaluating PPI protocols, the image subtraction method be used for SNR calculations due to its relative accuracy and ease of implementation.

Context: Acetaminophen (paracetamol, APAP) is widely used to relieve mild-to-moderate pain and reduce fever. Absorption of the drug can be impacted by dosage form; this may have implications for pain relief in some individuals, potentially accounting for suboptimal efficacy in analgesia., Objective: To assess the disintegration and dissolution of a new fast-dissolving acetaminophen tablet formulation (FD-APAP) and the impact on pharmacokinetic and pharmacodynamic parameters., Materials and Methods: Two randomized, single-center, open-label, single-dose, two-way crossover studies in healthy subjects to compare FD-APAP (2 × 500 mg tablets) with standard acetaminophen (2 × 500 mg tablets). Gamma scintigraphy was used to assess tablet disintegration (Study 1, N = 24), and plasma profiles were evaluated in the fasted state (Study 2, N = 40)., Results: In Study 1, the mean time to complete disintegration (12.9 vs. 69.6 min, P < 0.0001) and onset of disintegration were both significantly faster with FD-APAP than with standard acetaminophen (P < 0.0001). For Study 2, median T(max) was significantly faster for FD-APAP (0.50 vs. 0.67 h, P < 0.01) and AUC(0-30 min) was significantly greater (4.51 vs. 2.74, P < 0.05). AUC(0-t) and AUC(0-inf) were comparable between the two study treatments., Discussion: Despite the absence of comparative clinical data, the FD-APAP formulation may be expected to overcome some of the issues associated with the slow and variable absorption of standard acetaminophen tablet formulations, improving therapeutic outcome and avoiding the need to switch to alternative therapeutic options., Conclusion: Compared with standard acetaminophen, the FD-APAP formulation results in significantly faster onset of disintegration and more rapid absorption.

The aims of this study were to determine whether standard extracellular contrast agents of Gd(III) ions in combination with a polymeric entity susceptible to hydrolytic degradation over a finite period of time, such as Hyaluronic Acid (HA), have sufficient vascular residence time to obtain comparable vascular imaging to current conventional compounds and to obtain sufficient data to show proof of concept that HA with Gd-DTPA ligands could be useful as vascular imaging agents. We assessed the dynamic relaxivity of the HA bound DTPA compounds using a custom-made phantom, as well as relaxation rates at 10.72 MHz with concentrations ranging between 0.09 and 7.96 mM in phosphate-buffered saline. Linear dependences of static longitudinal relaxation rate (R1) on concentration were found for most measured samples, and the HA samples continued to produce high signal strength after 24 hours after injection into a dialysis cassette at 3T, showing superior dynamic relaxivity values compared to conventional contrast media such as Gd-DTPA-BMA.

Mice lacking the adenosine A(2A) receptor are less sensitive to nociceptive stimuli, and A(2A) receptor antagonists have antinociceptive effects. We have previously shown a marked reduction in the behavioural responses to formalin injection in A(2A) receptor knockout mice. This may be due to the presence of pronociceptive A(2A) receptors on sensory nerves, and if so spinal cords from A(2A) receptor knockout mice may have altered neurochemical responses to a nociceptive stimulus. We tested this hypothesis by studying two parameters known to change with spinal cord activity, NMDA glutamate receptor binding and [(14)C]-2-deoxyglucose uptake, following intraplantar formalin injection in wild-type and A(2A) receptor knockout mice. In naïve untreated A(2A) knockout mice [(14)C]-2-deoxyglucose uptake in all regions of the spinal cord was significantly lower compared to the wild-type, similar to the reduced NMDA receptor binding that we have previously observed. Following formalin treatment, there was an decrease in [(3)H]-MK801 binding to NMDA receptors and an increase in [(14)C]-2-deoxyglucose uptake in the spinal cords of wild-type mice, and these changes were significantly reduced in the A(2A) knockout mice. In addition to altered behavioural responses, there are therefore corresponding reductions in spinal cord neurochemical changes induced by formalin in mice lacking adenosine A(2A) receptors. These observations support the hypothesis that activation of A(2A) receptors enhances nociceptive input into the spinal cord and suggests a possible role for A(2A) antagonists as analgesics., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

The ability of 20-50 nm nanoparticles to target and modulate the biology of specific types of cells will enable major advancements in cellular imaging and therapy in cancer and atherosclerosis. A key challenge is to load an extremely high degree of targeting, imaging, and therapeutic functionality into small, yet stable particles. Herein we report approximately 30 nm stable uniformly sized near-infrared (NIR) active, superparamagnetic nanoclusters formed by kinetically controlled self-assembly of gold-coated iron oxide nanoparticles. The controlled assembly of nanocomposite particles into clusters with small primary particle spacings produces collective responses of the electrons that shift the absorbance into the NIR region. The nanoclusters of approximately 70 iron oxide primary particles with thin gold coatings display intense NIR (700-850 nm) absorbance with a cross section of approximately 10(-14) m(2). Because of the thin gold shells with an average thickness of only 2 nm, the r(2) spin-spin magnetic relaxivity is 219 mM(-1) s(-1), an order of magnitude larger than observed for typical iron oxide particles with thicker gold shells. Despite only 12% by weight polymeric stabilizer, the particle size and NIR absorbance change very little in deionized water over 8 months. High uptake of the nanoclusters by macrophages is facilitated by the dextran coating, producing intense NIR contrast in dark field and hyperspectral microscopy, both in cell culture and an in vivo rabbit model of atherosclerosis. Small nanoclusters with optical, magnetic, and therapeutic functionality, designed by assembly of nanoparticle building blocks, offer broad opportunities for targeted cellular imaging, therapy, and combined imaging and therapy.

Adenosine is a neuromodulator with complex effects on pain pathways. Mice lacking the adenosine A2A receptor are hypoalgesic, and have altered analgesic responses to receptor-selective opioid agonists. These and other findings suggest a role for the adenosine A2A receptor in sensitizing afferent fibres projecting to the spinal cord. To test this hypothesis formalin (20 microl, 5%) was injected into the paw and nociceptive responses were measured in wildtype and adenosine A2A receptor knockout mice. There was a significant reduction in nociception associated with sensory nerve activation in the knockout mice as measured by time spent biting/licking the formalin-injected paw and number of flinches seen during the first phase, but only the number of flinches was reduced during the second inflammatory phase. In addition, the selective adenosine A2A antagonist SCH58261 (3 and 10 mg/kg) also antagonised both phases of the formalin test. We also labelled NMDA glutamate and NK1 receptors in spinal cord sections as an indirect measure of nociceptive transmission from peripheral sites to the spinal cord. [3H]-Substance P binding to NK1 receptors was unaltered but there was a substantial reduction in binding of [3H]-MK801 to NMDA glutamate receptors in all regions of the spinal cord from knockout mice. The decrease in NMDA glutamate receptor binding may reflect reduced peripheral sensory input to the spinal cord during development and could relate to the hypoalgesia in this genotype. These results support a key role for the adenosine A2A receptor in peripheral nociceptive pathways.

Objective: Magnetic resonance imaging (MRI) at 3 T is significantly different than 1.5 T and needs to be optimized due to increased signal-to-noise ratio (SNR) and specific absorption ratio (SAR). This study tests the hypothesis that first-pass myocardial perfusion MRI using saturation recovery (SR)-TrueFISP with parallel imaging is superior to SR-TurboFLASH and a more achievable technique for clinical application at 3 T., Materials and Methods: Myocardial perfusion imaging was performed on 12 subjects using SR-TurboFLASH and SR-TrueFISP sequences combined with parallel imaging. Four myocardial slices were acquired and evaluated by image segmentation. Quality of the measurements was determined from SNR, contrast-to-noise ratio (CNR), enhancement-to-noise ratio (ENR), and myocardial perfusion upslope. Data were analyzed using a 2-way ANOVA with imaging method and segment number as the independent variables., Results: SNR, CNR, ENR, and upslope were significantly higher for SR-TrueFISP versus SR-TurboFLASH (P < 0.001). Significant differences in SNR, CNR, ENR, and upslope were found among the myocardial segments (P < 0.005)., Conclusions: Optimized SR-TrueFISP first-pass myocardial perfusion MRI at 3 T has superior image quality compared with SR-TurboFLASH, independent of the myocardial segment analyzed. However, coil sensitivity nonuniformities and dielectric resonance effects cause signal intensity differences between myocardial segments that must be accounted for when interpreting 3 T perfusion studies.

Paracetamol is an effective analgesic but its mechanism of action is unclear. We investigated the effect of paracetamol and the analgesic adjuvant caffeine on the activity of NO synthase in mouse spinal cord and cerebellar slices in vitro, by measuring the conversion of [(3)H]arginine to [(3)H]citrulline. Paracetamol (100 microM) had no effect on NO synthase activity in cerebellum, but in the spinal cord both paracetamol (100 microM) and caffeine (30 microM) attenuated glutamate (5 mM)-induced [(3)H]citrulline production and in combination they abolished it. In conclusion paracetamol inhibits spinal cord NO synthesis and this may be related to its analgesic effects.

Poor main magnetic field (B0) homogeneity (H(B)) leads to artifacts and signal losses in magnetic resonance imaging (MRI). The American College of Radiology's MRI quality control manual mandates annual checks of H(B), suggesting tests using spectral linewidth and phase-difference (delta phi) maps. A new method, the bandwidth-difference (deltaBW) method, which compares the distortion for small and large BW acquisitions to determine the HB, is proposed. The deltaBW method has the advantage that it can be used to measure multiple diameters of spherical volumes (DSV) in a single phantom. A phantom has been developed to exploit this method and results obtained with it are compared to those using three standard methods. Small receiver BW in the presence of poor H(B) leads to geometric distortions because gradients are reduced to the level of the B0 inhomogeneities. Data were acquired using seven MRI systems from different manufacturers, ranging in field strength from 0.2 to 3.0 T. Fast gradient echo pulse sequences were scanned twice using small and large BWs. H(B) was measured from the shift of landmarks between the two BW acquisitions. Results were compared with data from the full width at half maximum (FWHM) method, the delta phi method and one manufacturer's resonant frequency mapping data. The FWHM method was available on two systems and the detla phi method was available on one. The deltaBW method could be performed in all scanners investigated. The H(B) measured ranged 0.11-0.32 ppm to 6.7-12.9 ppm for DSV of 13-22.6 cm. Direct comparisons of the data obtained using the deltaBW method showed good agreement with data obtained using the FWHM method. Data obtained using the deltaBW method compared favorably with the manufacturer's resonant frequency map. The deltaBW method produces measurements of H(B) at various DSV values that can be obtained from a single set of phantom images. The accuracy of deltaBW B0 homogeneity measurements are comparable to the other methods tested.

Magnetic resonance first-pass perfusion imaging offers a noninvasive method for the rapid, accurate, and reproducible assessment of cardiac function without ionizing radiation. Quantitative or semiquantitative analysis of changes in signal intensity (SI) over the whole image sequence yields a more efficient analysis than direct visual inspection. In this paper, a method to generate maximum up-slope myocardial perfusion maps is presented. The maximum up-slope is defined by comparison of the SI variations using frame-to-frame analysis. A map of first-pass transit of the contrast agent is constructed pixel by pixel using a linear curve fitting model. The proposed method was evaluated using data from eight subjects. The data from the parametric maps agreed well with those obtained from traditional, manually derived region-of-interest methods as shown through ANOVA. The straightforward implementation and increase in image analysis efficiency resulting from this method suggests that it may be useful for clinical practice.

This study investigated the involvement of adenosine receptors in the interaction between paracetamol and caffeine in mice, using the adenosine A2A receptor antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261) and the adenosine A2B receptor antagonist 1-propyl-8-p-sulfophenylxanthine (PSB1115), in the tail immersion and hot-plate tests. Paracetamol (10-200 mg/kg) was antinociceptive in both tests, but, in contrast to previous studies, caffeine (10 mg/kg) was pronociceptive in the tail immersion test, and reduced the effects of paracetamol in both tests. SCH58261 (3 mg/kg) was antinociceptive in both tests and in its presence paracetamol (50 mg/kg) had no further effect. PSB1115 (10 mg/kg) had little effect alone but potentiated the effect of paracetamol (50 mg/kg) in the hot-plate test and abolished it in the tail immersion test. These results suggest that adenosine A2B receptors may be involved in the action of paracetamol in a pathway-dependent manner, and also support the existence of pronociceptive adenosine A2A receptors.

Background and Objectives: The PAIN (Paracetamol, Aspirin and Ibuprofen New tolerability) study published in 1999 assessed the tolerability of over-the- counter (OTC) analgesics in a French general practitioner (GP)-controlled population and found no apparent difference between the tolerability of ibuprofen and paracetamol (acetaminophen). However, patient selection in that study could cast doubt over the relevance of the results to a more generalised OTC population. The aim of our survey was to prospectively determine what proportion of a French GP-controlled population is able to take ibuprofen and paracetamol in order to allow appropriate interpretation of the PAIN study., Methods: This was a prospective survey to identify all contraindications/warnings on product labelling for ibuprofen and paracetamol in 5000 patients aged 18-75 years. 100 French GPs each collected anonymised data on 50 patients over a 1-week period using a standardised form. GPs were stratified by geographical location and size of practice. Demographic data for patients were summarised. Contraindications/warnings for ibuprofen and paracetamol were summarised overall and by individual criterion., Results: The mean age of patients was 45.8 (+/- 16.5) years; 42% were males and 58% females. Of these patients, 49.9% would have been ineligible for the PAIN study because of at least one contraindication/warning for ibuprofen, whereas only 6.8% would have been ineligible because of at least one contraindication/warning for paracetamol. More specifically, contraindications to use of ibuprofen was noted in 12.3% of patients and 37.6% of patients should have consulted a doctor before use of this drug. In contrast, contraindications to use of paracetamol were noted in only 0.7% of patients and only 6.1% should have consulted a doctor before use of this drug., Conclusions: Our survey demonstrates how careful patient selection can limit the generalisability of a study. The PAIN study excluded individuals 'at-risk' from ibuprofen and the tolerability results of this study should therefore be interpreted with extreme caution because the patient population may not be representative of unsupervised OTC analgesic users.

Phase-contrast magnetic resonance imaging (PC-MRI) is useful for assessing coronary artery flow reserves (CFR) in man and acute animal models with intermediate coronary lesions. The present study examines the use of PC-MRI for assessing CFR in a model with critical stenosis and collateral dependence. PC-MRI quantitative flow measurements from the proximal left anterior descending (LAD) and left circumflex (LCX) coronary arteries were compared with myocardial tissue perfusion reserve measurements (microsphere techniques) after placement of a 2.25-mm ameroid constrictor on the proximal LCX in a porcine model; measurements were obtained at implantation (n = 4) and at 3 to 4 weeks (n = 4) and 6 weeks (n = 5) postimplantation. CFR is defined as the ratio of maximal hyperemic flow to baseline flow. Hyperemia was induced using intravenous adenosine (140 mg/kg/min). Collateral dependence in the LCX distri bution was evidenced by angiographic findings of critical stenosis with minimal myocardial histological changes and normal baseline myocardial perfusion (microsphere techniques). In this setting, PC-MRI CFR was correlated with microsphere measures of perfusion reserve. Collateral dependence was confirmed by Evan's blue dye injection. This study provides angiographic, myocardial perfusion, and histological correlates associated with PC-MRI epicardial CFR changes during chronic, progressive coronary artery constriction. It also demonstrates the disparity between epicardial and myocardial measures of coronary flow reserve with collateral dependence and the caveats for PC-MRI use in models of progressive coronary constriction.

The proton signal changes as the long axis of tendon tissue is rotated with respect to the main magnetic field (B(0)). The orientational changes in the tendon signal obtained using the correlation spectroscopy revamped by asymmetric z-gradient echo detection (CRAZED) sequence, which allows the effects of intermolecular dipolar interactions to be observed, were investigated and compared with the orientational changes of the signals produced using correlation spectroscopy (COSY), spin-echo (SE), and one-pulse sequences. The intermolecular double quantum coherence (iDQC) signal obtained using the CRAZED sequence showed a variation in the signal from tendon tissue, with sharper peaks and greater relative differences between minimum and maximum signal values compared to the variations in the signal obtained from the COSY, SE, and one-pulse sequences. This result is attributed to the orientational dependence of the transverse relaxation rate of single (SQC) and double (DQH) quantum coherences R(2) and R(2,2), respectively., (Copyright 2005 Wiley-Liss, Inc.)

Quantitative autoradiography has been used to assess whether [3H]paracetamol (3 microM) binds specifically to any area of the murine brain and spinal cord and to investigate whether paracetamol (1-100 microM) competes for binding to the nociceptin opioid peptide (NOP) receptor or to the nitrobenzylthioinosine (NBTI)-sensitive adenosine transporter in the brains of mice. [3H]paracetamol binding was homogenous and, although there was some indication of specific binding overall, this binding in most individual regions failed to reach statistical significance. However, thoracic segments of the spinal cord were found to have significantly higher specific binding than cervical and lumbar regions. Paracetamol did not significantly compete for binding to the NOP receptor or to the NBTI-sensitive adenosine transporter, showing that it does not mediate its effect via these sites. Although paracetamol did bind specifically to the murine brain and spinal cord, the binding was not region-specific, suggesting binding is not related to any particular neurotransmitter system.

Murine NGD5 is a gene identified from NG108-15 cells which is postulated to be involved in opioid receptor function. Here we report the cloning and characterization of a cDNA C20orf9-003 (ACI-1) encoding the human orthologue of the mouse NGD5. Analysis of the genomic structure revealed that C20orf9-003 (ACI-1) contains 13 exons and 12 introns, spanning 52.5kb of genomic DNA and is a variant of C20orf9. Chromosomal localization of human C20orf9-003 (ACI-1) assigned this gene to chromosome 20q13.12. Genes at this locus have been associated with the progression and possibly the development of various cancers. In addition several linkage studies support the possibility that one or more genes affecting obesity are located in 20q13. No function can be clearly assigned to C20orf9-003 (ACI-1), however, the protein has a cytoplasmic subcellular location and the secondary structure contains a Rossman fold like feature which is found in many nucleotide binding proteins.

We describe a query-based web-accessible system (www.neurogadgets.com/bws.php) for facilitating comparative microbial genomics. A variety of query pages are available, each with numerous options, that allow a biologist to pose relevant questions of genomic data. We illustrate with a characterization of species-specific protein-coding genes (so-called "ORFans"), finding that they are on average smaller, faster evolving, and less G+C-rich, and that they encode proteins more basic in their predicted isoelectric point, compared with non-species-specific genes. Using a dual-threshold approach, we conclude that these are characteristics of true species-specific genes, rather than artifacts of mis-annotation.

The protein kinase Akt is involved in embryonic vascular development and neoangiogenesis as well as in several endothelial cell functions, including activation of endothelial NO-synthase (eNOS) and promotion of endothelial cell survival. We have examined the effects of G-protein activators thrombin and histamine as well as lysophosphatidylcholine (LPC) on Akt phosphorylation in cultured human umbilical vein endothelial cells (HUVEC). Akt phosphorylation was analyzed with the phosphospecific Akt (Ser473) antibody by Western blotting. While epidermal growth factor (EGF) was a potent stimulator of Akt phosphorylation histamine, thrombin and LPC blocked its activation when used in cotreatment with EGF. Following inhibition or downregulation of protein kinase C (PKC), the inhibitory effect of both histamine and thrombin on the endothelial response to EGF was prevented. Furthermore, stimulation of PKC, using short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, markedly inhibited the stimulatory effects of EGF on Akt phosphorylation. Rottlerin, an inhibitor of the PKCdelta, but not Gö6976, which is an inhibitor of alpha, beta, gamma and isoforms, reversed the inhibitory effects of histamine. Conversely, inhibition or downregulation of PKC did not prevent the inhibitory effect of LPC. Akt phosphorylation was also increased by sphingosine 1-phosphate (S1P) treatment and this activity was influenced by the various cotreatments in the same way as the activation by EGF. Overall, this study demonstrated that the G-protein activators thrombin and histamine inhibited both EGF- and S1P-mediated Akt phosphorylation in HUVEC by activation of PKCdelta, while the inhibitory effects of LPC were independent of PKCdelta.

AAPM Magnetic Resonance Task Group #9 on proton magnetic resonance spectroscopy (MRS) in the brain was formed to provide a reference document for acquiring and processing proton (1H) MRS acquired from brain tissue. MRS is becoming a common adjunct to magnetic resonance imaging (MRI), especially for the differential diagnosis of tumors in the brain. Even though MR imaging is an offshoot of MR spectroscopy, clinical medical physicists familiar with MRI may not be familiar with many of the common practical issues regarding MRS. Numerous research laboratories perform in vivo MRS on other magnetic nuclei, such as 31P, 13C, and 19F. However, most commercial MR scanners are generally only capable of spectroscopy using the signals from protons. Therefore this paper is of limited scope, giving an overview of technical issues that are important to clinical proton MRS, discussing some common clinical MRS problems, and suggesting how they might be resolved. Some fundamental issues covered in this paper are common to many forms of magnetic resonance spectroscopy and are written as an introduction for the reader to these methods. These topics include shimming, eddy currents, spatial localization, solvent saturation, and post-processing methods. The document also provides an extensive review of the literature to guide the practicing medical physicist to resources that may be useful for dealing with issues not covered in the current article.

Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the treatment of respiratory disease. These properties made it a suitable candidate for development. Described here is the discovery of three further derivatives of pyrrolidine trans-lactams, which fulfill the criteria required for back-up candidates 28, 29, and 32. These include increased activity in inhibiting HNE in human whole blood (HWB) and comparable pharmacokinetic properties, in particular clearance, in two species. To provide a rapid assessment of clearance, cassette dosing in dog was used. Modern array techniques, including the synthesis of mixtures, were used to synthesize compounds rapidly. Having selected three potential compounds as back-up candidates, they were prepared as single enantiomers and profiled in in vitro and in vivo assays and evaluated pharmacokinetically in rat and dog. These compounds are highly potent and selective HNE inhibitors, with a prolonged pharmacodynamic action. Pharmacokinetically, these compounds are comparable with 1 while they are more potent in HWB. Compound 28, however, has a higher clearance. One of these compounds, 32, was cocrystallized with HNE, and features of this structure are described and compared with the cocrystal structure of 1 in porcine pancreatic elastase.

Functional MR imaging (fMRI) based upon the Blood Oxygen Level Dependent (BOLD) effect is currently an important new tool for understanding basic brain function and specifically allowing the correlation of physiological activity with anatomical location without the use of ionizing radiation. The clinical role of fMRI is still being defined and is the subject of much research activity. In this report we present the underlying physical, technical and mathematical principals of BOLD fMRI along with descriptions of typical applications. Our purpose in this report is to provide, in addition to basic principles, an insight into the aspects of BOLD imaging, which may be used by the medical physicist to assist in the implement of fMRI procedures in either a hospital or research environment.

Darwin's paradigm holds that the diversity of present-day organisms has arisen via a process of genetic descent with modification, as on a bifurcating tree. Evidence is accumulating that genes are sometimes transferred not along lineages but rather across lineages. To the extent that this is so, Darwin's paradigm can apply only imperfectly to genomes, potentially complicating or perhaps undermining attempts to reconstruct historical relationships among genomes (i.e., a genome tree). Whether most genes in a genome have arisen via treelike (vertical) descent or by lateral transfer across lineages can be tested if enough complete genome sequences are used. We define a phylogenetically discordant sequence (PDS) as an open reading frame (ORF) that exhibits patterns of similarity relationships statistically distinguishable from those of most other ORFs in the same genome. PDSs represent between 6.0 and 16.8% (mean, 10.8%) of the analyzable ORFs in the genomes of 28 bacteria, eight archaea, and one eukaryote (Saccharomyces cerevisiae). In this study we developed and assessed a distance-based approach, based on mean pairwise sequence similarity, for generating genome trees. Exclusion of PDSs improved bootstrap support for basal nodes but altered few topological features, indicating that there is little systematic bias among PDSs. Many but not all features of the genome tree from which PDSs were excluded are consistent with the 16S rRNA tree.

Aims: To discover whether a new infra-red laser method could detect a change in pain threshold after as mild an analgesic as paracetamol and whether an effervescent liquid formulation produced a faster onset of action than tablets., Methods: This double-blind, placebo controlled randomized study used a portable, infra-red laser to measure "first pain" thresholds on the nondominant forearm in 12 normal volunteers before and after 1 g of paracetamol or placebo. The mean of six recordings was determined three times before dosing, the first being used as a familiarization procedure, and 14 times after dosing., Results: We detected a small (2%), statistically significant difference in pain threshold between a liquid formulation of paracetamol and placebo at 30 and 60 min (P = 0.004 and P = 0.001), but not between tablets and placebo. Liquid also increased the threshold significantly compared with tablets at 60 min (P = 0.01)., Conclusions: To detect such a small increase in pain threshold requires a highly consistent measure and the coefficient of variation was 2% for the study overall, surprisingly low for a subjective phenomenon. The reasons for this include minimizing reflectance by blacking the skin, using a nonhairy site, averaging six data points at each sample time and controlling closely the ambient conditions and the subjects' preparation for studies.

The discovery of a potent intracellular inhibitor of human neutrophil elastase which is orally active and has a long duration of action is described. The pharmacodynamic and pharmacokinetic properties of a trans-lactam development candidate, GW311616A, are described.

Described are the acylation binding of trans-lactam 1 to porcine pancreatic elastase, the selection of the SO2Me activating group for the lactam N which also confers metabolic stability in hamster liver microsomes, the introduction of aqueous solubility through the piperidine salt 9, the in vivo oral activity of 9 and its bioavailability, and the introduction of 9 as an intracellular neutrophil elastase inhibitor.

The image intensifier entrance exposure rate (IIEER)) and entrance skin exposure rate (ESER) are two characteristics that can be used to determine whether a fluoroscope is adjusted to operate at an optimal dose rate level. This article presents solutions to some of the practical problems that are encountered when measuring these parameters. Because the energy response of the ion chamber used to measure exposure rates is different from that of the image intensifier, a fluoroscope with a perfect automatic exposure rate control will have an IIEER that depends on the phantom composition, phantom thickness, and x-ray tube potential. The authors developed a simple mathematic model to investigate the relationship of ion chamber response to image intensifier response and to determine the effects of phantom composition and thickness. Results from this model were compared with measurements made with two C-arm fluoroscopes. Variations of 40% or more in the IIEER and ESER can be ascribed to these phenomena.

Background: After successful percutaneous coronary arterial revascularization, 25% to 60% of subjects have restenosis, a recurrent coronary arterial narrowing at the site of the intervention. At present, restenosis is usually detected invasively with contrast coronary angiography. This study was performed to determine if phase-contrast MRI (PC-MRI) could be used to detect restenosis noninvasively in patients with recurrent chest pain after percutaneous revascularization., Methods and Results: Seventeen patients (15 men, 2 women, age 36 to 77 years) with recurrent chest pain >3 months after successful percutaneous intervention underwent PC-MRI measurements of coronary artery flow reserve followed by assessments of stenosis severity with computer-assisted quantitative coronary angiography. The intervention was performed in the left anterior descending coronary artery in 15 patients, one of its diagonal branches in 2 patients, and the right coronary artery in 1 patient. A PC-MRI coronary flow reserve value /=70% and >/=50%, respectively., Conclusions: Assessments of coronary flow reserve with PC-MRI can be used to identify flow-limiting stenoses (luminal diameter narrowings >70%) in patients with recurrent chest pain in the months after a successful percutaneous intervention.

Previous studies in vitro have shown that NK3 receptors exist on primary afferent terminals in rat spinal cord and mediate potentiation of the depolarisation-evoked substance P (SP) release. In the present study we have investigated the role of the NK3 receptor-mediated SP release system in a model of inflammatory pain. Monoarthritis was induced in rats by unilateral injection of complete Freund's adjuvant (CFA); withdrawal latencies to a thermal stimulus were subsequently measured at various times following CFA. The CFA-treated paw displayed hyperalgesia as early as 4 h after CFA injection and hyperalgesia was maintained until day 4 but had disappeared by day 21. The thermal hyperalgesia was associated with an increase in basal SP release from spinal cord synaptosomes. The possible involvement of endogenous neurokinin B acting at NK3 receptors was tested by using SB 223412-A [(S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carbo xamide hydrochloride], a novel, potent (Ki=30 nM) and selective (Ki>10,000 nM for NK1 and NK2 receptors), non-peptidic NK3 receptor antagonist. In vitro SB 223412-A antagonised the potentiation of SP release produced by senktide in spinal cord synaptosomes. Administered systemically to monoarthritic rats (50 mg/kg, p.o., b.i.d., for 4 days), the NK3 receptor antagonist SB 223412-A significantly reduced thermal hyperalgesia and normalised the basal release of SP from spinal cord synaptosomes. The data suggest that neurokinin B acting at NK3 receptors that mediate SP release within the spinal cord play a role in inflammation. These NK3 receptors may represent, therefore, appropriate targets in the therapy of inflammatory pain.

We used a variety of methods to detect known gene conversions in the actin gene families of five angiosperm species, the beta-globin gene families of two primate species, and the Zfx/Zfy gene families of seven mammalian species. Our goal was to devise a working strategy which would allow the analysis of the members of a multigene family in order to determine whether there had been gene conversions between its members, identify the genes involved in the gene conversions, establish the lengths of the converted regions, and determine the polarities of the gene conversions. We show that three phylogenetic methods and the homoplasy test of Maynard Smith and Smith perform relatively poorly on our data sets because the sequences we analyzed had large levels of multiple substitutions. The method of Sawyer, the compatibility method of Jakobsen and Easteal, the partition matrix method of Jakobsen, Wilson, and Easteal, and the co-double method of Balding, Nichols, and Hunt can be used to identify the genes which have been involved in gene conversions. The co-double method is more powerful than other methods but requires orthologous sequences from related species. Compatibility, phylogenetic, and nucleotide substitution distribution statistics methods can be used to identify the location of the converted region(s). Site-by-site compatibility analyses can also be used to identify the direction of the conversion event(s). Combinations of these methods can therefore be used to establish the presence, locations, and polarities of gene conversions between multigene family members.

Background: Coronary artery bypass grafting improves survival in patients with >70% luminal diameter narrowing of the 3 major epicardial coronary arteries, particularly if there is involvement of the proximal portion of the left anterior descending (LAD) coronary artery. Measurement of coronary flow reserve can be used to identify functionally important luminal narrowing of the LAD artery. Although magnetic resonance imaging (MRI) has been used to visualize coronary arteries and to measure flow reserve noninvasively, the utility of MRI for detecting significant LAD stenoses is unknown., Methods and Results: Thirty subjects (23 men, 7 women, age 36 to 77 years) underwent MRI visualization of the left main and LAD coronary arteries as well as measurement of flow in the proximal, middle, or distal LAD both at rest and after intravenous adenosine (140 microgram/kg per minute). Immediately thereafter, contrast coronary angiography and when feasible, intracoronary Doppler assessments of coronary flow reserve, were performed. There was a statistically significant correlation between MRI assessments of coronary flow reserve and (a) assessments of coronary arterial stenosis severity by quantitative coronary angiography and (b) invasive measurements of coronary flow reserve (P<0.0001 for both). In comparison to computer-assisted quantitative coronary angiography, the sensitivity and specificity of MRI for identifying a stenosis >70% in the distal left main or proximal/middle LAD arteries was 100% and 83%, respectively., Conclusions: Noninvasive MRI measures of coronary flow reserve correlated well with similar measures obtained with the use of intracoronary Doppler flow wires and predicted significant coronary stenoses (>70%) with a high degree of sensitivity and specificity. MRI-based measurement of coronary flow reserve may prove useful for identification of patients likely to obtain a survival benefit from coronary artery bypass grafting.

Objective: We recently provided evidence for contraction-induced attenuation of reflex sympathetic vasoconstriction in human skeletal muscle microcirculation. We now asked whether contraction-induced modulation of alpha-adrenoceptor mediated vasoconstriction in the human forearm (a) is evident in a large artery supplying the contracting skeletal muscle and (b) implicates a post-junctional site of action., Methods and Results: To address these questions in humans, we used phase-contrast magnetic resonance imaging to measure blood flow velocity and cross-sectional area of the brachial artery during brachial-artery infusion of the alpha-adrenoceptor agonist norepinephrine (NE) (1.1 g/min for 5 min) at rest and during mild ipsilateral rhythmic handgrip (20% of maximum). At rest, brachial artery conductance decreased progressively during the entire 5 min period of infusion (baseline to first half to second half of infusion: 0.421 +/- 0.157 to 0.255 +/- 0.187 to 0.012 +/- 0.014 ml/min/mmHg, P < 0.05). When NE was superimposed on handgrip, conductance at first decreased sharply (1.205 +/- 0.127 to 0.330 +/- 0.097 ml/min/mmHg, P < 0.05). However, during the second half of the infusion, conductance did not decrease further but rather returned progressively toward baseline (0.476 +/- 0.199 ml/min/mmHg at the end of the exercise, P < 0.05 vs. NE alone)., Conclusion: These data provide new evidence in humans that alpha-adrenoceptor mediated vasoconstriction is sensitive to modulation by skeletal muscle contraction. Such modulation is evident at the level of a large conduit artery and it involves a post-junctional mechanism of action.

The macrolide antibiotic bafilomycin A1 is a highly potent and selective inhibitor of all the vacuolar ATPases (V-ATPases). With the aim of obtaining novel analogues specific for the osteoclast subclass of vacuolar ATPase, 31 derivatives of bafilomycin A1 were synthesized and tested for their ability to inhibit differentially the V-ATPase-driven proton transport in membrane vesicles derived from chicken osteoclasts (cOc) and bovine chromaffin granules (bCG). Although none of the new analogues were more potent than the parent compound, the obtained data provided a significant amount of information about the structural requirements for the inhibitory activity of bafilomycin A1. The different effects of a few analogues on the two enzymes could also suggest the possibility of a selective modulation of the V-ATPases in different tissues.

The vacuolar H+-ATPase (V-ATPase), located on the ruffled border of the osteoclast, is a proton pump which is responsible for secreting the massive amounts of protons that are required for the bone resorption process. With the aim to identify new agents which are able to prevent the excessive bone resorption associated with osteoporosis, we have designed a novel class of potent and selective inhibitors of the osteoclast proton pump, starting from the structure of the specific V-ATPase inhibitor bafilomycin A1. Compounds 3a-d potently inhibited the V-ATPase in chicken osteoclast membranes (IC50 = 60-180 nM) and were able to prevent bone resorption by human osteoclasts in vitro at low-nanomolar concentrations. Notably, the EC50 of compound 3c in this assay was 45-fold lower than the concentration required for half-maximal inhibition of the V-ATPase from human kidney cortex. These results support the validity of the osteoclast proton pump as a useful molecular target to produce novel inhibitors of bone resorption, potentially useful as antiosteporotic agents.

Magnetic resonance imaging (MRI) has the unique ability to demonstrate pulmonary emboli, venous thrombosis, and normal pulmonary arteries in a single noninvasive study. Spin echo and gradient echo pulse sequences take advantage of the natural high contrast between flowing blood and intraluminal thrombus or embolus. Magnetic resonance angiographic (MRA) techniques offer three-dimensional display of the pulmonary vasculature. Each of these techniques may be viewed in cinematic fashion to depict hemodynamic changes associated with the cardiac cycle. Clinical studies have demonstrated sensitivity in the 75% to 100% range and specificities between 42% and 90% depending on technique. MRI technology is still rapidly advancing and clinical accuracy will no doubt improve as experience with new techniques develops. At present, MRI should play a complimentary role to conventional methods of diagnosing thromboembolic disease.

This paper describes the design and synthesis of compounds belonging to a novel class of substituted pyrrolooctahydroisoquinolines which are potent and selective delta opioid agonists. Molecular modeling studies performed on known, selective delta ligands such as (+)-3 and the potent delta agonists SNC 80 led to the identification of the carboxamido moiety of the latter as a putative nonaromatic delta address. Insertion of this moiety onto the octahydroisoquinoline opioid message resulted in (+/-)-5b, a potent and selective delta ligand. The active enantiomer, (-)-5b, displayed nanomolar affinity for the delta receptor (Ki = 0.9 nM) with good mu/delta and kappa/delta binding selectivity ratios (140 and 1480, respectively). In addition, (-)-5b behaved as a full delta agonist in the mouse vas deferens bioassay having an IC50 = 25 nM and being antagonised in the presence of 30 nM naltrindole (NTI). These studies, based on the message-address concept, indicated that the nonaromatic (N,N-diethylamino)carbonyl moiety is a viable alternative to the classical benzene ring as a delta opioid address. Preliminary in vivo studies showed that (+/-)-5b produced a dose-related antinociception in the mouse abdominal constriction test after intracerebroventricular administration (ED50 = 1.6 micrograms/mouse).

Objective: To measure cerebral blood flow in women with eclampsia and severe preeclampsia using phase-contrast magnetic resonance imaging (MRI)., Methods: Women with eclampsia and severe preeclampsia were studied and compared with normotensive cohorts. Magnetic resonance imaging studies were performed initially in hypertensive women after seizure treatment or prophylaxis was given. Magnetic resonance imaging flow measurements were made using a phase contrast velocity imaging technique in each middle and posterior cerebral artery. Conventional brain MRI and magnetic resonance angiography of the circle of Willis were performed at the time of flow measurement. Women with preeclampsia and eclampsia served as their own controls and were matched with normotensive cohorts. All of the hypertensive women were studied again 4-5 weeks postpartum. Paired t test analysis and an analysis of variance were performed. Considering a 20% minimum detectable difference in flow, the power was 0.80, 0.92, 0.86, and 0.96 for the left and right middle cerebral arteries and the left and right posterior cerebral arteries, respectively., Results: All 28 women enrolled were studied initially within 24 hours of delivery or of their most recent seizure. There were no significant differences in blood flow in either the posterior or middle cerebral arteries in women with eclampsia or severe preeclampsia between the initial studies and those 4-5 weeks postpartum, or compared with their normal counterparts. No findings of vasospasm were seen. T2-weighted brain images were markedly abnormal in all eight women with eclampsia, mildly abnormal in two of ten with severe preeclampsia, and normal in all ten controls., Conclusions: No flow changes were seen in the posterior or middle cerebral arteries of women with eclampsia and severe preeclampsia despite the presence of remarkable brain lesions in all women with eclampsia. These findings question the role of vasospasm and cerebral hypoperfusion, although a vasodilatory effect of magnesium could not be excluded.

Strategies for developing selective water diuretic agents have involved development of kappa opioid receptor agonists and vasopressin V2 receptor antagonists; however, these two classes of compounds have not been compared directly. We have investigated the activity of three kappa receptor agonists and one nonpeptide vasopressin receptor antagonist in conscious dogs. SB 215520, SB 215519 and niravoline are selective kappa agonists with variable abilities to cause a water diuresis and ataxia in rats. When administered to conscious hydropenic dogs, the kappa agonists resulted in an increase in free water clearance; however, these effects were associated with an antinatriuresis, an increase in heart rate and, at the higher doses, central nervous system side effects. Conversely, the vasopressin receptor antagonist, OPC 31260, resulted in a significant water diuresis without any accompanying changes in sodium excretion and heart rate, and with no apparent central nervous system effects. These studies suggest that, at least in dogs, a vasopressin receptor antagonist is a more selective water diuretic than a kappa receptor agonist.

Blood flow information available from transcranial Doppler ultrasound is usually derived from velocity alone because no knowledge of vessel caliber is available. In cases such as vasospasm, where vessel size changes, the inference of flow from velocity becomes questionable. A computational technique was used to calculate a flow index and 2 vessel area indices based on the first and zero moments of the Doppler power spectrum. These indices were tested in a steady and pulsatile flow phantom using 6 different diameter elastic tubes. Changes in the flow index showed good agreement with changes in timed volume flow for different flow rates. The vessel caliber indices correctly predicted changes in area when different diameter tubes were examined. These indices may prove useful in clinical settings where the constancy of flow or vessel diameter between studies are in question.

The ovariectomized rat is the most commonly used animal model of human postmenopausal osteoporosis, exhibiting a high rate of bone turnover with resorption exceeding formation. At present, bone turnover is quantified directly by dynamic histomorphometry. The aim of the present study was to determine whether the measurement of the urinary output of some specific bone collagen catabolites--pyridinolines and hydroxylysine glycosides--could be used to indirectly monitor the initial phase of bone turnover increase in ovariectomized 90-day-old rats. Ninety-day-old female rats were randomly divided into three groups (n = 6): ovariectomized, sham-operated and non-treated controls. Urine samples (24 h) were collected 6 days before surgery and twice weekly for the 4 weeks following ovariectomy. Urinary excretion of pyridinoline (PYD), deoxypyridinoline (DPD), glucosyl-galactosyl-hydroxylysine (GGHYL) and galactosyl-hydroxylysine (GHYL) were measured. As expected, ovariectomy was associated with a significant decrease in bone mineral density in both the proximal tibial and distal femoral metaphysis. Compared with both sham-operated and control animals, ovariectomized rats showed significant increases in PYD, GGHYL, and GHYL urinary output 8 days after surgery and in DPD output after 15 days. These changes were maintained throughout the study. The results confirm that measurement of the urinary excretion of pyridinolines and hydroxylysine glycosides represents a powerful tool for detecting the onset of bone turnover in ovariectomized 90-day-old rats.

Phase-contrast magnetic resonance imaging (PC-MRI) can be used to produce multiframe cine flow images of the coronary arteries. Accurate coronary flow measurement requires the elimination of respiratory motion artifacts using k-space segmentation to acquire the data in a single breath-hold. However, the duration of the breath-hold is proportional to the number of cine frames. In the present study, the number of cine frames was varied and the accuracies of the coronary flow measurements were assessed using perivascular US. For the range of flows studied (2 ml/min to 147 ml/min), the correlation coefficients for PC-MRI and US increased (.70-.98) and the limits of agreement improved (+/-45 ml.min-1 to +/-10 ml.min-1) as the number of cine frames increased from one to six. The results suggest that the accuracy of breath-hold cine PC-MRI measurements of coronary artery flow improves as the number of cine frames increases.

MR imaging cardiac quantitation is accurate, highly reproducible, and feasible using equipment available in most hospitals. For determination of myocardial mass, evaluation of RV function, and quantitative measurements of flow in the great vessels and peripheral vasculature, MR imaging is the reference method. Availability of methods for rapid scanning and analysis will lead to increased use of cardiac MR imaging in quantifying cardiac function.

Background: The noninvasive measurement of absolute epicardial coronary arterial flow and flow reserve would be useful in the evaluation of patients with coronary circulatory disorders. Phase-contrast magnetic resonance imaging (PC-MRI) has been used to measure coronary arterial flow in animals, but its accuracy in humans is unknown., Methods and Results: Twelve subjects (7 men, 5 women: age 44 to 67 years) underwent PC-MRI measurements of flow in the left anterior descending coronary artery or one of its diagonal branches at rest and after administration of adenosine (140 microgram . kg(-1) . min (-1) IV). Immediately thereafter, intracoronary Doppler velocity (IDV) and flow measurements were made during cardiac catheterization at rest and after intravenous administration of adenosine. For the 12 patients, the correlation between MRI and invasive measurements of coronary arterial flow and coronary arterial flow reserve was excellent: coronary flow (MRI) (mL/min)= 0.85 x coronary flow (IDV) (mL/min)+17 (mL/min), r=.89, and coronary flow reserve (MRI) =0.79 x coronary velocity reserve (IDV) + 0.34, r=.89. For the range of coronary arterial flows (18 to 161 mL/min) measured by MRI, the limit of agreement between MRI and catheterization measurements of flow was -13+/-30 mL/min; for the range of coronary reserves (0.7 to 3.7) measured by MRI, the limit of agreement between the two techniques was 0.1+/-0.4., Conclusions: Cine velocity-encoded PC-MRI can noninvasively measure absolute coronary arterial flow in the left anterior descending artery in humans. PC-MRI can detect pharmacologically induced changes in coronary arterial flow and can reliably distinguish between those subjects with normal and abnormal coronary artery flow reserve.

The synthesis and biological evaluation of a series of 2-substituted 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), the only benzodiazepine that acts simultaneously as a kappa-opioid agonist and a cholecystokinin-A (CCK-A) antagonist, are reported. The radioligand binding models used in these studies were [(125)I](BH)-CCK-8 in rat pancreas (CCK-A), [(3)H]-(MENLE(28,31))-cck-8 in guinea pig cerebral cortex (CCK-B), and [(3)H]U-69593 (kappa(1)), [(3)H]DAMGO (mu), and [(3)H]DADLE (delta) in guinea pig brain. All the title compounds were devoid of significant affinity for both CCK-A and CCK-B receptors, while some of them bound with nanomolar affinity and high selectivity for kappa-opioid receptors. In particular, the 2-thienyl derivative 7A(X = H) with a K(i) = 0.50 nM represents a clear improvement with respect to tifluadom, showing a comparable potency but higher selectivity. The application of computational simulations and linear regression analysis techniques to the complexes between guinea pig kappa (kappa(1))-receptor and the title compounds allowed the identification of the structural determinants for recognition and quantitative elucidation of the structure-affinity relationships in this class of receptors.

Magnetic resonance imaging has been demonstrated to be useful in the assessment of aortic and pericardial disease, cardiac masses, and congenital heart disease. Recently, developments in rapid imaging, assessment of regional function, evaluation of intracardiac shunts and valvular regurgitation, and magnetic resonance coronary angiography have been achieved, indicating an increasing role for magnetic resonance techniques in clinical cardiology.

The present study compares the electroencephalographic (EEG) and behavioural effects of highly selective kappa-opioid agonists, spiradoline (U62066), enadoline (CI-977), BRL 52656, and BRL 53001, after SC administration to conscious rats. All compounds caused a distinctive dose- and time-related EEG effect and behavioural profile. The EEG power spectra (PS) of treated animals were characterised by power reduction indicative of CNS activation and an unusual spectral peak at 4-7 Hz, compared to controls. Behaviourally, however, the animals appeared to be sedated, with a reduction of locomotor activity, loss of postural tone, ataxia, and unusual hyperreactivity. The compounds differed in their liability to produce these CNS effects, with kappa-opioid analgesics such as enadoline and BRL 53001 showing a reduced propensity at equivalent antinociceptive doses. Where tested, these effects were inhibited by the nonselective opioid antagonist naloxone. The non-brain penetrating kappa-opioid agonist, BRL 52974, failed to produce alterations in EEG PS or behaviour, up to a dose of 10 mg/kg, indicating that the effects depend on activation of centrally located kappa-receptors.

Over the past decade there has been great interest by the pharmaceutical industry in the development of novel analgesics which act by activation of central kappa-opioid receptors. However, in view of the spectrum of unwanted CNS effects associated with such agents, recent efforts have been focused on peripherally-selective compounds with limited ability to cross the blood-brain barrier (BBB). In this review, the authors consider the chemical strategies and associated synthetic procedures employed by various research groups to produce hydrophilic compounds with retained kappa-opioid agonist activity. Physico-chemical (clogP, delta logP) and biological methods (antinociception following administration by peripheral and central routes; ex-vivo binding to detect plasma and brain levels of the drugs) utilized to assess brain penetration are described and compared. Overall, in-vivo ratios correlate better with delta logP values than with clogP.

Background: Noninvasive measurement of absolute coronary arterial flow and coronary flow reserve would be of considerable use in the diagnosis and management of patients with coronary artery disease. Phase-contrast magnetic resonance imaging (MRI) has been used to measure flow in a variety of vessels. The goal of the present study was to determine if MRI measurements of coronary artery flow in a single breath-hold can be used to determine flow reserve and the severity of pericardial stenosis., Methods and Results: In eight mongrel dogs, a closed chest model of partial left anterior descending coronary artery (LAD) occlusion was created. Coronary flows in the left circumflex artery (LCx) and LAD were measured at rest and during adenosine infusion using velocity-encoded, breath-hold MRI and perivascular ultrasound (US) flowmeters. MRI measurements of absolute coronary flow and coronary flow reserve were highly correlated with US (r = .96 and .94, respectively). Flow reserve measured in the constricted LAD was significantly lower than that in the unconstricted LCx by both US (P = .002) and MRI (P = .011)., Conclusions: MRI measurements of coronary flow and flow reserve were in good agreement with US measurements. In addition, MRI measurements of coronary flow reserve successfully discriminated stenotic from normal vessels. These results indicate that MRI is a useful method for the noninvasive assessment of coronary flow and stenosis.