Novel classes of pain-relieving molecules are needed to fill the void between nonsteroidal anti-inflammatory agents and narcotics. Our studies have identified superoxide as a novel mediator of hyperalgesia (clinically defined as an augmented sensitivity to painful stimuli) and have exposed potential pathways through which this radical modulates the hyperalgesic response. The role of superoxide in pain was elucidated using a superoxide dismutase mimetic, M40403 [a manganese(II) complex with a bis(cyclo-hexylpyridine-substituted) macrocyclic ligand]. Intraplantar injection of carrageenan in rats led to timedependent development of peripheral inflammation [measured parameters of inflammation included paw edema, cytokine release in the paw exudates, nitrotyrosine formation (a marker of peroxynitrite formation and oxidative stress), and poly-ADPribose-polymerase activation (the nuclear enzyme activated by superoxide/peroxynitrite)] and hyperalgesia. M40403 blocked all measured parameters of inflammation and hyperalgesia. Furthermore, when given therapeutically (2 h after the induction of hyperalgesia) either by intravenous or intrathecal administration, M40403 but not its inactive congener M40404 inhibited hyperalgesia with a rapid onset of action. Our results also show that, at the level of the spinal cord and time of peak hyperalgesia, endogenous manganese superoxide dismutase was nitrated and subsequently deactivated, losing its capacity to remove superoxide. The antihyperalgesic effects of M40403 were not reversed by naloxone excluding the potential involvement of an opiate pathway. Collectively, these studies have unraveled a critical role for superoxide in the nociceptive signaling cascade both peripherally and centrally. The discovery of this pathway opens a new therapeutic strategy for the development of novel nonnarcotic antihyperalgesic agents.
Ultrasound medical systems can resolve backscatter signals from individual microbubbles of ultrasound contrast, both in solution and in the targeted immobilized state, implying picogram sensitivity.
Purpose: To compare the binding and agonistic activity of Acthar V R Gel and synthetic melanocortin receptor (MCR) agonists and examine how the activity of select agonists affects the in vivo production of corticosterone. Materials and Methods: In vitro binding was determined using concentration-dependent displacement of the ligand [ 125 I]Nle 4 , D-Phe 7-a-melanocyte-stimulating hormone (a-MSH) on cells expressing MC1R, MC3R, MC4R, or MC5R. Functional activity was determined using a time-resolved fluorescence cyclic adenosine monophosphate (cAMP) assay in cells expressing MC1R, MC2R, MC3R, MC4R, or MC5R. In vivo corticosterone analyses were performed by measuring plasma corticosterone levels in Sprague Dawley rats. Results: Acthar Gel and synthetic MCR agonists exhibited the highest binding at MC1R, lowest binding at MC5R, and moderate binding at MC3R and MC4R. Acthar Gel stimulated the production of cAMP in all 5 MCR-expressing cell lines, with MC2R displaying the lowest level of full agonist activity, 3-, 6.6-, and 10-fold lower than MC1R, MC3R, and MC4R, respectively. Acthar Gel was a partial agonist at MC5R. The synthetic MCR agonists induced full activity at all 5 MCRs, with the exception of a-MSH having no activity at MC2R. Acthar Gel treatment had less of an impact on in vivo production of corticosterone compared with synthetic ACTH 1-24 depot. Conclusions: Acthar Gel bound to and activated each MCR tested in this study, with partial agonist activity at MC5R and the lowest level of full agonist activity at MC2R, which distinguished it from synthetic MCR agonists. The minimal activity of Acthar Gel at MC2R corresponded to lower endogenous corticosteroid production.
The utility of clinical magnetic resonance contrast media (MRCM) in the evaluation of pathologies within the central nervous system (CNS) is well established (1-9). Bloodbrain-barrier (BBB) disruption in tumors and other lesions of the CNS is attributable to abnormal endothelial junctions, and is a key feature of the aggressive neovascular formations within malignant tumors. This characteristic of BBB disruption accounts for the increased enhancement of intracranial tumors on MRI after administration of MRCM, which is helpful in delineating tumor anatomy. For gliomas, increased enhancement is suggestive, although not absolutely indicative, of an increased histological grade of malignancy. Degrees of tumor malignancy previously have been assessed in animal models using covalently Gd-conjugated macromolecule-based MRCM as MRI signal enhancers (3-6). However, these covalently-bound Gd-macromolecules have not been studied in clinical trials in humans. Hence, the available low-molecular-weight extracellular MRCM are now exploited under dynamic protocols for tumor assessment (7-9). These agents extravasate into extracellular space throughout non-CNS tissues, and thus present a limited time window at high concentration for the detection of CNS tumors. Despite successes achieved with the extracellular agents to date, the need for intravascular agents that would extravasate only in the face of BBB disruption continues to be advocated as a next step in improving the diagnostic utility of these and related techniques (10,11).Noncovalent albumin-binding Gd-chelates represent a new class of agents. These agents, unlike the covalently bound Gd-macromolecules, are small chelates with side chains that undergo reversible noncovalent interactions with circulating albumin (12,13). The bound form (the dominant species, with a Ͼ10-fold signal-enhancing potential) assumes the macromolecular attributes of albumin and remains intravascular, while the nonbound minor component (with the low relaxivity typical of small Gdchelates) is free and extravasates. MP-2269 (Mallinckrodt, Inc., St. Louis, MO) is an experimental monomeric Gd-DTPA-derived blood pool agent with a molecular weight of 1179 g/mol. It is the Gd complex of 4-pentylbicyclo-
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