indazoles

..This multi-institutional study assessed the activity and safety of axitinib, an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 in patients with advanced thyroid cancer...

..The unique phase I study design allowed early identification of important absorption and metabolic issues critical to phase II testing of this agent...

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..Moreover, it halted tumor growth in immunodeficient mice without serious toxicity during the treatment period. Thus, we propose that YC-1 is a good lead compound for the development of new anti-HIF-1, anticancer agents...

..The aim of this study was to assess the safety and efficacy of gemcitabine plus axitinib versus gemcitabine alone...

..This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer...

..7. These results would suggest that YC-1 activates sGC of human platelets by a NO-dependent mechanism, and exerts its antiplatelet effects through the sGC/cyclic GMP pathway...

..08 microg/mL, >or=7 hours) than with plasma area under the curve or Cmax. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer...

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..Thus, a clinical trial using sequence-dependent combination therapy with ABT-869 in AML is warranted...

..LND plus diazepam may be interesting in the adjuvant setting or associated to chemotherapy to act on different targets and increase the therapeutic index...

..In tumors, ABT-869 inhibited FLT3 phosphorylation, induced apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL]) and decreased proliferation (Ki67). ABT-869 is under clinical development for AML...

..Taken together, our results suggest a potential use of LND as an anti-cancer drug to bypass drug resistance and to trigger tumour destruction through apoptosis in HepG2 and R-HepG2 cells...

..Equal numbers of Japanese and Caucasian subjects were enrolled to assess the potential differences in axitinib pharmacokinetics between the two ethnicities...

..We provide a comprehensive description of its in vitro characteristics and activities, in vivo antiangiogenesis, and antitumor efficacy and translational pharmacology data...

..These results revealed that YC-1 might attenuate glutamate-induced PC12 cell apoptosis via a sGC-cGMP involved pathway...

..YC-1 may be mediated by increasing cyclic GMP, followed by, at least partly, inhibition of JNK/SAPK and NF-kappaB activations, thereby leading to inhibition of iNOS expression...

..Overall, we identify a potential molecular mechanism whereby YC-1 serves to reduce HIF-1 expression...

..Several pyrazolopyridinylpyrimidines are shown to relax aortic rings and revealed a long-lasting blood pressure lowering effect in rats after oral application...

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..This study investigated the effects of the nitric oxide (NO)-independent activators of soluble guanylate cyclase (sGC), YC-1, and BAY-58-2667 on TM cell volume and the signal transduction pathways and ion channel involved...

..Replacement of azolium cations by sodium had significant effects; cytotoxicity increased in the case of the pyrazole system from 3 (A549) to the 5.5-fold (CH1)...

..The pleiotropic effects of YC-1 allude to its possible use as a promising therapeutic iNOS inhibitor candidate for the treatment of retinal neovascularization...

..1 xenograft...

..In conclusion, HIF-1alpha appears to be a critical contributor to the progression of renal fibrosis and could be a useful target for its treatment...

..These results imply that YC-1 does not promote the regrowth of hypoxic tumors because of its cell cycle arrest effect. Furthermore, YC-1 may induce the combined anticancer effects of HIF-1alpha inhibition and cell growth inhibition...

..YC-1 has the potential to become the first antiangiogenic anticancer agent to target HIF-1 alpha...

..Taken together, these results indicate that YC-1 may inhibit HIF-1alpha accumulation and VEGF production, which in turn protect BBB from injury caused by hypoxia...

..However, their binding to HIF-1alpha was not affected by YC-1, suggesting that they are not involved in the YC-1 action. It is also suggested that YC-1 targets a novel pathway regulating HIF-1alpha stability...

..Replacement of this substituent by 4-amino(5-methyl-1H-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties...

..These results indicate that ANT is a target of lonidamine, arsenite, and CD437 and unravel an unexpected heterogeneity in the mode of action of these three compounds...

..This study was designed to evaluate therapeutic effects of bindarit, an indazolic derivative able to inhibit monocyte chemoattractant protein-1 (MCP-1) production, in adjuvant induced arthritis in rats...

..In addition, our results also show that the RNA interference-based inducible knockdown model can be a valuable platform for further evaluation of the combination treatment of other cancer therapeutics with HIF-1 inhibition...

..This type of sGC activators represent a new class of compounds with a different pharmacological profile in comparison to the classical NO-donors and they could be beneficial for the treatment of male erectile dysfunction...

..Our results indicate that the nitrergic neurotransmission exerts a modulatory role in the proneness to the epileptogenic phenomena through the activation of sGC metabolic pathway...

..CONCLUSIONS: The results suggest that remote seizure activity caused by the transneuronal spread of kainate-induced discharges may be related to NO derived from neuronal NOS...

..This results in antiplatelet activity, a strong decrease in blood pressure and an increase in survival in a low-NO rat model of hypertension, and as such may offer an approach for treating cardiovascular diseases...

..Here we report on the use of inhibition of synthesis as a potentially viable and selective approach to modify the chemokine system...

..We hypothesize that nitric oxide neurotransmission could exert a tonic modulatory influence upon spontaneously discharging subthalamic neurons, with a prevalent excitatory effect...

..Receptor tyrosine kinase inhibitors (RTKIs) and mTOR inhibitors are potential novel anticancer therapies for HCC. We hypothesized that combination targeted on distinctive signal pathways would provide synergistic therapeutics...

..Having access to the human key enzyme of NO signalling will now permit the study of novel sGC-modulating compounds with therapeutic potential...

..The results of the present study provide evidence for a trigger role of neuronally produced NO in epileptogenesis induced by PCT and the participation of nNOS inhibitory mechanisms in the action of AEDs...

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..In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models...

..We aimed to assess the activity and safety of axitinib in patients with metastatic renal-cell cancer who had failed on previous cytokine-based treatment...

..This observation implies that the inhibitory effects of YC-1 on hypoxic responses can be developed to suppress EPO-overproduction by tumor cells and tumor angiogenesis...

..Our findings show virtually all exhaled NO in the rabbit lung is produced by eNOS, which is present throughout the airways, alveoli, and vessels. Both vascular and epithelial-derived NO modulate HPV...

..Furthermore 32 has an excellent selectivity profile notably showing no significant inhibition of phosphodiesterases or nitric oxide synthases...

..These results show the use of a cell-based assay to confirm the inhibitory activity of lead compounds and drug candidates, such as ABT-869, against the CSF-1R protein in situ...

..These findings indicate that YC-1 activation of sGC can occur independently of heme, but that activation is substantially increased when the heme moiety is present in the enzyme...

..ABT-869 also reduced the leukemia burden and prolonged survival. Our study supports the rationale for clinically testing an anti-angiogenesis agent in AML with wild-type FLT3...

..The described method should help to facilitate the investigation of the new therapeutic principle of NO-independent guanylyl cyclase activators...

..With the chronic loss of neuronal NOS in mice, other mechanisms apparently suppress 20-HETE synthesis or signaling...

..These findings suggest that neuronal NOS is the main mediator of NO production associated with increase in CBF leading to the appearance of electrical discharge during HBO(2) exposure...

..In summary, our results provide evidence of compartmentalization of sGC, PKG, and PKA in endothelial caveolae contributing to NO signaling cascade, giving new insights by which the endothelium mediates vascular smooth muscle relaxation...

..In a context broader than thermoregulation, NO production and transmission may play an important role in baclofen pharmacology...

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..Selective inhibition of neuronal NO synthase may have the potential to both reduce infarct size and enhance neurogenesis in stroke...

..Finally, it is concluded that nNOS participates in the homeostatic cardiovascular and renal response to hypertonic saline loading by attenuating the blood pressure increase and hypernatremia, and facilitating natriuresis...

..4) NO does not substantially modulate neuromuscular transmission in normal and endotoxemic rats...

..These results suggest that the GABA/benzodiazepine receptor and the NO-cGMP pathway participate in the "antinociceptive-like effect" of diazepam...

..This neurogenic oedema formation was not inhibited by neither L-NNA nor 3Br-7NI. It is concluded that neural nitrergic mechanisms are involved in the meningeal vasodilatation evoked by electrical stimulation of the trigeminal ganglion...

..In conclusion, normally, salt delivered to the macula densa (MD) exerts immediate control over MD NOS I activity. In diabetes, there is ongoing overactivity of NOS I that is not regulated by MD salt...

..The source of NO is the vascular endothelium...

..The present data show an anticonvulsant effect for melatonin in i.v. PTZ seizure paradigm, which may be mediated via NO/L-arginine pathway by constitutively expressed NOS...

..Since inhibition of nNOS decreased medullary NO by 80% and MBF by 20% only, this isoform has probably minor role in the maintenance of medullary perfusion...

..Therefore, due to NO, gland cells become more sensitive to calcium signaling and are able to maintain electrolyte secretion without desensitization...

..On the other hand, activation of NMDA receptors may elicit NO increased levels enhancing dopamine release...

..Although several effects mediated by NO involve the activation of soluble guanylyl cyclase (sGC), the transduction mechanism of the catalepsy-inducing effect of NO has not yet been investigated...

..The epileptic activity of the dentate gyrus was obtained through the repetitive stimulation of the angular bundle and maximal dentate gyrus activation latency, duration and post-stimulus afterdischarge duration were evaluated...

..Conflicting results have been reported regarding the role of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the hippocampus on anxiety modulation...

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..Spermidine (SPD) is an endogenous polyamine that modulates N-methyl-D: -aspartate receptor functions, which has been reported to facilitate memory formation...

..p.). Experiments revealed that L-NAME (1 mg/rat, i.c.v.) attenuated SNC-80-induced hypothermia. The present data demonstrate that central NO production is necessary for delta opioid receptor-induced hypothermia...

..These results show that interference with NO-mediated neurotransmission in the DRN induced significant and complex motor and emotional effects. Further studies are needed to elucidate the mechanisms involved in these effects...

..Data suggest that gabapentin-induced spinal antiallodynia could be due to activation of the NO-cyclic GMP-PKG-K+ channel pathway...

..In conclusion, we show here for the first time that hypoxia induces NO-dependent complex I inhibition and ultrastructural damage by increasing mitochondrial NO in the developing brain...

..These effects are mediated by glutamate via both NMDA and non-NMDA receptors. NO, derived from neuronal NO synthase, also contributes to the ADM-induced vasopressor effects via a soluble guanylyl cyclase-associated signaling pathway...

..NO, possibly generated by endothelial NO synthase, exerts its effects in obese rats through a renal-nerve-independent mechanism, while the effect of NO generated by inducible NO synthase requires intact renal innervation...

..These data suggest that ionotropic glutamate receptors and the associated NO/cGMP transduction mechanism contribute downstream to the pressor effect elicited by 5-HT3 receptor stimulation in the NTS...

..We hypothesize that NO neurotransmission could exert a tonic inhibitory influence upon sporadically discharging striatal neurons, which are presumably striatal output neurons...

..Acute NOS inhibition unmasked renal vasoconstriction with COX-2 inhibition, suggesting that the influence of COX-2-derived vasodilator eicosanoids is exaggerated to maintain renal perfusion, compensating for the acute loss of NO...

..These findings suggest that the NO-sGC-cGMP pathway may play an important role in the mediation of the behavioural effect in the FST without influence on motor activity...

..Our results suggest that downregulation of nNOS in the antrum pylorus of the stomach and synthesis of prostaglandins mediate the delay in gastric emptying of a solid nutrient meal induced by endotoxin...

..It is also suggested that NO synthesis during ischemia is closely related to CBF, and that severe CBF reduction may inhibit NO synthesis...

..These data suggest that chronic inhibition of cyclooxygenase can increase the contribution of NO to cerebrovascular circulatory control in piglets...

..NO associated with hemoglobin. These findings highlight the complexity of oxidative stress responses and may help explain some of the dose responses associated with therapeutic applications of hyperbaric oxygen...

..Ebselen does not appear to directly interact with NO, but it may inhibit NO release from nitrosothiols by a thiol- and/or copper-dependent mechanism...

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..Moreover, the findings have revealed that the presence of NO is necessary to ensure that renal nerves can stimulate fluid reabsorption by the proximal tubules, requiring NO generated from both nNOS and iNOS...

..Neuroprotective effects of PPBP are lost when nNOS is not present or is inhibited; therefore, PPBP likely acts upstream from NO generation and its subsequent neurotoxicity...

..Taken together, these data do not support a primary role for NO in rat WBC functional hyperemia and suggest that previous reports of inhibition may have been secondary to the anesthesia employed...

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..These findings suggest that NO is involved in the NMDA-induced cardiovascular responses in the RVLM...

..The results obtained thus indicate that augmentation of free radical generation from rat PMNs following LPS treatment appears to be regulated by NO and MPO...

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..CONCLUSIONS: These findings suggest that L-NAME and 7-NI may increase the potency of cocaine and other indirect DA agonists through a central mechanism whereby DA neurotransmission is directly enhanced by NOS inhibition...

..It may be that the recorded changes in 5-HT release are secondary to changes in the release of amino acid transmitters which we have previously found to be dependent on the prevailing extracellular NO concentration...

..c.v. injection of 7-NI also blocked the development of tolerance to the hypothermic effect of ethanol. These results support the hypothesis that nNOS-derived NO participates in the development of rapid tolerance to ethanol...

..These results show that submillimolar concentrations of HCY can induce oxidative injury to nerve terminals, and this effect involves NMDAr stimulation, NOS activation, and associated free radicals formation...

..This project will have broad implications for the immunoregulation of cancer and how expression and modulation of COX-2 expression influences the immune response to cancer. ..

..The elucidation of molecular mechanisms of NMDA receptor modification in response to hypoxia will aid in the development of novel preventive strategies for hypoxia-induced brain dysfunction in the newborn. ..

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..Results of these studies would provide new information on mechanisms that underlie the development of hypersensitivity to these drugs from adolescence through adulthood. ..

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..In summary, our primary goals are to determine the fundamental relationships between molecular and pathophysiological changes in disparate tumor models and whether observed differences can be therapeutically exploited. ..

..The research plan is aimed to test the hypothesis that immune responses and the associated oxidative stress cause neurological injuries. ..

..These results with lead to the more rational and optimal design of effective combined therapies, thereby ultimately accelerating their implementation into clinical protocols. ..

..Our outcomes will be a first step in determining whether blocking endocannabinoid inactivation offers any therapeutic advantage over direct activation of cannabinoid receptors with marijuana. ..

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..Impaired cGMP synthesis will be investigated as a possible mechanism for inhibition of B2 integrin function caused by both nitric oxide and hyperbaric oxygen treatment of CO-poisoned rats. ..

..A final goal will be to combine oxygen manipulative agents with fractionated radiotherapy, in order to better understand the combined physiological effects and to provide a basis for selecting optimal time points. ..

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..These results with lead to the more rational and optimal design of effective combined therapies, thereby ultimately accelerating their implementation into clinical protocols. ..

..The present project utilizes a selective pharmacologic approach that targets a novel protein which appears to be important in the trafficking of all leukocyte subsets and, therefore, may prove to have wide-ranging clinical efficacy. ..

..We will also monitor treatment/management changes, and evaluate acceptability of computer assessments and the perceived benefits of the recommendations. ..

..Such a tool would have wide applicability in this patient population and would have tremendous impact on their treatment. ..

..At the conclusion of the trial RAPA toxicity and effect on p-S6K will be defined over a range of doses as well as the MTD for use in future studies that will develop this agent. ..

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..In addition, intradermal microdialysis will be combined with measurements of bioavailable NO by NO-selective amperometric electrode to define further how the NO system functions in cutaneous active vasodilation. ..

..In addition intradermal microdialysis will be combined with measurements of bioavailable NO by hemoglobin-trapping to define further how the NO system functions in cutaneous active vasodilation. ..

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..The results of this exploratory study will provide the preliminary data for a larger study designed to more accurately estimate the predictive power of NM-404 for staging and/or following response to therapy in NSCLC. ..