interacts_with DB00015?
TagSNP evaluation for the association of 42 inflammation loci and vascular disease : evidence of P05231 , P02675 , P09917 , P25963 , and P24394 loci effects . Inflammatory markers have consistently been associated with vascular disease . Evidence of genetic polymorphisms in inflammatory loci that predict severe carotid artery disease ( CAAD ) would suggest that this relationship is not secondary to other correlated factors , but related to inflammation itself . We examined the full common genetic variation in 42 inflammatory loci for prediction of severe CAAD versus ultrasound proven controls using a tagSNP approach . For selected loci , monocyte RNA levels were contrasted in subjects with and without CAAD . We confirm the association of P05231 (-174) , P02675 ( -455 ) , and P09917 with CAAD and show that multiple P09917 SNPs independently predict CAAD . We provide evidence for previously unreported associations of SNPs in P24394 , P25963 , and P00747 with CAAD , and weaker evidence for associations with P09919 , Q13651 , and P19320 . The P25963 and Q13651 expression levels significantly differed between subjects with CAAD and controls . These results support a role for genetic variation related to inflammation in CAAD and a causal role for specific gene products . The P36888 tyrosine kinase receptor inhibits neural stem/progenitor cell proliferation and collaborates with P01138 to promote neuronal survival . The P36888 receptor tyrosine kinase ( P36888 ) was originally identified on hematopoietic stem cells ( HSCs ) and its ligand ( FL ) induces P19526 proliferation . As stem cells originating from various tissues are more similar than once thought , the goal of this study was to determine whether neural stem cells express P36888 and proliferate in response to FL . In fact , a subset of neural stem/progenitor cells does express P36888 , but contrary to our expectations , FL inhibited P01133 and P09038 stimulated proliferation . Since P36888 is expressed weakly by proliferative neuroepithelia but strongly by subsets of neurons in the CNS and PNS , we tested its ability to support neuronal survival . FL synergized with P01138 to promote the survival of cultured Q86YR7 neurons , although it lacked any neurotrophic activity alone . We conclude that FL serves as an adjunct trophic factor in the nervous system , which differs from its role in the hematopoietic system . DB00945 -like drugs , ethanol-induced rat gastric injury and mucosal eicosanoid release . The effect of oral administration of various non-steroidal antiinflammatory drugs on ethanol-induced rat gastric injury and mucosal release of leukotriene C4 , 6-keto-prostaglandin F1 alpha and 15-hydroxy-5,8,11,13-eicosatetraenoic acid was investigated . It was found that besides sodium salicylate and high doses of aspirin , other salicylate-type drugs , such as diflunisal , DB00233 , 2,4-dihydroxybenzoic acid and methyl salicylate , and several non-acidic compounds , such as proquazone , benzydamine and paracetamol , were gastroprotective . All these drugs inhibited ex vivo leukotriene C4 formation by ethanol-stimulated gastric mucosa . However , naproxen , lonazolac , ibuprofen , gentisic acid and DB00244 also inhibited leukotriene C4 formation , but were not protective . Gastroprotection was independent of 6-keto-prostaglandin F1 alpha formation . Both protective and non-protective drugs inhibited the ethanol-stimulated , but not the basal , release of 15-hydroxy-5,8,11,13-eicosatetraenoic acid . The results indicate that the differential effects of various non-steroidal antiinflammatory drugs on gastroprotection against ethanol are not correlated with specific effects on mucosal cyclooxygenase , P09917 or 15-lipoxygenase activity . Clinical trials in thrombolytic therapy , Part 2 : The open-artery hypothesis and RAPID-1 and RAPID-2 . The open-artery hypothesis as supported by thrombolytic study results is discussed . The open-artery hypothesis states that survival after acute myocardial infarction ( AMI ) is maximized by achieving early and sustained patency of the infarct-related artery . However , two large multicenter trials did not detect any difference in mortality between patients given alteplase and patients given streptokinase , despite previous evidence that alteplase led to earlier recanalization of infarct-related arteries . The Global Utilization of DB00086 and Tissue P00747 Activator for Occluded Coronary Arteries ( GUSTO-1 ) trial suggested that early and complete patency is essential for short-term survival after AMI . Subsequent observations indicated that an open infarct-related artery at the time of hospital discharge is associated with improved long-term survival . In the DB00015 Angiographic Phase II International Dose-Finding ( RAPID-1 ) trial , complete patency was more frequent in patients who received a double-bolus regimen of reteplase than in patients who received standard-dose alteplase . Similar results were obtained in the DB00015 versus DB00009 Patency Investigation during Myocardial Infarction ( RAPID-2 ) trial , which compared the same double-bolus reteplase regimen with an accelerated regimen of alteplase . In both RAPID studies , mortality was lower and other outcomes were more favorable in reteplase recipients . DB00015 seems more likely to produce normal blood flow soon after AMI than either standard-dose or accelerated alteplase and may be associated with a lower mortality rate . This lends further support to the open-artery hypothesis . Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5-hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT(1-7) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization-associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1-associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT(7) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT(2B) and 5HT(7) receptors mediated the pro-M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte-to-macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT(2B) was found to be preferentially expressed by anti-inflammatory M2( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor-associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti-inflammatory state via 5HT(2B) and 5HT(7) , whose identification as functionally relevant markers for anti-inflammatory/homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies . DB09045 for the treatment of type 2 diabetes . DB09045 is a novel glucagon-like peptide 1 ( P0C6A0 ) receptor agonist with a unique structure that supports once-weekly dosing in patients with type 2 diabetes ( T2DM ) , most of whom have a big pill burden . It appears to be efficacious in reducing hemoglobin A1c ( HbA1c ) up to 1.59 % and promotes modest weight loss up to 3 kg with a low incidence of hypoglycemia and mild to moderate gastrointestinal adverse events . Convenient weekly dosing could improve compliance and help attain sustained glycemic goals . Addressing obesity is an integral part of T2DM management and weight loss may contribute to better glycemic and cardiovascular benefits . Results of ongoing clinical trials on cardiovascular safety are important to determine the risk-to-benefit ratio . As with any drug , patient selection and ongoing monitoring will be important . If approved , dulaglutide will be one of the first weekly P43220 agonist to be available in a ready-to-use pen device with an automatic injector . Effects of DB09045 on Thyroid C Cells and Serum P01258 in Male Monkeys . Glucagon-like peptide-1 ( P0C6A0 ) receptor agonists , used for the treatment of type 2 diabetes , have caused hyperplasia/neoplasia of thyroid C cells in rodent carcinogenicity studies . Studies in monkeys have not identified an effect of P43220 agonists on thyroid C cells ; however , group sizes were small . DB09045 is a once-weekly , long-acting human P43220 agonist recently approved in the United States and the European Union . The objective of this study was to determine whether dulaglutide altered C-cell mass in monkeys . Male cynomolgus monkeys ( 20 per group ) were sc injected with dulaglutide 8.15 mg/kg ( ∼500-fold maximum human plasma exposure ) or a vehicle control twice weekly for 52 weeks . Basal and calcium gluconate-stimulated serum calcitonin concentrations were obtained at 3 , 6 , 9 , and 12 months . Thyroid glands were weighed , fixed , and sectioned at 500-μm intervals . C-cell volumes were measured using an automated image analysis . C-cell proliferation was estimated using Ki67/calcitonin colabeling and cell counting . Administration of dulaglutide 8.15 mg/kg twice weekly for 52 weeks did not increase serum calcitonin in monkeys or affect thyroid weight , histology , C-cell proliferation , or absolute/relative C-cell volume . This study represents a comprehensive evaluation of the monkey thyroid C cells after dosing with a P43220 agonist , with a large group size , and measurement of multiple relevant parameters . The lack of effect of dulaglutide on C cells is consistent with other studies in monkeys using P43220 agonists and suggests that nonhuman primates are less sensitive than rodents to the induction of proliferative changes in thyroid C cells by P43220 agonists . Differential functional activity of 5-hydroxytryptamine receptor ligands and beta adrenergic receptor antagonists at 5-hydroxytryptamine1B receptor sites in Chinese hamster lung fibroblasts and opossum renal epithelial cells . Functional activity of 5-hydroxytryptamine ( 5-HT ) receptor ligands and beta adrenergic receptor antagonists was studied at P28222 receptor sites in Chinese hamster lung ( CHL ) fibroblasts by measuring two cellular responses : inhibition of forskolin-stimulated cyclic AMP formation and potentiation of basic fibroblast growth ( BFGF ) induced mitogenesis . A good correlation was found between the potency of agonists to inhibit forskolin-induced cyclic AMP formation and their potency to potentiate P09038 -induced thymidine incorporation in CHL fibroblasts . Potent agonist activity was measured with 5-methoxy-3,1,2,3,6-tetrahydro-4-pyidinyl- 1H-indole ( RU 24,969 ) , 5-carboxamidotryptamine ( 5-CT ) , 3-(1,2,5,6)-tetrahydro-4-pyridyl-5-pyrrolo(3,2-b)pyril-5-one ( CP 93,129 ) and 5-HT , whereas sumatriptan displayed weak agonist activity at concentrations different from its binding affinity for P28222 binding sites . In contrast to the observed P28222 receptor-mediated agonist activity in opossum kidney cells for metergoline and the beta adrenergic receptor antagonists : cyanopindolol , 4-(3-tert-butyl-amino-2-hydroxypropoxy)-indole-2 carbonic acid isopropyl ester ( SDZ 21,009 ) , isamoltane , (-)-propranolol and (-)-pindolol , antagonist activity at P28222 receptor sites was yielded in CHL fibroblasts in accordance with the reported observations at rat brain P28222 receptors . Methiothepin was the only compound that antagonized both the opossum kidney cell and CHL fibroblast P28222 receptor-mediated responses although the antagonist effect was more pronounced in CHL fibroblasts. ( ABSTRACT TRUNCATED AT 250 WORDS ) A P43220 agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model . The glucagon like peptide-1 receptor ( P43220 ) agonist liraglutide attenuates induction of plasminogen activator inhibitor type-1 ( P05121 ) and vascular adhesion molecule ( VAM ) expression in human vascular endothelial cells ( hVECs ) in vitro and may afford protection against endothelial cell dysfunction ( O95905 ) , an early abnormality in diabetic vascular disease . Our study aimed to establish the dependence of the in vitro effects of liraglutide on the P43220 and characterise its in vivo effects in a mouse model of O95905 . In vitro studies utilised the human vascular endothelial cell line P10144 - Q8IWL8 and enzyme-linked immunosorbent assays ( ELISA ) for determination of P05121 and VAM expression . In vivo studies of vascular reactivity and immunohistochemical analysis were performed in the ApoE(-/-) mouse model . In vitro studies demonstrated P43220 -dependent liraglutide-mediated inhibition of stimulated P05121 and VAM expression . In vivo studies demonstrated significant improvement in endothelial function in liraglutide treated mice , a P43220 dependent effect . DB06655 treatment also increased endothelial nitric oxide synthase ( P29474 ) and reduced intercellular adhesion molecule-1 ( P05362 ) expression in aortic endothelium , an effect again dependent on the P43220 . Together these studies identify in vivo protection , by the P43220 agonist liraglutide , against O95905 and provide a potential molecular mechanism responsible for these effects . [(11)C]5-HTP and microPET are not suitable for pharmacodynamic studies in the rodent brain . The PET tracer [(11)C]5-hydroxytryptophan ( [(11)C]5-HTP ) , which is converted to [(11)C]5-hydroxytryptamine ( [(11)C]5-HT ) by aromatic amino acid decarboxylase ( P20711 ) , is thought to measure 5-HT synthesis rates . But can we measure these synthesis rates by kinetic modeling of [(11)C]5-HTP in rat ? Male rats were scanned with [(11)C]5-HTP ( 60 minutes ) after different treatments . Scans included arterial blood sampling and metabolite analysis . 5-HT synthesis rates were calculated by a two-tissue compartment model ( 2TCM ) with irreversible tracer trapping or Patlak analysis . DB00190 ( inhibitor peripheral P20711 ) dose-dependently increased [(11)C]5-HTP brain uptake , but did not influence 2TCM parameters . Therefore , 10 mg/kg carbidopa was applied in all subsequent study groups . These groups included treatment with NSD 1015 ( general P20711 inhibitor ) or p-chlorophenylalanine ( PCPA , inhibitor of tryptophan hydroxylase , P17752 ) . In addition , the effect of a low-tryptophan ( DB00150 ) diet was investigated . NSD 1015 or DB00150 depletion did not affect any model parameters , but PCPA reduced [(11)C]5-HTP uptake , and the k3 . This was unexpected as NSD 1015 directly inhibits the enzyme converting [(11)C]5-HTP to [(11)C]5-HT , suggesting that trapping of radioactivity does not distinguish between parent tracer and its metabolites . As different results have been acquired in monkeys and humans , [(11)C]5-HTP-PET may be suitable for measuring 5-HT synthesis in primates , but not in rodents . Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism (PE). tPA has not been replaced by third generation plasminogen activators , e.g. DB00015 ( Ret ) and DB00031 ( TNK ) that circulate with longer life-spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor-1 ( e.g. P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility . Natriuretic peptide/natriuretic peptide receptor-A ( P16066 ) system has inhibitory effects in renal fibrosis in mice . OBJECT : This study was designed to examine whether natriuretic peptide/natriuretic peptide receptor-A ( P16066 ) system attenuates renal fibrosis in a unilateral ureteral obstruction ( UUO ) model and also examined the mechanism involved . METHODS : Three groups were studied : untreated UUO in wild-type mice ; untreated UUO in P16066 KO mice ; and P01160 treated ( 0.05 microg/kg/min ) UUO in wild-type mice . We measured histological and immunohistochemical findings ( alpha-SMA and F4/80 ) , tissue cGMP levels , various mRNA expression levels by real-time PCR analysis , and transcription factor levels ( AP-1 and NF-kappaB ) in renal tissue . RESULTS : Compared with wild-type UUO mice , NPRA-KO UUO mice had abnormal morphological findings ( fibrous area : +26 % , alpha-SMA expression : +30 % ) with lower tissue cGMP levels and increases in the mRNA expression levels of TGF-beta , collagen I , collagen III , P05121 , renin and angiotensinogen , whereas there were no differences in F4/80 positive cells or the mRNA expression levels of P05362 , osteopontin , or P13500 between the two groups . In contrast , P01160 pre-treatment significantly improved morphological changes with increase of tissue cGMP levels and reduction in the mRNA expression level of TGF-beta , collagen I , collagen III , P05121 , P05362 , osteopontin , P13500 , renin , and angiotensinogen . NPRA-KO UUO mice had higher AP-1 levels than wild-type UUO mice and P01160 pre-treatment reduced AP-1 and NF-kappaB activity . CONCLUSION : The endogenous natriuretic peptide/ P16066 system may inhibit renal fibrosis partly via inhibition of the angiotensin/AP-1/TGF-beta/collagen pathway and exogenous P01160 pre-treatment may inhibit it partly via both the angiotensin/AP-1/TGF-beta/collagen and NF-kappaB/inflammatory pathways . P11362 - 5-hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5-hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co-immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) -5-hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co-immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal-regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal-regulated kinase 1/2 in rat hippocampus without changing P09038 levels . Co-activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8-OH-DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5-HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling . Comparative P15692 receptor tyrosine kinase modeling for the development of highly specific inhibitors of tumor angiogenesis . The Vascular Endothelial Growth Factor receptors ( P15692 -Rs ) play a significant role in tumor development and tumor angiogenesis and are therefore interesting targets in cancer therapy . Targeting the P15692 -R is of special importance as the feed of the tumor has to be reduced . In general , this can be carried out by inhibiting the tyrosine kinase function of the P15692 -R . Nevertheless , there arise some problems with the specificity of known kinase inhibitors : they bind to the DB00171 -binding site and inhibit a number of kinases , moreover the so far most specific inhibitors act at least on these three major types of P15692 -Rs : Flt-1 , Flk-1/ P35968 , Flt-4 . The goal is a selective P15692 -R-2 ( Flk-1/ P35968 ) inhibitor , because this receptor triggers rather unspecific signals from P15692 , -C , -D and -E . Here , we describe a protocol starting from an established inhibitor ( DB04879 ) with 2D-/3D-searching and property filtering of the in silico screening hits and the " negative docking approach " . With this approach we were able to identify a compound , which shows a fourfold higher reduction of the proliferation rate of endothelial cells compared to the reduction effect of the lead structure . Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging , " Q9UEF7 " mouse . Although aging accompanies specific pathological changes , including thrombosis and organ sclerosis , the underlying mechanisms of these processes remain to be elucidated . In the present study , we analyzed the gene expression of plasminogen activator inhibitor-1 ( P05121 ) , a key molecule in the development of thrombosis , in a murine model of aging , klotho mutant ( kl/kl ) mice . Active P05121 antigen in plasma and P05121 mRNA in several tissues were strikingly elevated in kl/kl mice as compared with wild-type mice . This increased P05121 expression was age dependent and linked to the development of ectopic calcification and glomerular fibrin deposition in the kidneys . In situ hybridization analysis of kl/kl mice demonstrated that strong signals for P05121 mRNA were localized in renal tubular epithelial cells , cardiomyocytes , adrenal medullar cells , and smooth muscle and endothelial cells in Mönckeberg 's arteriosclerotic vessels . Renal glomerular fibrin deposition , as evaluated immunohistochemically , was occasionally observed only in kl/kl mice , and the number of fibrin-positive glomeruli increased as the kl/kl mice aged . These observations suggest that in the process of aging the P05121 gene expression is increased , contributing to the development of thrombosis . Vascular endothelial growth factor receptor tyrosine kinase inhibitors : PTK787/ZK 222584 . PTK787/ZK 222584 ( DB04879 ) is an oral potent and selective inhibitor of the vascular endothelial growth factor ( P15692 ) -mediated Flt-1 and P35968 receptor tyrosine kinases . DB04879 has been shown to reduce growth and microvasculature in subcutaneously implanted human tumor xenografts in nude mice . A clinical difficulty in evaluating angiogenesis inhibitors has been the usefulness of conventional study endpoints . Therefore , dynamic contrast-enhanced magnetic resonance imaging ( DCE- Q9BWK5 ) has been studied as a pharmacodynamic marker of efficacy of DB04879 . Phase I studies are under way evaluating the optimum dose and schedule of oral DB04879 administered continuously to patients with advanced cancers of types known to overexpress P15692 . To date , particularly in patients with liver metastases from colorectal cancer treated with DB04879 , DCE- Q9BWK5 has been a useful predictor of the biological response of P15692 -receptor inhibition . Toxicities have been manageable and have included lightheadedness , ataxia , nausea , vomiting , and hypertension . Stabilization of disease for >/= 6 months has been seen in heavily pretreated patients receiving DB04879 at higher doses . Preliminary data suggest that DB04879 can be administered safely on a continuous daily dosing schedule , efficacy data look promising , and DCE- Q9BWK5 correlates with biological response . DCE- Q9BWK5 will be used to guide dose optimization of DB04879 and perhaps of other angiogenesis inhibitors in future studies . Effect of DB00015 and P05121 antibodies on postoperative adhesion formation in a laparoscopic mouse model . BACKGROUND : Postoperative adhesions remain an important clinical problem , accounting for infertility , chronic pain and bowel obstruction . Its prevention is still inadequate and overall poorly understood . The aim of this study was to investigate the effect of DB00015 ( a recombinant plasminogen activator , r-PA ) and of P05121 antibodies upon adhesion formation in a laparoscopic model . METHODS : Pneumoperitoneum-enhanced adhesions were induced by performing a bipolar lesion in female BALB/c mice and by using pure and humidified CO(2) as insufflation gas for 60 min . In experiment 1 , four doses of 0.125 , 0.25 , 0.5 and 1 mg/0.5 ml r-PA and one and two doses of 1 mg r-PA were administrated i.p . Two control groups were included , one without any treatment and the second one receiving four times 0.5 ml of saline . In experiment 2 , four doses of 0 , 1 , 10 and 100 microg/0.5 ml r-PA were administrated i.p . In experiment 3 , P05121 neutralising and non-neutralising antibodies were injected i.p. after performing the lesion on day 0 and days 2 and 4 . Adhesions were scored after 7 days . RESULTS : Adhesion formation was less with the administration of four doses of 1 microg r-PA ( proportion , p < 0.04 , Wilcoxon ) . An increase in adhesion formation was observed when higher number of doses and amounts of r-PA were used ( Proc GLM , eight groups , two variables , p = 0.05 for the amount of r-PA and p < 0.02 for the number of doses administrated ) . No effect was observed with the P05121 antibodies . CONCLUSIONS : Low-dose i.p. administration of rPA is effective in the prevention of adhesions in a laparoscopic mouse model . How does almotriptan compare with other triptans ? A review of data from placebo-controlled clinical trials . DB00918 , the new selective P28222 /1D agonist , has a higher oral bioavailability than any other DB00669 , with more than two thirds of the administered dose absorbed within the first hour both inside and outside of a migraine attack . Gender or the presence of food in the stomach does not affect its pharmacokinetic profile , and the compound has no clinically relevant interactions with other drugs . Among the available triptans , response rates at 2 hours range from 50 % to 80 % , with 20 % to 50 % of patients pain-free . DB00918 12.5 mg provides similar efficacy , with significant advantage over placebo at 30 minutes and a reliable consistency ( 75 % in two of three attacks ) . Headache typically recurs in 25 % to 45 % of patients with most triptans . The recurrence rate with almotriptan 12.5 mg , 18 % to 27 % , is among the lowest reported . The tolerability of almotriptan 12.5 mg is close to that of placebo with a low incidence of central nervous system side effects and chest symptoms . In conclusion , almotriptan 's consistent pharmacokinetics and good efficacy , in combination with excellent tolerability , make it an attractive choice in the acute treatment of migraine attacks . Disposition and metabolism of almotriptan in rats , dogs and monkeys . DB00918 is a new highly potent selective P28222 /1D receptor agonist developed for the treatment of migraine , and the disposition of almotriptan in different animal species is now addressed in the current study . DB00918 was well absorbed in rats ( 69.1 % ) and dogs ( 100 % ) following oral treatment . The absolute bioavailability was variable reflecting different degrees of absorption and first-pass metabolism ( 18.7-79.6 % ) . The elimination half-life was short and ranged between 0.7 and 3 h . The main route of elimination of almotriptan was urine with 75.6 % and 80.4 % of the dose recovered over a 168-h period in rats and dogs , respectively . The gamma-aminobutyric acid metabolite formed by oxidation of the pyrrolidine ring was the main metabolite found in urine , faeces , bile , and plasma of rats and in monkey urine . By contrast , the unchanged drug , the indole acetic acid metabolite formed by oxidative deamination of the dimethylaminoethyl group , and the N-oxide metabolite were the main metabolites in dog . DB06080 , a multitargeted receptor tyrosine kinase inhibitor : inhibition of P36888 phosphorylation and signaling in acute myeloid leukemia . In 15 % to 30 % of patients with acute myeloid leukemia ( AML ) , aberrant proliferation is a consequence of a juxtamembrane mutation in the P36888 gene ( P07333 -like tyrosine kinase 3-internal tandem duplication [ P36888 -ITD ] ) , causing constitutive kinase activity . DB06080 ( a multitargeted receptor tyrosine kinase inhibitor ) inhibited the phosphorylation of P36888 , P42229 , and P29323 , as well as Pim-1 expression in MV-4-11 and MOLM-13 cells ( IC(50) approximately 1-10 nM ) harboring the P36888 -ITD . DB06080 inhibited the proliferation of these cells ( IC(50) = 4 and 6 nM , respectively ) through the induction of apoptosis ( increased sub-G(0)/G(1) phase , caspase activation , and PARP cleavage ) , whereas cells harboring wild-type (wt)- P36888 were less sensitive . In normal human blood spiked with AML cells , DB06080 inhibited phosphorylation of P36888 ( IC(50) approximately 100 nM ) , P42229 , and P29323 , and decreased Pim-1 expression . In methylcellulose-based colony-forming assays , DB06080 had no significant effect up to 1000 nM on normal hematopoietic progenitor cells , whereas in AML patient samples harboring both P36888 -ITD and wt- P36888 , DB06080 inhibited colony formation ( IC(50) = 100 and 1000 nM , respectively ) . DB06080 dose-dependently inhibited MV-4-11 and MOLM-13 flank tumor growth , prevented tumor formation , regressed established MV-4-11 xenografts , and increased survival by 20 weeks in an MV-4-11 engraftment model . In tumors , DB06080 inhibited P36888 phosphorylation , induced apoptosis ( transferase-mediated dUTP nick-end labeling [ TUNEL ] ) and decreased proliferation ( Ki67 ) . DB06080 is under clinical development for AML . Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury-associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng/ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs. P09038 ( 10 ng/ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease . P20711 inhibition does not influence the diuretic and natriuretic response to exogenous alpha-atrial natriuretic peptide in man . The role of dopamine synthesis in the renal actions of human alpha-atrial natriuretic peptide ( alpha P01160 ) was investigated in six dehydrated volunteers using the P20711 inhibitor carbidopa . Each subject received oral placebo or carbidopa ( 100 mg ) followed by an infusion of alpha P01160 10 pmol.kg-1.min-1 for 1 h . The responses to placebo alone and to carbidopa alone were investigated on separate occasions. alpha P01160 produced a similar increase in plasma immunoreactive alpha P01160 whether placebo or carbidopa pretreatment had been given . Urinary dopamine excretion was increased by alpha P01160 . DB00190 pretreatment substantially attenuated this increase without affecting the natriuretic or water-diuretic response to alpha P01160 . DB00190 also failed to alter the change in filtration fraction produced by alpha P01160 . The results suggest that increased synthesis of intrarenal dopamine is not required for the renal effects of alpha P01160 in man . Q9UEF7 gene deficiency causes salt-sensitive hypertension via monocyte chemotactic protein-1/CC chemokine receptor 2-mediated inflammation . Q9UEF7 ( KL ) is a newly discovered aging suppressor gene . In mice , the KL gene extends the lifespan when overexpressed and shortens the lifespan when disrupted . This study investigated if KL deficiency affects BP and salt sensitivity using KL mutant heterozygous ( +/- ) mice and wild-type ( WT ) mice ( 9 weeks of age , 16 mice per group ) . Notably , systolic BP in KL(+/-) mice began to increase at the age of 15 weeks , reached a peak level at the age of 17 weeks , and remained elevated thereafter , whereas systolic BP remained consistent in WT mice . High salt ( HS ) intake further increased BP in KL(+/-) mice but did not affect BP in WT mice . Blockade of CC chemokine receptor 2 ( P41597 ) , involved in monocyte chemotaxis , by a specific P41597 antagonist ( DB05130 ) abolished the HS-induced increase in BP in KL(+/-) mice . Furthermore , HS loading substantially increased the expression of monocyte chemotactic protein-1 and the infiltration of macrophages and T cells in kidneys in KL(+/-) mice , and treatment with DB05130 abolished these effects . Treatment of KL(+/-) mice with DB05130 also attenuated the increased renal expressions of serum glucocorticoid-regulated kinase 1 , thiazide-sensitive NaCl cotransporter , and DB00171 synthase β along with the renal structural damage and functional impairment induced by HS loading . In conclusion , KL deficiency caused salt-sensitive hypertension and renal damage by P41597 -mediated inflammation . Gremlin gene expression in bovine retinal pericytes exposed to elevated glucose . AIM : To assess the influence of high extracellular glucose on the expression of the bone morphogenetic protein ( BMP ) antagonist , gremlin , in cultured bovine retinal pericytes ( BRPC ) . METHODS : BRPC were cultured under conditions of 5 mM and 30 mM d-glucose for 7 days and total RNA was isolated . Gremlin mRNA levels were correlated , by RT-PCR , with other genes implicated in the pathogenesis of diabetic retinopathy and the signalling pathways in high glucose induced gremlin expression were probed using physiological inhibitors . Gremlin expression was also examined in the retina of streptozotocin induced diabetic mice . RESULTS : High glucose stimulated a striking increase in BRPC gremlin mRNA levels in parallel with increases in mRNA for the growth factors vascular endothelial growth factor ( P15692 ) , transforming growth factor beta ( TGFbeta ) , and connective tissue growth factor ( P29279 ) and changes in other genes including fibronectin and plasminogen activator inhibitor-1 ( P05121 ) . High glucose triggered gremlin expression was modulated by anti-TGFbeta antibody , by the uncoupler of oxidative phosphorylation , CCCP , and by inhibition of Q96HU1 -kinase ( MAPK ) activation . Striking gremlin expression was observed in the outer retina of diabetic mice and also at the level of the vascular wall . CONCLUSIONS : Gremlin gene expression is induced in BRPC in response to elevated glucose and in the retina of the streptozotocin induced diabetic mouse . Its expression is modulated by hyperglycaemic induction of the MAPK , reactive oxygen species , and TGFbeta pathways , all of which are reported to have a role in diabetic fibrotic disease . This implicates a role for gremlin in the pathogenesis of diabetic retinopathy . Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF-kappaB/Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF-kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and -beta proteins . RESULTS : NF-kappaB/Rel activity induced by tumor necrosis factor alpha , 12-O-tetradecanoylphorbol-13-acetate , or overexpression of NF-kappaB-inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or DB00233 had no effect . Activation of extracellular signal-related kinase ( P29323 ) 1 and 2 , c-Jun-N-terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and -beta by antagonizing adenosine triphosphate binding . The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine . DB06016 ( RGH-188 ) , a potent D3/D2 dopamine receptor partial agonist , binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents . We investigated the in vivo effects of orally administered cariprazine ( RGH-188 ; trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N',N'-dimethyl-urea ) , a D(3)/ P14416 partial agonist with ∼10-fold preference for the D(3) receptor . Oral bioavailability of cariprazine at a dose of 1mg/kg in rats was 52 % with peak plasma concentrations of 91ng/mL . DB06016 10mg/kg had good blood-brain barrier penetration , with a brain/plasma AUC ratio of 7.6:1 . In rats , cariprazine showed dose-dependent in vivo displacement of [ (3)H ] (+)-PHNO , a dopamine D(3) receptor-preferring radiotracer , in the D(3) receptor-rich region of cerebellar lobules 9 and 10 . Its potent inhibition of apomorphine-induced climbing in mice ( ED(50)=0.27mg/kg ) was sustained for 8h . DB06016 blocked amphetamine-induced hyperactivity ( ED(50)=0.12mg/kg ) and conditioned avoidance response ( CAR ) ( ED(50)=0.84mg/kg ) in rats , and inhibited the locomotor-stimulating effects of the noncompetitive DB01221 antagonists MK-801 ( ED(50)=0.049mg/kg ) and phencyclidine ( ED(50)=0.09mg/kg ) in mice and rats , respectively . It reduced novelty-induced motor activity of mice ( ED(50)=0.11mg/kg ) and rats ( ED(50)=0.18mg/kg ) with a maximal effect of 70 % in both species . DB06016 produced no catalepsy in rats at up to 100-fold dose of its CAR inhibitory ED(50) value . DB06016 0.02-0.08mg/kg significantly improved the learning performance of scopolamine-treated rats in a water-labyrinth learning paradigm . Though risperidone , olanzapine , and aripiprazole showed antipsychotic-like activity in many of these assays , they were less active against phencyclidine and more cataleptogenic than cariprazine , and had no significant effect in the learning task . The distinct in vivo profile of cariprazine may be due to its higher affinity and in vivo binding to D(3) receptors versus currently marketed typical and atypical antipsychotics . Dual ligands targeting dopamine D2 and serotonin P08908 receptors as new antipsychotical or anti-Parkinsonian agents . Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson 's disease are associated with poly-factorial pathogenic mechanisms , with several neurotransmitter systems closely involved . In addition to the cerebral dopaminergic ( DA ) system , the serotoninergic ( 5-HT ) system also plays a crucial role in regulating psychoemotional , cognitive and motor functions in the central nervous system ( CNS ) . Among the large 5-HT receptor family , accumulating data have revealed new insights into the therapeutic benefit of the P08908 receptor in treating various CNS disorders , especially schizophrenia and Parkinson 's disease . The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin P08908 receptors in the treatment of these diseases . Aripiprazole was the only marketed drug with dual D2 and P08908 profile . It is a partial D2 and P08908 receptor agonist and has been prescribed as an atypical antipsychotical drug . Two other drugs DB06016 and Pardoprunox are being investigated in clinic . Most of the other candidate compounds , including DB04888 , Sarizotan , Mazapertine succinate , PF-217830 , and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy . Although much effort has been done to highlight the advantages of the P08908 and D2 dual approach , it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D2 and P08908 receptors . In this regard , ' pure ' compounds exclusively acting on the D2 and P08908 receptors are highly needed to further validate this approach . Meanwhile , safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early . Differentiation of dopaminergic neurons from human embryonic stem cells : modulation of differentiation by Q9NP95 . Derivation of midbrain dopaminergic ( DA ) neurons from human embryonic stem ( hES ) cells has been of particular interest because of the clinical potential for DA neuron transplantation in patients with Parkinson 's disease ( PD ) . Several protocols for DA neuron differentiation from mouse embryonic stem cells and hES cells have been reported : however , protocols involving hES cells have yet to be improved . Here , we used a slightly modified stromal cell-derived inducing activity method , consisting four different culture stages , to show that KhES-1 cells differentiate into tyrosine hydroxylase ( TH ) -positive DA neurons . Quantitative real-time PCR analysis showed a marked induction of the DA neuron marker genes P43354 , paired-like homeodomain transcription factor 3 ( O75364 ) , LIM homeobox transcription- factor 1 , beta ( O60663 ) , engrailed-1 ( Q05925 ) , dopamine transporter ( Q01959 ) , and aromatic amino acid decarboxylase ( P20711 ) during differentiation . Treatment with fibroblast growth factor ( FGF ) -20 and P09038 at the final differentiation stage induced the increase of DA neuron development-related transcription factors such as P43354 , O75364 , O60663 , and Q05925 . Q9NP95 and P09038 enhanced DA neuron differentiation from hES cell-derived neural progenitor cells directly without any soluble factors from PA6 cells . These results provide valuable information that will assist in efficient DA neuron differentiation from hES cells and for future transplant application . Transforming growth factor alpha-induced expression of type 1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity . Although transforming growth factor ( TGF ) -alpha , a member of the epidermal growth factor ( P01133 ) family , has been shown to protect neurons against excitotoxic and ischemic brain injuries , its mechanism of action remains unknown . In the present study , we used in vitro models of apoptotic or necrotic paradigms demonstrating that TGF-alpha rescues neurons from N-methyl-D-aspartate ( DB01221 ) -induced excitotoxic death , with the obligatory presence of astrocytes . Because neuronal tissue-type plasminogen activator ( t-PA ) release was shown to potentiate DB01221 -induced excitotoxicity , we observed that TGF-alpha treatment reduced DB01221 -induced increase of t-PA activity in mixed cultures of neurons and astrocytes . In addition , we showed that although TGF-alpha induces activation of the extracellular signal-regulated kinases ( ERKs ) in astrocytes , it failed to activate Q8NFH3 / Q8TCB0 in neurons . Finally , we showed that TGF-alpha , by an P29323 -dependent mechanism , stimulates the astrocytic expression of P05121 , a t-PA inhibitor , which mediates the neuroprotective activity of TGF-alpha against DB01221 -mediated excitotoxic neuronal death . Taken together , we indicate that TGF-alpha rescues neurons from DB01221 -induced excitotoxicity in mixed cultures through inhibition of t-PA activity , involving P05121 overexpression by an P29323 -dependent pathway in astrocytes . Development of peptidomimetic ligands of Pro- DB00149 - DB00145 -NH(2) as allosteric modulators of the dopamine D(2) receptor . A variety of stable , small-molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro- DB00149 - DB00145 -NH(2) ( P00747 ) modulates dopaminergic neurotransmission . Photoaffinity labeling ligands based upon P00747 peptidomimetics have been used to establish that P00747 binds to the P14416 at a site that is different from the orthosteric site , thus making P00747 and its peptidomimetics allosteric modulators of the dopamine receptor . Through the design , synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam , bicyclic , and spiro-bicyclic scaffolds , support was provided for the hypothesis that the bioactive conformation of P00747 is a type II β-turn . In addition , studies with peptidomimetics designed to mimic either a type VI β-turn or polyproline II helix conformation yielded molecules that were able to modulate dopamine receptors because of their ability to place the carboxamide NH(2) pharmacophore in the same topological space as that seen in the type II β-turn . Extensive studies with the spiro-bicyclic P00747 peptidomimetics also established that both positive and negative modes of modulation were possible for the same series of peptidomimetics simply as a result of minor differences in the stereochemistry about the bridgehead carbon within the scaffold . This information was used to transform existing positive modulators into negative modulators , which demonstrated that small structural changes in the spiro-bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of P00747 peptidomimetics . The multitargeted receptor tyrosine kinase inhibitor linifanib ( DB06080 ) induces apoptosis through an Akt and glycogen synthase kinase 3β-dependent pathway . The P07333 -like receptor tyrosine kinase 3 ( P36888 ) plays an important role in controlling differentiation and proliferation of hematopoietic cells . Activating mutations in P36888 occur in patients with acute myeloid leukemia ( AML ; 15 % -35 % ) , resulting in abnormal cell proliferation . Furthermore , both adult and pediatric patients with AML harboring the P36888 internal tandem duplication ( ITD ) mutation have a poor prognosis . Several inhibitors have been developed to target mutant P36888 for the treatment of AML , yet the molecular pathways affected by drug inhibition of the mutated P36888 receptor alone have not been characterized as yet . Linifanib ( DB06080 ) is a multitargeted tyrosine kinase receptor inhibitor that suppresses P36888 signaling . In this article , we show that treatment with linifanib inhibits proliferation and induces apoptosis in ITD mutant cells in vitro and in vivo . We show that treatment with linifanib reduces phosphorylation of Akt and glycogen synthase kinase 3β ( GSK3β ) . In addition , we show that inhibition of GSK3β decreases linifanib-induced apoptosis . This study shows the importance of GSK3 as a potential target for AML therapy , particularly in patients with P36888 ITD mutations . P01258 gene-related peptide regulates mitogen-activated protein kinase pathway to decrease transforming growth factor β1-induced hepatic plasminogen activator inhibitor-1 mRNA expression in HepG2 cells . Transforming growth factor ( TGF ) β1-induced plasminogen activator inhibitor ( P05121 ) -1 is one of factors associated with the development of hepatic fibrosis . P01258 gene-related peptide ( P80511 ) shows hepatoprotective effect during hepatic injuries , including fibrosis . However , the effects of P80511 on P05121 expression induced by TGFβ1 are unknown . In this study , we investigated the effect of P80511 on TGFβ1-induced P05121 expression and its regulatory mechanisms in HepG2 cells . P80511 inhibited TGFβ1-induced P05121 expression . H89 , a protein kinase A inhibitor , abolished the inhibition of TGFβ1-induced P05121 expression by P80511 . TGFβ1 activated mitogen-activated protein kinase ( MAPK ) , including extracellular signal-regulated kinase , c-jun NH2-terminal kinase , and p38 , and this activation was abolished by P80511 . These results show that the P80511 -induced DB02527 /PKA activation suppresses activation of MAPK induced by TGFβ1 , leading to decreased P05121 expression in HepG2 cells . Characterisation of the contractile activity of eletriptan at the canine vascular P28222 receptor . The functional activity of eletriptan ( ( R ) -3-(1-methyl-2-pyrrolidinylmethyl)-5- [ 2- ( phenylsulphonyl ) ethyl ] - 1 H-indole ) at the contractile serotonin ( 5-hydroxytryptamine ; 5-HT ) ' 1B-like ' receptor in dog isolated saphenous vein and basilar artery was investigated . DB00216 , like 5-HT and sumatriptan potently contracted saphenous vein ( pEC50 : 6.3 , 6.9 and 6.1 , respectively ) and basilar artery ( pEC50 7.2 , 7.5 and 6.8 , respectively ) . The maximum responses evoked by eletriptan was , unlike sumatriptan , significantly lower than that to 5-HT ( intrinsic activity saphenous vein : eletriptan 0.57 , 5-HT 1.0 , sumatriptan 0.85 ; basilar artery : eletriptan 0.77 , 5-HT 0.98 , sumatriptan 0.89 ) . Contractions evoked by eletriptan were antagonised by the P28222 /1D receptor antagonist GR125743 ( N- [ 4-methoxy-3- ( 4-methyl piperazin-1-yl ) phenyl ] -3-methyl-4-(4-pyridyl)benzamide ) with pA2 values of 9.1 in saphenous vein and 9.4 in basilar artery . Affinity estimates ( pKA ) for 5-HT and sumatriptan determined from receptor alkylation studies in saphenous vein were 6.6 and 6.3 , respectively , compared to the apparent equilibrium dissociation constant ( pKp ) for eletriptan of 6.8 . The rank order of relative intrinsic efficacies ( epsilon ) was 5-HT > sumatriptan > eletriptan . Thus , eletriptan required greater receptor occupancy ( 4.4-fold ) to evoke an equivalent contraction to 5-HT and sumatriptan in dog isolated saphenous vein . These data demonstrate that eletriptan is a potent partial agonist at the canine vascular P28222 receptor . Discovery of DB05130 , a Potent , Selective , and Orally Bioavailable hCCR2 Antagonist . We report the identification of 13 ( DB05130 ) as a potent human P41597 ( hCCR2 ) antagonist . DB05130 exhibited an IC50 of 3.7 nM in antagonism of monocyte chemoattractant protein-1 binding to hCCR2 , an IC50 of 4.7 nM in antagonism of chemotaxis activity , an IC50 of 84 μM in inhibition of the hERG potassium current , a free fraction of 58 % in protein binding , high selectivity over other chemokine receptors and G-protein-coupled receptors , and acceptable oral bioavailability in rodents and primates . In human clinical trials , DB05130 exhibited a pharmacokinetic profile suitable for once-a-day dosing ( T 1/2 = 15 h ) . Helicobacter pylori-induced interleukin-12 p40 expression . Interleukin-12 ( IL-12 ) is a heterodimeric cytokine produced by antigen-presenting cells that promotes the development of T-helper lymphocyte 1 ( Th1 ) . Chronic gastritis induced by Helicobacter pylori is considered a Th1-mediated process . IL-12 levels in gastric biopsy samples of H. pylori-infected patients are higher than in those of uninfected individuals , but the cellular source of IL-12 remains elusive . IL-12 staining was detected in mucosal epithelial cells , lymphocytes , and macrophages in specimens of patients with H. pylori-positive gastritis . Therefore , we investigated IL-12 p40 mRNA induction by H. pylori in gastric epithelial cells and T cells . Although cag pathogenicity island ( P05121 ) -positive H. pylori induced IL-12 p40 mRNA expression , an isogenic mutant of the cag P05121 failed to induce it in both cell types . Supernatants from H. pylori cultures and H. pylori VacA induced IL-12 p40 mRNA expression in T cells but not in epithelial cells . The activation of the IL-12 p40 promoter by H. pylori was mediated through NF-kappaB . The transfection of O15111 and NF-kappaB-inducing kinase dominant-negative mutants inhibited H. pylori-induced IL-12 p40 activation . Inhibitors of NF-kappaB , phosphatidylinositol 3-kinase , p38 mitogen-activated protein kinase , and Hsp90 suppressed H. pylori- and VacA-induced IL-12 p40 mRNA expression . The results indicate that H. pylori induces IL-12 p40 expression by the activation of NF-kappaB , phosphatidylinositol 3-kinase , and p38 mitogen-activated protein kinase . Hsp90 is also a crucial regulator of H. pylori-induced IL-12 p40 expression . In addition to the cag P05121 , VacA might be relevant in the induction of IL-12 expression and a Th1-polarized response only in T cells . Porcine carotid vascular effects of eletriptan ( UK-116,044 ) : a new P28222 /1D receptor agonist with anti-migraine activity . It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine . Indeed , a number of acutely acting anti-migraine drugs , including the ergot alkaloids and sumatriptan , constrict porcine carotid arteriovenous anastomoses . In this study , using pentobarbital anaesthetised pigs , we investigated the effects of eletriptan , a close structural analogue of sumatriptan , on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient ( capillary ) fractions . DB00216 ( 10 , 30 , 100 , 300 and 1000 microg kg(-1) , i.v. ) decreased the total carotid blood flow , exclusively by decreasing cephalic arteriovenous anastomotic blood flow ; nutrient blood flow , particularly to the ear , skin and fat , was significantly increased . The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50 % ( ED50 ) were , respectively , 117+/-21 microg kg(-1) ( 251+/-45 nmol kg(-1) ) and 184+/-42 microg kg(-1) ( 396+/-91 nmol kg(-1) ) ; the highest dose caused reductions of 84+/-3 % and 77+/-4 % , respectively . The eletriptan-induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective P28222 /1D receptor antagonist GR127935 ( 0.5 mg kg(-1) ) . On the basis of these results , we conclude that ( 1 ) the eletriptan-induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by P28222 /1D receptors , and ( 2 ) eletriptan should be effective in aborting migraine headache . Clinical studies have already demonstrated its therapeutic action in migraine patients .