interacts_with DB00005?
DB00005 ( Enbrel ) : update on therapeutic use . Tumour necrosis factor ( P01375 ) is an important inflammatory disease mediator in a wide spectrum of articular diseases , including adult and juvenile rheumatoid arthritis ( RA , JRA ) . DB00005 ( Enbrel ) , approved in the United States and in Europe for use in patients with RA and JRA , is an effective inhibitor of P01375 that has been shown to provide rapid and sustained improvement in both of these diseases . Long term studies continue to show that etanercept controls signs and symptoms of RA and JRA with no change in rate or type of adverse event over time . To demonstrate that etanercept is effective as first line treatment for patients with early active RA who have not been previously treated with methotrexate , and to examine the effect of etanercept on radiographic progression , a double blind , placebo controlled study was recently conducted , comparing etanercept with methotrexate ( median dose 20 mg per week ) . Both etanercept 25 mg twice weekly and rapidly escalated methotrexate were effective in reducing the signs and symptoms of RA , and etanercept was significantly better than methotrexate in slowing the rate of radiographic erosions . In patients with severe psoriatic arthritis ( PsA ) , a double blind , placebo controlled study demonstrated that etanercept was also effective in reducing disease activity in PsA . DB00005 has been well tolerated in all of these clinical trials and offers an important new treatment option to patients with inflammatory articular diseases . Case reports of heart failure after therapy with a tumor necrosis factor antagonist . BACKGROUND : DB00005 and infliximab are U.S . Food and Drug Administration-approved tumor necrosis factor ( P01375 ) antagonists . OBJECTIVE : To describe adverse event reports of heart failure after P01375 antagonist therapy . DESIGN : Case series . SETTING : The U.S . Food and Drug Administration 's MedWatch program . PATIENTS : 47 patients who developed new or worsening heart failure during P01375 antagonist therapy . MEASUREMENTS : Clinical and laboratory reports . RESULTS : After P01375 antagonist therapy , 38 patients developed new-onset heart failure and 9 patients experienced heart failure exacerbation . Of the 38 patients with new-onset heart failure , 19 ( 50 % ) had no identifiable risk factors . Ten patients younger than 50 years of age developed new-onset heart failure after receiving P01375 antagonists . After P01375 antagonist therapy was discontinued and heart failure therapy was started in these 10 patients , 3 had complete resolution of heart failure , 6 improved , and 1 died . CONCLUSION : In a fraction of patients , P01375 antagonists might induce new-onset heart failure or exacerbate existing disease . Inhibition of JAKs in macrophages increases lipopolysaccharide-induced cytokine production by blocking P22301 -mediated feedback . Macrophages are an important source of cytokines following infection . Stimulation of macrophages with TLR agonists results in the secretion of P01375 -α , P05231 , and IL-12 , and the production of these cytokines is controlled by multiple feedback pathways . Macrophages also produce P22301 , which acts to inhibit proinflammatory cytokine production by macrophages via a JAK/ P40763 -dependent pathway . We show in this paper that , DB08877 , a recently described selective inhibitor of JAKs , increases P01375 , P05231 , and IL-12 secretion in mouse bone marrow-derived macrophages stimulated with LPS . This effect is largely due to its ability to block P22301 -mediated feedback inhibition on cytokine transcription in macrophages . Similar results were also obtained with a second structurally unrelated Jak inhibitor , DB08895 . In addition , LPS induced the production of IFN-β , which was then able to activate JAKs in macrophages , resulting in the stimulation of P42224 phosphorylation . The initial induction of P22301 was independent of JAK signaling ; however , inhibition of JAKs did reduce P22301 secretion at later time points . This reflected a requirement for the IFN-β feedback loop to sustain P22301 transcription following LPS stimulation . In addition to P22301 , IFN-β also helped sustain P05231 and IL-12 transcription . Overall , these results suggest that inhibition of JAKs may increase the inflammatory potential of macrophages stimulated with O00206 agonists . Hypersensitivity reaction against influenza vaccine in a patient with rheumatoid arthritis after the initiation of etanercept injections . A 58-year-old Japanese woman with rheumatoid arthritis ( RA ) suffered from high fever triggered by administration of an influenza vaccine after a 4-month-long effective treatment course with the P01375 inhibitor etanercept . Influenza vaccine had been previously administrated safely to the patient before initiation of etanercept therapy . The fever occurred without other symptoms soon after vaccine administration , progressed to high fever 1 day later , and spontaneously resolved the second day . The clinical course appears to be compatible with drug fever closely associated with immediate hypersensitivity ( in particular , late-phase type I allergic reaction ) , in which T helper ( Th ) 2 cells play a crucial role . DB00005 can strongly suppress Th1-mediated reactions ; therefore , Th2 activity may be augmented by etanercept treatment in aspect of antagonism between Th1 and Th2 mechanisms . In RA patients who receive treatment with P01375 inhibitor such as etanercept , activation of Th2-mediated immune responses such as immediate hypersensitivity may be a necessary side effect for those who receive vaccinations . Switching to etanercept in patients with rheumatoid arthritis with no response to infliximab . P01375 is thought to play a pivotal role in the initiation and perpetuation of the chronic inflammatory process in rheumatoid arthritis . P01375 blockers such as infliximab and etanercept are currently used in the treatment of active rheumatoid arthritis ( RA ) when traditional DMARDs have failed and are effective in a significant proportion of patients . However , about one third are non-responders to anti- P01375 . The aim of this study was to verify whether rheumatoid patients , after failing infliximab , can benefit from etanercept . We analysed 18 patients with active RA with no response to at least 3 DMARDs and where infliximab therapy had failed . The patients had received infliximab associated with methotrexate : eleven of them did not show any significant response , while seven patients , after a good response , relapsed . DB00005 was then started . EULAR criteria of response were used with calculation of activity index DAS28 at baseline , after 2 weeks , 3 months and every third month until last follow-up . A moderate or good response was achieved with etanercept in 13 out of 18 patients . From our experience , etanercept can be considered as a good alternative choice when infliximab has failed . Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5-hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor-mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8.42 and 8.72 ) . DB01200 acted as a partial agonist ( pEC50 6.86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5-HT-induced relaxation ( pKB 10.32 and 8.49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines . Tumefactive demyelinating lesions during etanercept treatment requiring decompressive hemicraniectomy . P01375 alpha ( P01375 -α ) is a pro-inflammatory and immunoregulatory cytokine involved in the pathogenesis of several autoimmune disorders . DB00005 , a P01375 -α antagonist ( anti- P01375 -α ) acting as a soluble P01375 -α receptor , has been associated with neurological demyelinating disorders . This paper aims to report an unusual case showing tumefactive central nervous system ( CNS ) inflammatory demyelination in a patient in the course of P01375 -α antagonist therapy , requiring decompressive hemicraniectomy . This report is based on magnetic resonance imaging ( Q9BWK5 ) findings and histology . A biopsy confirmed the inflammatory demyelinating nature of the lesions . The clinical presentation is unusual due to the severity of the disease process , requiring decompressive hemicraniotomy with a clinically favorable outcome . Adverse dermatological reactions in rheumatoid arthritis patients treated with etanercept , an anti-TNFalpha drug . DB00005 is an anti- P01375 drug with marked efficacy in inflammatory arthritis . This review addresses dermatological side effects that have been encountered in our 85 patients on the drug for rheumatoid arthritis , and reviews other reported cutaneous adverse events . Injection site reactions are common and usually self-limiting . We and others have encountered patients with recall site reactions where the four rotated injection sites simultaneously develop a hypersensitivity reaction . In all cases , the rash has responded to antihistamines and the etanercept was thereby continued . Other injection site reactions include discoid lupus and cutaneous vasculitis that respond to cessation of treatment and appropriate therapy . Skin reactions more distant from the injection site are also reviewed , with erythema nodosum , widespread lupus rashes , infections and skin tumours summarised . A patient who developed a purpuric rash at the site of last injection with a drug induced worsening of thrombocytopaenia is described . Although the therapeutic advantages of etanercept outweigh the side effects , clinicians need to be aware of the adverse reactions of these drugs with their increasing use . A non-innovator version of etanercept for treatment of arthritis . DB00005 is a soluble tumor necrosis factor ( P01375 ) receptor originally approved for treatment of moderate-to-severe rheumatoid arthritis , juvenile rheumatoid arthritis , and psoriatic arthritis . We have developed a non-innovator version of the recombinant protein etanercept , with the investigational name AVG01 ( trade name AVENT™ ) , using a novel expression vector-based technology . Here we show , by extensive analytical characterization , that AVG01 is highly similar to the reference product Enbrel® and demonstrates similar efficacy in pre-clinical studies . DB00005 . Soluble tumour necrosis factor receptor , P01375 receptor fusion protein , TNFR-Fc , Q92752 001 , Enbrel . Role of tumor necrosis factor ( P01375 ) receptor-associated factor 2 ( TRAF2 ) in distinct and overlapping P25942 and P01375 receptor 2/ DB00005 -mediated B lymphocyte activation . Members of the tumor necrosis factor receptor ( TNFR ) family play a variety of roles in the regulation of lymphocyte activation . An important TNFR family member for B cell activation is P25942 . P25942 signals stimulate B cell P01375 secretion , which subsequently signals via P20333 ( DB00005 ) to enhance B cell activation . Although the function of the pro-apoptotic and pro-inflammatory receptor P19438 ( CD120a ) has been the subject of much research , less is understood about the distinct contributions of DB00005 to cell activation and how it stimulates downstream events . Members of the tumor necrosis factor receptor family bind various members of the cytoplasmic adapter protein family , the tumor necrosis factor receptor-associated factors ( TRAFs ) , during signaling . Both P25942 and DB00005 bind Q12933 ( TRAF2 ) upon ligand stimulation . Wild type and TRAF2-deficient B cells expressing P25942 or the hybrid molecule ( human ) P25942 (mouse)- DB00005 were examined . P25942 - and DB00005 -mediated IgM secretion were partly TRAF2-dependent , but only P25942 required TRAF2 for c-Jun N-terminal kinase activation . P25942 and DB00005 used primarily divergent mechanisms to activate NF-kappaB , exemplifying how TNFR family members can use diverse mechanisms to mediate similar downstream events . P01375 receptors ( Tnfr ) in mouse fibroblasts deficient in Tnfr1 or Tnfr2 are signaling competent and activate the mitogen-activated protein kinase pathway with differential kinetics . To dissect tumor necrosis factor receptor ( Tnfr ) -1 ( CD120a ) and Tnfr2 ( DB00005 ) -dependent signal transduction pathways , primary fibroblasts isolated from inguinal adipose tissue of wild type ( wt ) , tnfr1(o) , tnfr2(o) , and tnfr1(o)/tnfr2(o) mice were studied . The mitogen-activated protein kinases Erk1 and Erk2 were found to be tyrosine-phosphorylated and activated by Tnf treatment in all wt , tnfr1(o) , and tnfr2(o) fibroblasts ; the activation was down-regulated 60 min after the start of steady state Tnf treatment . Distinct kinetics of Erk1 and Erk2 activation were detected ; the Tnfr1-mediated activation of Erk1 and Erk2 started more slowly and persisted for more prolonged times as compared with Tnfr2 activation . P04049 , Raf-B , Mek-1 , Mek kinase , and p90(rsk) kinases were also shown to be activated independently in a distinct time-dependent pattern through the two Tnf receptors . In addition , both Tnfr1 and Tnfr2 mediated independently the activation of the transcription factor Ap-1 albeit with parallel activation kinetics . In contrast , Tnfr1 exclusively mediated activation of NF-kappaB and fibroblast proliferation ; however , Tnfr2 enhanced proliferation triggered through Tnfr1 . These findings indicate distinct but also overlapping roles of Tnfr1 and Tnfr2 in primary mouse fibroblasts and suggest different regulation mechanisms of signal transduction pathways under the control of both Tnf receptors . DB00005 in the treatment of rheumatoid arthritis . INTRODUCTION : Biologic agents have transformed clinical outcomes in rheumatoid arthritis , and there are now several immune-modulating therapies available . Tumour necrosis factor-α ( P01375 -α ) inhibitors were the first biologic drug class licensed for the treatment of rheumatoid arthritis . DB00005 is a fusion protein composed of two P01375 receptors bound to the constant portion ( Fc ) of human immunoglobulin G ( IgG ) . AREAS COVERED : This article will consider the pharmacological properties of etanercept and the clinical efficacy data presented in clinical trials . Its safety in clinical practice will be reviewed . EXPERT OPINION : There is overwhelming evidence to support the use of etanercept in rheumatoid arthritis . Trial data demonstrate etanercept 's efficacy in reducing structural damage , improving clinical outcomes and inducing remission . Optimal response to therapy is seen when used in combination with methotrexate and when initiated early . DB00005 is an attractive therapeutic option given the excellent safety profile , reduced immunogenicity and ease of administration . DB00005 reduces acute tissue injury and mortality associated to zymosan-induced multiple organ dysfunction syndrome . It has been well demonstrated that P01375 is integral to the pathogenesis of multiple organ dysfunction syndrome ( MODS ) . In this study , we investigate the effects of etanercept ( 10 mg/kg , s.c. ) , a specific P01375 -soluble inhibitor , on the acute phase and late mortality in a murine model of MODS of nonseptic origin induced by zymosan ( 500 mg/kg , suspended in saline solution , i.p. ) . DB00005 was administered 1 h after the injection of zymosan . Animals were killed after 18 h . In another set of experiments , mice were monitored for systemic toxicity , loss of body weight , and mortality for 12 days . Sham-treated and P01375 receptor 1 ( P19438 ) -deficient animals were used as control . Treatment of mice with DB00005 and P19438 gene deletion decreased the peritoneal exudation and the migration of neutrophils caused by zymosan . In addition , pharmacological and genetic neutralization of P01375 attenuated pancreas and ileum injury ( histology ) , the increase in myeloperoxidase activity in the ileum and in the lung , and the formation of P01375 and IL-1beta . Immunohistochemical analysis for P01375 , transforming growth factor beta , and vascular endothelial growth factor revealed a positive staining in pancreas and ileum sections . The degree of immunostaining was markedly reduced after etanercept treatment and in P19438 knockout mice . Furthermore , P01375 neutralization decreased the potent apoptotic stimulus induced by zymosan . All of these findings ultimately led to an amelioration of organ functions at 18 h and to a better survival rate at 12 days . Therefore , we demonstrate that etanercept reduces acute tissue injury and mortality associated to MODS of nonseptic origin in mice . Slow overmethylation of housekeeping genes in the body mucosa is associated with the risk for gastric cancer . Helicobacter pylori infection increases age-related diverse overmethylation in gene-control regions , which increases the risk of gastric cancer . The H. pylori-associated overmethylation changes subsequently disappear when gastric atrophy and cancer develop . To identify cancer-risk epigenotypes , we traced dynamic methylation changes in the background mucosa of the stomach depending on the extent of gastric atrophy . Paired biopsy specimens were obtained from the noncancerous antrum and body mucosa of 102 patients with cancer and 114 H. pylori-positive and 112 H. pylori-negative controls . The grade of gastric atrophy was evaluated using the endoscopic atrophic border score . The methylation-variable sites at the CpG-island margins and near the transcriptional start sites lacking CpG islands were semiquantitatively analyzed by radioisotope-labeling methylation-specific PCR . We selected eight housekeeping genes adjacent to Alu ( CDH1 , Q8NCT1 , P37231 , and Q9UL33 ) or LTR retroelements ( P08253 , CDKN2A , Q13950 , and Q13761 ) and eight stomach-specific genes ( Q03403 , P20142 , P51164 , P04155 , Q07654 , Q9UBU3 , DB00158 , and P20648 ) . Analysis of age-related methylation in the H. pylori-positive controls revealed slow overmethylation in the body and in the LTR-adjacent genes . A high-frequency overmethylation defined based on the slowly overmethylated genes was frequently observed in the body of patients with gastric cancer with open-type atrophy ( OR , 12.7 ; 95 % confidence interval , 3.2-49.8 ) . The rapidly changing methylation of Alu-adjacent genes was barely increased in the antrum of patients with gastric cancer . Among diverse methylation changes associated with H. pylori infection , an increase in slowly changing methylation could serve as a cancer-risk marker . Characterization of the immune response in the synovitis , acne , pustulosis , hyperostosis , osteitis ( SAPHO ) syndrome . OBJECTIVE : The aetiology of SAPHO ( synovitis , acne , palmoplantar pustulosis , hyperostosis , osteitis ) syndrome seems to involve genetic , infectious and immunological components . We examined innate and adaptive immune responses in SAPHO syndrome , as compared with PsA and RA . We also studied the effect of etanercept on immunological parameters . METHODS : We studied 29 patients with SAPHO syndrome , as well as 22 patients with RA , 21 patients with PsA and 15 healthy controls . Adaptive immune responses were investigated by assaying total serum immunoglobulins and several autoantibodies . Innate immunity was studied by quantifying blood PMN functions and plasma cytokine levels . PMN responses to Propionibacterium acnes were tested ex vivo . Eight patients who received etanercept for refractory rheumatic disorders were tested before and after 28 days of treatment . RESULTS : SAPHO syndrome was associated with elevated P10145 and Q14116 plasma levels . P10145 and P01375 production by purified PMN was higher in the three patient groups than in the healthy controls , but the oxidative burst and Q14116 production were normal . No autoantibodies were detected in SAPHO patients . Induction of PMN P10145 and P01375 production by P. acnes was impaired in the SAPHO group as compared with the RA and PsA groups . After 28 days of etanercept therapy , PMN P10145 and P01375 production was down-regulated and P01375 plasma levels were increased . CONCLUSIONS : These results support the view that the SAPHO syndrome may be triggered by an infectious state involving P. acnes , contributing to the strong humoral and cellular pro-inflammatory responses . DB00005 modulation of PMN activation status emphasizes these new immunological findings . P15056 inhibitors suppress apoptosis through off-target inhibition of JNK signaling . DB08881 and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug-induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib-treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK-dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http://dx.doi.org/10.7554/eLife.00969.001 . Thrombin and activated protein C inhibit the expression of secretory group IIA phospholipase A(2) in the P01375 -activated endothelial cells by Q9UNN8 and P25116 dependent mechanisms . INTRODUCTION : Thrombin and tumor necrosis factor ( P01375 ) -alpha up-regulate the expression of proinflammatory molecules in human umbilical vein endothelial cells ( HUVECs ) . However , activated protein C ( P25054 ) down-regulates the expression of the same molecules . The expression level of secretory group IIA phospholipase A(2) ( sPLA(2)-IIA ) is known to be elevated in inflammatory disorders including in sepsis . Here , we investigated the effects of P25054 and thrombin on the expression of sPLA(2)-IIA and extracellular signal-regulated kinase ( P29323 ) in HUVECs . MATERIALS AND METHODS : The expression level of sPLA(2)-IIA was quantitatively measured by an enzyme-linked-immunosorbent-assay following stimulation of HUVECs with either thrombin or P01375 in the absence and presence of the phosphatidylinositol 3-kinase ( P19957 -kinase ) inhibitor LY294002 and the cholesterol-depleting drug methyl-beta-cyclodextrin ( MbetaCD ) . RESULTS AND CONCLUSIONS : Thrombin had no effect on the expression of sPLA(2)-IIA in HUVECs , however , P01375 potently induced its expression . The prior treatment of cells with P25054 inhibited expression of sPLA(2)-IIA through the Q9UNN8 -dependent cleavage of P25116 . Further studies revealed that if HUVECs were pretreated with the zymogen protein C to occupy Q9UNN8 , thrombin also inhibited the P01375 -mediated expression of sPLA(2)-IIA through the cleavage of P25116 . The Q9UNN8 -dependent cleavage of P25116 by both P25054 and thrombin increased the phosphorylation of P29323 1/2 . Pretreatment of cells with either LY294002 or MbetaCD abolished the inhibitory activity of both P25054 and thrombin against sPLA(2)-IIA expression , suggesting that the protein C occupancy of Q9UNN8 confers a P19957 -kinase dependent protective activity for thrombin such that its cleavage of the lipid-raft localized P25116 inhibits the P01375 -mediated expression of sPLA(2)-IIA in HUVECs . Spotlight on etanercept in plaque psoriasis and psoriatic arthritis . DB00005 ( Enbrel ) , a tumor necrosis factor ( P01375 ) -alpha antagonist produced by recombinant technology , is approved for use in the US as subcutaneous monotherapy in adults with moderate-to-severe psoriasis who are candidates for systemic therapy or phototherapy . The drug is also indicated in patients with psoriatic arthritis , in whom it may be used in combination with methotrexate . In well designed trials in patients with moderate-to-severe psoriasis , short-term etanercept therapy ( typically 25 or 50mg twice weekly ) significantly increased the proportion of patients achieving a 75 % reduction in the Psoriasis Area and Severity Index score compared with placebo . Similarly , in well designed trials in patients with psoriatic arthritis , treatment with short-term etanercept 25mg twice weekly , alone or in combination with methotrexate , improved clinical features of the disease , while radiographic progression of joint damage appeared to be significantly slowed in a nonblind 1-year extension . Short-term etanercept therapy was well tolerated in patients with psoriasis or psoriatic arthritis . DB00005 is thus a valuable new option for the treatment of patients with chronic moderate-to-severe plaque psoriasis ( who are candidates for systemic therapy or phototherapy or have failed other systemic therapies ) or with psoriatic arthritis . Reactive oxygen species-dependent P01375 converting enzyme activation through stimulation of P41595 and alpha1D autoreceptors in neuronal cells . A major determinant of neuronal homeostasis is the proper integration of cell signaling pathways recruited by a variety of neuronal and non-neuronal factors . By taking advantage of a neuroectodermal cell line ( 1C11 ) endowed with the capacity to differentiate into serotonergic ( 1C115-HT ) or noradrenergic ( 1C11NE ) neurons , we identified serotonin ( 5-hydroxytryptamine , 5-HT ) - and norepinephrine ( NE ) -dependent signaling cascades possibly involved in neuronal functions . First , we establish that P41595 receptors and 1D adrenoceptors are functionally coupled to reactive oxygen species ( ROS ) synthesis through NADPH oxidase activation in 1C115-HT and 1C11NE cells . This observation constitutes the prime evidence that bioaminergic autoreceptors take part in the control of the cellular redox equilibrium in a neuronal context . Second , our data identify P78536 ( P01375 - Converting Enzyme ) , a member of a disintegrin and metalloproteinase ( ADAM ) family , as a downstream target of the P41595 and 1D receptor-NADPH oxidase signaling pathways . Upon P41595 or 1D receptor stimulation , ROS fully govern P01375 - shedding in the surrounding milieu of 1C115-HT or 1C11NE cells . Third , P41595 and 1Dreceptor couplings to the NADPH oxidase- P78536 cascade are strictly restricted to 1C11-derived progenies that have implemented a complete serotonergic or noradrenergic phenotype . Overall , these observations suggest that P41595 and 1D autoreceptors may play a role in the maintenance of neuron- and neurotransmitter-associated functions . Eventually , our study may have implications regarding the origin of oxidative stress as well as up-regulated expression of proinflammatory cytokines in neurodegenerative disorders , which may relate to the deviation of normal signaling pathways . DB00005 attenuates traumatic brain injury in rats by reducing brain P01375 - α contents and by stimulating newly formed neurogenesis . It remains unclear whether etanercept penetrates directly into the contused brain and improves the outcomes of TBI by attenuating brain contents of P01375 - α and/or stimulating newly formed neurogenesis . Rats that sustained TBI are immediately treated with etanercept . Acute neurological and motor injury is assessed in all rats the day prior to and 7 days after surgery . The numbers of the colocalizations of 5-bromodeoxyuridine and doublecortin specific markers in the contused brain injury that occurred during TBI were counted by immunofluorescence staining . Enzyme immunoassay for quantitative determination of P01375 -α or etanercept in brain tissues is also performed . Seven days after systemic administration of etanercept , levels of etanercept can be detected in the contused brain tissues . In addition , neurological and motor deficits , cerebral contusion , and increased brain P01375 -α contents caused by TBI can be attenuated by etanercept therapy . Furthermore , the increased numbers of the colocalizations of 5-bromodeoxyuridine and doublecortin specific markers in the contused brain tissues caused by TBI can be potentiated by etanercept therapy . These findings indicate that systemically administered etanercept may penetrate directly into the contused brain tissues and may improve outcomes of TBI by reducing brain contents of P01375 - α and by stimulating newly formed neurogenesis . Neurological deficits during treatment with tumor necrosis factor-alpha antagonists . INTRODUCTION : Neurological deficits that occur during treatment with tumor necrosis factor ( P01375 ) -α antagonists are rare , and their clinical features have not been fully elucidated . METHODS : Retrospective review of medical records of 9 patients who were given P01375 -α antagonists , subsequently developed neurological deficits and were cared for at the Medical University of South Carolina between January 2002 and May 2010 . Adverse drug reaction probability scale was used for the assessment of their causal connection . RESULTS : The underlying diseases for which P01375 -α antagonists were administered included rheumatologic disorders ( 4 ) , sarcoidosis ( 3 ) , psoriasis ( 1 ) and Crohn 's disease ( 1 ) . DB00005 , infliximab or adalimumab was administered to these patients . Neurological complications included central or peripheral demyelination ( 5 ) , antiphospholipid syndrome/central nervous system lupus ( 1 ) , Epstein-Barr virus encephalitis ( 1 ) , axonal sensory polyneuropathy ( 1 ) and small fiber polyneuropathy ( 1 ) . P01375 -α antagonists were discontinued in 8 patients and clinical improvement was seen in 3 of them . Additional therapies were given in 4 patients . An adverse drug reaction probability score suggested probable ( 3/9 ) and possible ( 6/9 ) causal relationships . CONCLUSIONS : Neurological deficits that develop during treatment with P01375 -α antagonists are relatively rare but important potential complications of these drugs . Determining if the relationship between the neurological deficits and P01375 -α antagonist therapy is causal can be challenging and can impact patient care . The effect of etanercept on osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic arthritis . OBJECTIVE : The frequency of osteoclast precursors ( OCPF ) and the presence of bone marrow oedema ( BMO ) are potential response biomarkers in psoriatic arthritis ( PsA ) . Previous studies suggest a central role for tumour necrosis factor ( P01375 ) in the formation of osteoclast precursors . To better understand this association , the effect of etanercept on OCPF and BMO was analysed in PsA patients with erosive arthritis . METHODS : A total of 20 PsA patients with active erosive PsA were enrolled . DB00005 was administered twice weekly for 24 weeks . OCPF was measured and clinical assessments were performed at baseline , 2 , 12 and 24 weeks . Gadolinium enhanced MR images were obtained at baseline and 24 weeks . RESULTS : Significant improvements in joint score ( p < 0.001 ) , HAQ scores ( p < 0.001 ) and SF-36 parameters were observed after 6 months of therapy with etanercept compared to baseline . The median OCPF decreased from 24.5 to 9 ( p = 0.04 ) and to 7 ( p = 0.006 ) after 3 months and 6 months of treatment , respectively . MR images were available for 13 patients . The BMO volume decreased in 47 and increased in 31 sites at 6 months . No correlation was noted between OCPF , BMO and clinical parameters . CONCLUSION : The rapid decline in OCPF and overall improvement in BMO after anti-TNFalpha therapy provides one mechanism to explain the anti-erosive effects of P01375 blockade in PsA . Persistence of BMO after etanercept treatment , despite a marked clinical response , was unexpected , and suggests ongoing subchondral inflammation or altered remodelling in PsA bone . MnSOD drives neuroendocrine differentiation , androgen independence , and cell survival in prostate cancer cells . An increase in neuroendocrine ( NE ) cell number has been associated with progression of prostate tumor , one of the most frequent cancers among Western males . We previously reported that mitochondrial manganese superoxide dismutase ( MnSOD ) increases during the NE differentiation process . The goal of this study was to find whether MnSOD up-regulation is enough to induce NE differentiation . Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected ( MnSOD-S4 and MnSOD- P28222 ) . MnSOD overexpression induces NE morphological features as well as coexpression of the NE marker synaptophysin . Both MnSOD clones exhibit lower superoxide levels and higher H(2)O(2) levels . MnSOD-overexpressing cells show higher proliferation rates in complete medium , but in steroid-free medium MnSOD- P28222 cells are still capable of proliferation . MnSOD up-regulation decreases androgen receptor and prevents its nuclear translocation . MnSOD also induces up-regulation of Bcl-2 and prevents docetaxel- , etoposide- , or P01375 -induced cell death . Finally , MnSOD-overexpressing cells enhance growth of androgen-independent PC-3 cells but reduce growth of androgen-dependent cells . These results indicate that redox modulation caused by MnSOD overexpression explains most NE-like features , including morphological changes , NE marker expression , androgen independence , inhibition of apoptosis , and enhancement of cell growth . Many of these events can be associated with the androgen dependent-independent transition during prostate cancer progression . Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC-4047 ( Actimid , DB08910 ) have been used as anti-inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-alpha ( P01375 ) , interleukins ( IL ) 1-beta , 6 , 12 , and granulocyte macrophage-colony stimulating factor ( GM- P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti-angiogenic , anti-proliferative , and pro-apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies . DB01590 exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer . Signaling pathways that activate P42345 ( mammalian target of rapamycin ) are altered in many human cancers and these alterations are associated with prognosis and treatment response . P42345 inhibition can restore sensitivity to DNA damaging agents such as cisplatin . The rapamycin derivative everolimus exhibits antitumor activity and is approved for patients with renal cell cancer . Clinically , everolimus has also been evaluated in patients with advanced non-small cell lung cancer ( NSCLC ) that were refractory to chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors . We tested the effects of combined treatment with everolimus ( RAD001 ) and fractionated radiation using a xenograft model of human NSCLC ( A549 cells ) . In growth studies , mean tumor volume was reduced in the everolimus plus 30 Gy cohort with significant tumor growth suppression compared to 30 Gy alone ( p=0015 ) , or everolimus alone ( p < 0.001 , Q9UNW9 ) . everolimus ( 20 nM ) significantly reduced protein levels of the P42345 downstream effector P08133 -S6K compared with radiation and vehicle ( p=0.05 , Q9UNW9 ) and significantly suppressed phospho- P08133 -S6K levels compared with all other treatments ( p < 0.001 , Q9UNW9 ) . We also evaluated everolimus and radiation effects on gene expression in A549 cells . DB01590 ± 5 Gy suppressed endothelin 1 and lactate dehydrogenase expression and increased P15692 , P38936 , hypoxia-inducible factor-1α and P11166 ( facilitated glucose transporter 1 ) . P42345 mRNA levels were unaffected while P01375 -α levels were increased with everolimus + 5 Gy compared to either treatment alone . These findings suggest that everolimus increases the antitumor activity of radiation . Clinical trials combining everolimus with fractionated radiation in patients with NSCLC are warranted . The treatment of established murine collagen-induced arthritis with a P19438 -selective antagonistic mutant P01375 . Blocking the binding of P01375 to P01375 receptor subtype-1 ( P19438 ) is an important strategy for the treatment of rheumatoid arthritis ( RA ) . We recently succeeded in developing a P19438 -selective antagonistic P01375 mutant , R1antTNF . Here , we report the anti-inflammatory effects of R1antTNF in a murine collagen-induced arthritis model . To improve the in vivo stability of R1antTNF , we first engineered PEG ( polyethylene glycol ) -modified R1antTNF ( PEG-R1antTNF ) . In prophylactic protocols , PEG-R1antTNF clearly improved the incidence , and the clinical score of arthritis due to its long plasma half-life . Although , the effect of PEG-R1antTNF on the incidence and production of IL1-beta was less than that of the existing P01375 -blocking drug DB00005 , its effect on severity was almost as marked as DB00005 . Interestingly , in therapeutic protocols , PEG-R1antTNF showed greater therapeutic effect than DB00005 . These data suggest that the anti-inflammatory effects of PEG-R1antTNF depend on the stage of arthritis . Recently , there has been much concern over the reactivation of viral infection caused by P01375 blockade . Unlike DB00005 , PEG-R1antTNF did not reactivate viral infection . Together , these results indicate that selective inhibition of P01375 / P19438 could be effective in treating RA and that PEG-R1antTNF could serve as a promising anti-inflammatory drug for this purpose . Rheumatoid arthritis in pregnancy : successful outcome with anti- P01375 agent ( DB00005 ) . Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells . PURPOSE : Cannabinoids have been recently proposed as a new family of potential antitumor agents . The present study was undertaken to investigate the expression of the two cannabinoid receptors , P21554 and CB2 , in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation . EXPERIMENTAL DESIGN : Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD-1 and HT29 colon cancer cell lines . The effects of the P21554 agonist arachinodyl-2'-chloroethylamide and the CB2 agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1H)-on-3-carboxamide ( CB13 ) on tumor cell apoptosis and ceramide and tumor necrosis factor ( P01375 ) -alpha production were evaluated . The knockdown of P01375 mRNA was obtained with the use of selective small interfering RNA . RESULTS : We show that the P21554 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor . The activation of the P21554 and , more efficiently , of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD-1 and HT29 cells . Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis . The CB2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer . The knockdown of P01375 mRNA abrogated the ceramide increase and , therefore , the apoptotic effect induced by cannabinoid receptor activation . CONCLUSIONS : The present study shows that either P21554 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells . Our data unveiled , for the first time , that P01375 acts as a link between cannabinoid receptor activation and ceramide production . New disease modifying agents in adult rheumatoid arthritis . In recent years , new disease modifying agents including leflunomide and tumour necrosis factor ( P01375 ) antagonists have been used to treat patients with rheumatoid arthritis ( RA ) . Leflunomide prevents proliferation of activated lymphocytes by inhibiting dihydroorotate dehydrogenase , a critical step in de novo pyrimidine synthesis . Leflunomide has been shown to be as effective as sulfasalazine and methotrexate ( MTX ) in placebo-controlled trials . It also improves physical function , quality of life measures and retards radiographic progression . P01375 antagonists include infliximab and etanercept . DB00065 is a chimeric P01375 monoclonal antibody . Repeated infusions of low dose infliximab ( 1 mg/kg ) are ineffective if given alone . Addition of MTX to infliximab has been shown to prolong the duration of clinical response . DB00005 is a human P01375 receptor p75 Fc fusion protein . In active RA patients with suboptimal response to MTX , additional clinical benefit was obtained by the addition of infliximab or etanercept to MTX . The main side effect of etanercept is injection site reaction . However , the long-term effect of P01375 antagonists in the development of infection , malignancy and autoimmune disease remains unknown . DB00005 attenuates short-term cigarette-smoke-exposure-induced pulmonary arterial remodelling in rats by suppressing the activation of P01375 /NF-kB signal and the activities of P08253 and P14780 . The pathogenesis of cigarette-smoke-exposure-induced pulmonary vasculature impairment is unclear . Cigarette-smoke-exposure-induced the accumulation of tumour necrosis factor-alpha ( P01375 -α ) and upregulates the expression and activities of matrix metalloproteinases ( MMPs ) involved in smoke-induced vascular remodelling , which are important processes in the pathogenesis of vasculature impairment . The P01375 -α antagonist DB00005 is an anti-inflammatory drug with a potential role in regulating MMP expression . To determine the effect of DB00005 on short-term smoke-induced pulmonary arteriole impairment and investigate its possible mechanism , male Sprague-Dawley rats were exposed to cigarette-smoke daily for two weeks in both the absence and presence of DB00005 . Cigarette-smoke-exposure-induced elevation of mean pulmonary artery pressures and medial hypertrophy of pulmonary arterioles were partially reduced by DB00005 . Up-regulation of the expression and activities of P08253 and P14780 , induced by cigarette-smoke , were also suppressed significantly by DB00005 . Furthermore , DB00005 treatment significantly attenuated cigarette-smoke-induced TNFα accumulation and activation of nuclear factor NF-kB signal . These results suggest that DB00005 have the protective effects in cigarette-smoke-induced pulmonary vascular remodelling , with the attenuation of the up-regulated expression and activities of P08253 and P14780 and activation of P01375 -α/NF-kB signal pathway probably being involved as part of its mechanism . Our study might provide insight into the development of new interventions for vasculature impairment . Experimental autoimmune encephalomyelitis in the Wistar rat : dependence of MBP-specific T cell responsiveness on P33681 costimulation . Experimental autoimmune encephalomyelitis ( EAE ) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology . EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains . In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin ( PT ) . T cell responses were induced to myelin basic protein . Autoreactive T cells could be totally blocked by the in vitro treatment with DB01281 , a protein that blocks the costimulation of autoreactive T cells . The addition of P60568 could reverse the inhibition seen in vitro with DB01281 . The effects of inhibition of P33681 costimulation were also examined by an analysis of cytokine responses and P60568 receptor on T cells . DB01281 treatment in vitro reduced the expression of P60568 receptor on T cells , enhanced T cell apoptosis and decreased the synthesis of P60568 , P01579 and P01375 . DB01281 treatment had no effect on P22301 synthesis by T cells , a cytokine implicated in the functions of regulatory T cell subsets . Overall , our studies support the rationale of P33681 blocking therapies as a potential treatment for models of multiple sclerosis . The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity . P01375 -alpha , an initiator , and etanercept , an inhibitor of cochlear inflammation . OBJECTIVES/HYPOTHESIS : The inner ear rapidly mounts an immune response that can lead to cochlear degeneration and permanent hearing loss . Identification of proinflammatory cytokine expression during the initiation of the response should lead to rational therapeutic strategies that block the response , reducing damaging sequelae . STUDY DESIGN : A cochlear immune response to DB05299 ( KLH ) injected into the inner ear or subarachnoid space of sensitized animals was created . DB00005 was administered to a group of animals to blunt the immune response . METHODS : Cochleae were immunoassayed for expression of interleukin-1beta , tumor necrosis factor-alpha , and interleukin-6 and evaluated for the amount of cochlear-infiltrated cells . RESULTS : P01375 -alpha and interleukin-1beta were expressed by infiltrated cells shortly after KLH injection . P01375 -alpha was expressed whether the antigen was introduced with or without surgical trauma . Interleukin-1beta was also expressed by the cochlear fibrocytes during the immune response and in surgical control animals , but not after intrathecal injection of antigen . P05231 expression was minimal during the response . Based on this observation , animals were treated with systemic injection of DB00005 , which reduced cochlear infiltrating cell number and cochlear fibrosis . CONCLUSION : Interleukin-1beta expression is a general cochlear response to trauma , whereas tumor necrosis factor-alpha expression in the infiltrated immunocompetent cells is the cytokine that induces amplification of the response that leads to cochlear disease . AM2389 , a high-affinity , in vivo potent P21554 -receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( DB00486 (®) ) . OBJECTIVE : To characterize the novel , high-affinity cannabinoid receptor 1 ( CB(1)R ) HHC-ligand AM2389 [ 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol in two rodent pre-clinical assays . MATERIALS AND METHODS : CB(1)R mediation of AM2389-induced hypothermia in mice was evaluated with AM251 , a CB(1)R-selective antagonist/inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0.18 and 0.56 mg/kg ) from vehicle 20 min post-injection in a two-choice operant conditioning task motivated by 0.1 % saccharin/water . Generalization/substitution tests were conducted with AM2389 , AM5983 , and Δ(9)-tetrahydrocannabinol ( Δ(9)-THC ) . RESULTS : Δ(9)-THC (30 mg/kg)-induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0.1 and 0.3 mg/kg ) . AM251 ( 3 and 10 mg/kg ) attenuated/blocked hypothermia induced by 0.3 mg/kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ(9)-THC with ED(50) values of 0.0025 , 0.0571 , and 0.2635 mg/kg , respectively , in the low-dose condition . The corresponding ED(50) values in the high-dose condition were 0.0069 , 0.1246 , and 0.8438 mg/kg , respectively . Onset of the effects of AM2389 was slow with a protracted time-course ; the functional , perceptual in vivo half-life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time-course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation . Cell-cell interaction promotes rat marrow stromal cell differentiation into endothelial cell via activation of P78536 / P01375 signaling . Marrow stromal cells ( MSCs ) are capable of differentiating into various cell types including endothelial cells . Microenvironment is important in cell fate determination . P01375 -alpha converting enzyme ( P78536 ) , a well-characterized " sheddase , " participates in the differentiation process of multiple lineages by the proteolytic release of membrane-bound proteins such as tumor necrosis factor-alpha ( P01375 ) . We investigated the endothelial differentiation of MSCs under two coculture conditions : 1 ) direct MSCs-rat brain microvascular endothelial cells ( rBMECs ) contact coculture ; and 2 ) indirect coculture of MSCs and rBMECs . Also , we examined the role of P78536 / P01375 signaling in the process of differentiation under direct coculture condition . We found that endothelial differentiation of MSCs was substantially enhanced in MSCs-rBMECs direct contact coculture , but not in indirect transwell coculture condition . Transcript levels of P78536 and P01375 as well as P78536 protein expression were significantly upregulated in direct , but not in indirect , coculture condition . Addition of human recombinant P78536 promoted gene expression of endothelial specific markers including P04275 , CD31 , P33151 , Flk-1 , and Flt-1 in the differentiating MSCs . Furthermore , inhibition of P78536 with TAPI-2 or inhibition of P01375 with DB00005 attenuated endothelial differentiation of MSCs in the direct coculture condition . We demonstrated for the first time that direct MSCs-rBMECs interaction stimulated the endothelial differentiation of MSCs via P78536 /TNFalpha signaling . Pulmonary Sarcoidosis following DB00005 Treatment . Tumour necrosis factor ( P01375 ) is an important cytokine involved in the pathology of a number of inflammatory conditions , and thus blockade with anti- P01375 therapies is becoming the cornerstone in managing such diseases . With increasing use , evidence is collected for the association of sarcoid-like granulomatous disease developing after the initiation of anti- P01375 -α therapy , with disease reversal after discontinuation . Acute exacerbation of preexisting interstitial lung disease after administration of etanercept for rheumatoid arthritis . A 70-year-old woman with a 6-year history of seropositive rheumatoid arthritis ( RA ) and asymptomatic interstitial lung disease ( ILD ) began taking etanercept for ongoing arthritis despite treatment with methotrexate ( MTX ) and bucillamine . MTX was discontinued before introduction of etanercept . She developed lung injury 8 weeks after starting etanercept . DB00005 was discontinued and oral prednisolone 40 mg/day was begun , and her clinical findings gradually improved . Lung injury , although rare , is a recently noticed , potentially fatal adverse effect of all 3 licensed biological anti-tumor necrosis factor ( P01375 ) agents . We recommend caution in the use of anti- P01375 agents in elderly RA patients with preexisting ILD . DB00005 : long-term clinical experience in rheumatoid arthritis and other arthritis . DB00005 is a dimeric fusion protein based on the p75 P01375 receptor . It binds to P01375 and blocks its biologic activity . In randomized , double-blind , placebo-controlled trials , etanercept has therapeutic activity in rheumatoid arthritis , psoriatic arthritis , polyarticular-course juvenile idiopathic arthritis and ankylosing spondylitis . DB00005 improves joint inflammation , physical function and slows/halts structural damage , especially when combined with methotrexate . A sustained response is observed in a substantial percentage of patients . Although some safety issues should be considered before starting etanercept treatment , in general terms , etanercept is a well tolerated drug with an acceptable safety profile . The use of any P01375 antagonist must be in agreement with the National Recommendations for Biologic Therapy , and in difficult clinical situations , a balance between risk/benefit needs to be obtained . Safety and efficacy of etanercept in children with juvenile-onset Behcets disease . Behcets disease ( BD ) is a chronic , relapsing , multi-system inflammatory disorder , clinically characterized by recurrent oral and genital ulcers , skin lesions , and uveitis . Other manifestations include arthritis , a positive pathergy test , thrombophlebitis , central nervous system disease and gastrointestinal ulcerations . The majority of affected individuals do not have life-threatening disease , although mortality can be associated with vascular-thrombotic and neurological manifestations . Currently , treatment of BD is symptomatic and empirical , and is tailored according to the severity of clinical features . In the past few years , isolated reports and case-series have been published on adult BD patients suggesting that inhibition of P01375 is a promising therapeutic approach for severe ocular and various extra-ocular manifestations , including central nervous system involvement . In this study we present our promising experience with DB00005 therapy in juvenile-onset BD patients , characterized by refractory multiorgan involvement . Immune function in patients with rheumatoid arthritis treated with etanercept . DB00005 , a recombinant human tumor necrosis factor ( P01375 ) inhibitor that binds both soluble and cell-bound P01375 , has been shown to reduce disease activity and inhibit joint destruction when administered to patients with rheumatoid arthritis ( RA ) . Because P01375 receptors are found on many types of cells that modulate the immune response , we evaluated the general immune function of a subset of RA patients in a blinded clinical study . No significant differences were seen between patients treated with etanercept or placebo in the surface antigen phenotypes of peripheral blood leukocytes , T cell proliferative responses , neutrophil function , delayed-type hypersensitivity ( DTH ) reactions , serum immunoglobulin levels , or incidence of infections . Although this observational study was relatively small and could detect only major changes in immunological status , the stability of immune function over time in patients receiving etanercept corroborates the findings in clinical studies , which suggest that etanercept does not alter overall global immune function . [ Swiss registry for P01375 blockers in children and adolescents with rheumatological diseases ] . We created a registry to evaluate long term outcome , efficacy and adverse events for children treated wit P01375 inhibitors in Switzerland . 106 patients ( 68 female/38 male ) were included . 61 patients were treated with DB00005 ( Enbrel ) and 45 with DB00065 ( Remicade ) . Concomitant treatment at baseline included corticosteroids in 26 % and DB00563 in 75 % of the patients . Subjective disease activity three months after initiation of P01375 was better in 81 % , worse in 4 % and stable in 15 % of the patients . In total 24 adverse events in 21 patients were reported . Treatment with P01375 inhibitors seems to be safe and effective for children and adolescents with rheumatologic diseases . A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue-specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two-hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 's DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull-down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co-immunoprecipitation of Q9Y6X2 . Co-transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP-6 promoter-luciferase reporter demonstrated up to 94 % inhibition of O75030 -mediated transcriptional activation . Using a gel-shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development . Prolonged effects of tumor necrosis factor-alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng/ml recombinant murine tumor necrosis factor ( P01375 ) -alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH-releasing hormone ( P01148 ) -stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0.1-10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4-day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12-day-old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell-type specific and age dependent . Photoacoustic tomography of joints aided by an DB00005 -conjugated gold nanoparticle contrast agent-an ex vivo preliminary rat study . Monitoring of anti-rheumatic drug delivery in experimental models and in human diseases would undoubtedly be very helpful for both basic research and clinical management of inflammatory diseases . In this study , we have investigated the potential of an emerging hybrid imaging technology-photoacoustic tomography-in noninvasive monitoring of anti- P01375 drug delivery . After the contrast agent composed of gold nanorods conjugated with DB00005 molecules was produced , ELISA experiments were performed to prove the conjugation and to show that the conjugated anti- P01375 -α drug was biologically active . PAT of ex vivo rat tail joints with the joint connective tissue enhanced by intra-articularly injected contrast agent was conducted to examine the performance of PAT in visualizing the distribution of the gold-nanorod-conjugated drug in articular tissues . By using the described system , gold nanorods with a concentration down to 1 pM in phantoms or 10 pM in biological tissues can be imaged with good signal-to-noise ratio and high spatial resolution . This study demonstrates the feasibility of conjugating P01375 antagonist pharmaceutical preparations with gold nanorods , preservation of the mechanism of action of P01375 antagonist along with preliminary evaluation of novel PAT technology in imaging optical contrast agents conjugated with anti-rheumatic drugs . Further in vivo studies on animals are warranted to test the specific binding between such conjugates and targeted antigen in joint tissues affected by inflammation . P01375 -α in vitiligo : direct correlation between tissue levels and clinical parameters . BACKGROUND : Experimental evidences have shown that tumor necrosis factor ( P01375 ) -α may play a role in the pathogenesis of nonsegmental vitiligo , and successful cases of vitiligo treated with P01375 -α inhibitors have been recently reported . MATERIALS AND METHODS : Two cases of refractory generalized vitiligo , which showed high tissue levels of P01375 -α , were commenced anti- P01375 -α antibody etanercept 50 mg weekly . A retrospective study , considering chart review and immunohistochemical staining for P01375 -α , was then carried out on eight additional patients affected by untreated vitiligo . RESULTS : DB00005 achieved improvement of vitiligo in two patients at 6-month follow-up . Five out of eight specimens showed a strong cytoplasmic staining for P01375 -α . Considering all 10 cases , patients with a strong P01375 -α staining were characterized by a higher vitiligo disease activity score than patients with a weak staining . DISCUSSION : These findings , albeit limited in significance by the low number of cases and the retrospective nature of the study , confirm a probable role of P01375 -α in the pathogenesis of vitiligo . The intensity of P01375 -α staining in vitiligo lesions may be worth to be further studied as a biomarker for potentially successful anti- P01375 -α treatment of nonsegmental vitiligo in cases refractory to conventional treatment . Pharmacologic therapies in endometriosis : a systematic review . To assess the literature on preclinical and clinical efficacy and safety data of pharmacologic groups proposed in the treatment of endometriosis , we performed a systematic review of publications from March 2002 to January 2012 via PubMed search . Additional relevant articles were identified from citations within these publications . A high number of medications were tested in preclinical models of endometriosis due to their theoretic capacity of disrupting important pathophysiologic pathways of the disease , such as inflammatory response , angiogenesis and cell survival , proliferation , migration , adhesion , and invasion . P01375 α-blockers , nuclear factor κB inhibitors , antiangiogenic agents , statins , antioxidants , immunomodulators , flavonoids , histone deacetylase inhibitors , matrix metalloproteinase inhibitors , metformin , novel modulators of sex steroids expression , and apoptotic agents were all effective in in vitro/animal models . Most of these agents have not been tried in the clinical setting , mainly because of the high risk of adverse effects . However , some of them can be used in humans . Dopamine agonists and valproic acid have already been tested in pilot studies with good results . DB00005 , metformin , and statins are used in humans for other indications , and endostatin is now being tested in phase 2 oncologic trials . These drugs may constitute alternatives to conventional therapy with estrogen inhibitors and anti-inflammatory agents . Use of etanercept in the dermatology setting . A review . As psoriasis and psoriatic arthritis are chronic in nature , ideal treatment should have sustained efficacy , with minimal short- and long-term toxicities to allow lifelong treatment . Traditional therapies used for psoriatic arthritis or psoriasis , including phototherapies and systemic agents , do not satisfy these criteria . Ninety percent of patients surveyed in 1998 by The National Psoriasis Foundation were not satisfied with their treatment options . Several observations have supported the introduction of the tumor necrosis factor ( P01375 ) antagonist etanercept as a treatment for psoriatic disease , including the failure of traditional therapies to meet patient needs , evidence that P01375 plays a fundamental role in the inflammatory processes underlying psoriatic arthritis and psoriasis , and the safety and efficacy of this agent in other inflammatory , immune-mediated diseases , such as rheumatoid arthritis ( RA ) . DB00005 prevents initiation of the proinflammatory cascade by competitively binding P01375 . First indicated for RA , etanercept is also approved for the treatment of psoriatic arthritis , juvenile RA , ankylosing spondylitis , and most recently psoriasis . DB00005 provides dermatologists with a safe , effective , and convenient treatment option for patients with psoriatic arthritis and psoriasis , which can be used continuously with or without traditional therapies . The self-administered injections provide a distinct advantage over traditional therapies that often require frequent office visits and laboratory monitoring , and other biologic agents that require administration in the doctor 's office . Dermatologists should be aware of the ongoing research with etanercept in psoriasis and other dermatologic conditions . DB00005 maintains the clinical benefit achieved by infliximab in patients with rheumatoid arthritis who discontinued infliximab because of side effects . OBJECTIVE : To evaluate the efficacy of switching to etanercept treatment in patients with rheumatoid arthritis who already responded to infliximab , but presented side effects . METHODS : Charts of 553 patients with rheumatoid arthritis were retrospectively reviewed to select patients who responded to the treatment with infliximab and switched to etanercept because of occurrence of adverse effects . Clinical data were gathered during 24 weeks of etanercept treatment and for the same period of infliximab treatment before infliximab was stopped . Disease Activity Score computed on 44 joints ( DAS-44 ) , erythrocyte sedimentation rate ( P03372 ) 1st hour , Visual Analogue Scale ( VAS ) of pain , Health Assessment Questionnaire ( HAQ ) , and C reactive protein ( CRP ) were assessed every 8 weeks . RESULTS : 37 patients were analysed . Adverse events to infliximab were mostly infusion reactions . No statistically significant difference between infliximab , before withdrawal , and etanercept , after 24 weeks , was detected in terms of DAS-44 ( 2.7 and 1.9 , respectively ) , HAQ ( 0.75 and 0.75 , respectively ) , P03372 ( 21 and 14 , respectively ) and CRP ( 0.5 and 0.3 , respectively ) . VAS pain decreased significantly after switching to etanercept treatment ( 40 and 24 , respectively ; p < 0.05 ) . CONCLUSIONS : Our study shows that etanercept maintains the clinical benefit achieved by infliximab , and suggests that a second tumour necrosis factor ( P01375 ) alpha inhibitor can be the favourable treatment for rheumatoid arthritis when the first TNFalpha blocker has been withdrawn because of adverse events . DB00005 for therapy-resistant macrophage activation syndrome . Macrophage activation syndrome ( P04201 ) is a severe , potentially fatal complication of childhood rheumatic diseases , especially systemic onset juvenile idiopathic arthritis ( SoJIA ) . We report a 4-year-old girl with probable SoJIA who presented with P04201 . She did not respond to pulse methyl prednisolone and DB00091 A ( DB00091 ) . She also failed to respond to intravenous immunoglobulin ( IVIG ) therapy . DB00005 was started , based on the observation of increased serum levels of tumor necrosis factor-alpha ( P01375 ) in patients with P04201 . Her condition improved following etanercept , suggesting that etanercept might have a therapeutic role in resistant P04201 . DB00005 : a review of its use in the management of rheumatoid arthritis . DB00005 ( Enbrel ) , a soluble fusion protein that binds specifically to the cytokine human tumour necrosis factor ( P01375 ) , is approved for subcutaneous use in the treatment of patients with moderate to severe active rheumatoid arthritis , juvenile rheumatoid arthritis , psoriatic arthritis , ankylosing arthritis and plaque psoriasis in the US , Italy , the rest of the EU and other countries worldwide . Subcutaneous etanercept was efficacious and generally well tolerated in several large , well designed , clinical trials and in the clinical-practice setting in adult patients with rheumatoid arthritis , including methotrexate-naive patients with early disease and those with long-standing , treatment-resistant active disease . DB00005 plus methotrexate combination therapy was generally superior to either monotherapy in reducing disease activity and structural joint damage , as well as improving health-related quality of life ( HR-QOL ) . Furthermore , etanercept monotherapy was superior to placebo and at least as effective as methotrexate therapy in reducing disease activity and improving HR-QOL in patients with early or refractory disease . The beneficial effects of etanercept monotherapy or combination therapy were sustained in the long term ( < or =9 years ) . Some pharmaco-economic analyses suggest that etanercept is a cost-effective option in the treatment of patients with rheumatoid arthritis . Direct head-to-head comparisons with other biological agents would help to definitively position etanercept with respect to these agents . Nevertheless , extensive clinical experience indicates that etanercept is a valuable treatment option in adult patients with long-standing moderate to severe active rheumatoid arthritis and an emerging option in those with early disease . Q9Y6X2 negatively regulates O14788 -mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts . Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor ( NF ) -kappaB ligand ( O14788 ) -mediated osteoclast differentiation from monocyte/macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction . Protein inhibitor of activated P40763 ( Q9Y6X2 ) was initially identified as a molecule that inhibits DNA binding of P40763 and regulates many transcription factors through distinct mechanisms . To analyze Q9Y6X2 function in osteoclasts in vivo , we have generated transgenic mice in which Q9Y6X2 is specifically expressed in the osteoclast lineage using the tartrate-resistant acid phosphatase ( TRAP ) gene promoter . Q9Y6X2 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation . Overexpression of Q9Y6X2 in RAW264.7 cells suppressed O14788 -induced osteoclastogenesis by inhibiting the expression of c-Fos and O95644 . Interestingly , Q9Y6X2 inhibits the transcriptional activity of microphthalmia-associated transcription factor ( O75030 ) independent of sumoylation . Down-regulation of Q9Y6X2 markedly enhances O14788 -mediated osteoclastogenesis in RAW264.7 cells . Furthermore , overexpression of Q9Y6X2 in mouse primary osteoblast ( DB00925 ) , down-regulates O14788 expression induced by interleukin-6 ( P05231 ) cytokine family , and inhibits osteoclast formation from bone marrow macrophages ( BMMs ) in vitro coculture system . Down-regulation of Q9Y6X2 leads to the accelerated expression of O14788 in DB00925 stimulated with P05231 and soluble P05231 receptor ( sIL-6R ) . Taken together , our results clearly indicate that Q9Y6X2 negatively regulates O14788 -mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts . DB00005 for the treatment of psoriasis : combination therapy with other modalities . DB00005 is a self-administered medication that has FDA approval for the treatment of rheumatoid arthritis , juvenile rheumatoid arthritis , psoriatic arthritis , and ankylosing spondylitis . DB00005 is a human fusion protein of the tumor necrosis factor receptor ( TNFR ) and the Fc region of IgG1 that binds to and presumably inhibits the pro-inflammatory and pro-proliferative activity of the tumor necrosis factor ( P01375 ) . A recent multisite , randomized , double-blind , placebo-controlled study conclusively demonstrates that etanercept as monotherapy effectively treats patients with moderate-to-severe plaque psoriasis . This effect is dose-responsive , with the etanercept 50 mg twice-weekly dose significantly more effective than the 25 mg twice-weekly dose in reducing the Psoriasis Area and Severity Index ( PASI ) score over both 12 and 24 weeks of continuous therapy . Nevertheless , clinical trials do not instruct the dermatologist on how to practically integrate etanercept into a patient 's pre-existing treatment regimen . Many psoriasis patients are already on other systemic therapies or have a medical history that necessitates a tailored approach to their therapy . Further , in some patients , etanercept at 25 mg twice weekly is ineffective in maximally clearing a patient of psoriasis . Below are cases that demonstrate how etanercept can be combined with other medications in order to both maximize clinical efficacy and minimize potential risk . DB00338 , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . DB00338 is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P-type H+/K+ ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . DB00338 topically applied to the skin of UV-irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . DB00338 had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P-type ATPase in the trans-Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans-Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . DB00338 treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase . Activation of gonadotropin-releasing hormone receptors induces a long-term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole-cell patch-clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin-releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . DB00007 ( 10(-9)-10(-7) M ) , a specific DB00644 analog , concentration-dependently elicited a long-lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 -induced synaptic potentiation was blocked by 1 microM [ Acetyl-3,4-dehydro-Pro1,D-p-F-Phe2,D-Trp3,6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 -induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H-7 ) . The results suggest a long-term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes . No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( DB00422 ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to DB00422 in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between DB00422 responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of DB00422 among adults with ADHD . P01375 alpha inhibition as treatment modality for certain rheumatologic and gastrointestinal diseases . With the development of biologicals that specifically target tumor necrosis factor ( P01375 )alpha , our therapeutic approach to inflammatory diseases has dramatically changed . There are currently three anti-TNFalpha drugs available : etanercept , infliximab , and adalimumab . DB00005 is a recombinant fusion protein that can be used alone or in combination with other medications for conditions such as rheumatoid arthritis , juvenile rheumatoid arthritis , psoriatic arthritis , psoriasis , and ankylosing spondylitis . DB00065 , a chimeric humanized monoclonal antibody and adalimumab , a fully human monoclonal antibody are approved for the treatment of rheumatoid arthritis , psoriasis , psoriatic arthritis , ankylosing spondylitis , and moderate to severe Crohn 's disease . DB00065 is also approved for ulcerative colitis . Another anti-TNFalpha drug , certolizumab pegol , was declined approval as treatment option for active Crohn 's disease due to a lack of sufficient efficacy . Phase III studies for the treatment of rheumatoid arthritis patients are still pending . It is the goal of this review article to summarize various therapeutic indications , underlying studies , safety , and use during pregnancy , as well as future directions for anti- P01375 therapies . DB00005 attenuates the development of cerulein-induced acute pancreatitis in mice : a comparison with P01375 genetic deletion . P01375 plays a pivotal role in the pathogenesis of acute pancreatitis . Recent studies have shown that P01375 inhibition significantly ameliorates the course of experimental acute pancreatitis , but in this context , the effects of DB00005 , a novel anti- P01375 agent , have not been investigated so far . The aims of the present study are ( i ) to assess the effects of pharmacological inhibition of P01375 by means of DB00005 on the inflammatory response and apoptosis in a murine model of necrotizing acute pancreatitis and ( ii ) to compare the results to those observed in P01375 receptor 1 knockout ( P19438 -KO ) mice . Necrotizing acute pancreatitis was induced in P01375 wild type for P19438 ( WT ) and P19438 -KO mice by intraperitoneal injection of cerulein ( hourly x5 , 50 microg/kg ) . In another group of WT mice , DB00005 was administered ( 5 or 10 mg/kg , s.c. ) at 1 h after first cerulein injection . Control groups received saline treatment . After 24 h , biochemical , histological , and immunohistochemical evidences of acute pancreatitis developed in all cerulein-treated mice ; apoptosis was also present in the pancreas . Contrarily , pancreatitis histological features , amylase and lipase levels , pancreas water content , and myeloperoxidase activity were reduced in a similar degree in DB00005 -treated and P19438 -KO mice . Likewise , in these two groups , immunohistochemical stainings and terminal deoxynucleotidyltransferase-mediated UTP nick-end labeling assay were found negative . P01375 receptor 1 gene deletion and DB00005 administration ameliorate the course of experimental acute pancreatitis in a similar degree . Future studies on clinical applications of DB00005 in pancreatitis seem promising . [ Anti- P01375 treatment and spondyloarthropathies ] . Spondyloarthropathies are characterized by both axial and peripheral joint involvement , by the association with " other diseases " mainly Psoriasis , Crohn 's and Anterior Uveitis and by the high prevalence of HLA B-27 . While disease modifying drugs , such as DB00563 or Sulfasalazine , are only partially effective in controlling peripheral arthritis , the treatment of the axial part remained only symptomatic . The recently introduced anti- P01375 drugs DB00065 ( Remicade ) and DB00005 ( Enbrel ) for the treatment of Crohn 's disease and Rheumatoid Arthritis has been expended to Spondyloarthropathies with highly promising results . The rationale and the early beneficial results of this new approach in spondyloarthropathies are reviewed . DB00005 in the treatment of rheumatoid arthritis . DB00005 ( DB01613 ) is the first anti-tumor necrosis factor ( P01375 ) agent to be approved for the treatment of rheumatoid arthritis ( RA ) . Over the last 8 years , several clinical trials have shown its efficacy and safety in established and early RA , as well as a monotherapy or in combination with methotrexate . DB01613 not only reduces the signs and symptoms of RA , but also retards the progression of radiographic damage and improves the quality of life and function of patients . Its safety profile has been predictable since the first clinical trials with no new major safety concerns . Beyond its efficacy in RA , DB01613 is also indicated for the treatment of psoriatic arthritis . This current report reviews the evidence and the data in RA and psoriatic arthritis ( PsA ) .