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DB00005 SUB ( Enbrel ) : update on therapeutic use . Tumour necrosis factor ( P01375 REA ) is an important inflammatory disease mediator in a wide spectrum of articular diseases , including adult and juvenile rheumatoid arthritis ( RA , JRA ) . DB00005 SUB ( Enbrel ) , approved in the United States and in Europe for use in patients with RA and JRA , is an effective inhibitor of P01375 REA 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 SUB 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 SUB and infliximab are U . S . Food and Drug Administration-approved tumor necrosis factor ( P01375 REA ) antagonists . OBJECTIVE : To describe adverse event reports of heart failure after P01375 REA 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 REA antagonist therapy . MEASUREMENTS : Clinical and laboratory reports . RESULTS : After P01375 REA 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 REA antagonists . After P01375 REA 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 REA antagonists might induce new-onset heart failure or exacerbate existing disease .

Inhibition of JAKs in macrophages increases lipopolysaccharide-induced cytokine production by blocking P22301 REA - mediated feedback . Macrophages are an important source of cytokines following infection . Stimulation of macrophages with TLR agonists results in the secretion of P01375 REA - α , P05231 REA , and IL - 12 , and the production of these cytokines is controlled by multiple feedback pathways . Macrophages also produce P22301 REA , which acts to inhibit proinflammatory cytokine production by macrophages via a JAK / P40763 REA - dependent pathway . We show in this paper that , DB08877 , a recently described selective inhibitor of JAKs , increases P01375 REA , P05231 REA , and IL - 12 secretion in mouse bone marrow-derived macrophages stimulated with LPS . This effect is largely due to its ability to block P22301 REA - 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 REA phosphorylation . The initial induction of P22301 REA was independent of JAK signaling ; however , inhibition of JAKs did reduce P22301 REA secretion at later time points . This reflected a requirement for the IFN-β feedback loop to sustain P22301 REA transcription following LPS stimulation . In addition to P22301 REA , IFN-β also helped sustain P05231 REA and IL - 12 transcription . Overall , these results suggest that inhibition of JAKs may increase the inflammatory potential of macrophages stimulated with O00206 REA 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 REA 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 SUB 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 REA 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 REA is thought to play a pivotal role in the initiation and perpetuation of the chronic inflammatory process in rheumatoid arthritis . P01375 REA 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 REA . 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 SUB was then started . EULAR criteria of response were used with calculation of activity index DAS 28 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 REA 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 - hydroxytryptamine 2B ( P41595 REA ) receptors . To evaluate whether agonism at P41595 REA receptors is a phenomenon of the class of the ergolines , we studied P41595 REA 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 ( pEC 50 8.42 and 8.72 ) . DB01200 MEN acted as a partial agonist ( pEC 50 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 REA receptors seems not to be a class effect of the ergolines .

Tumefactive demyelinating lesions during etanercept treatment requiring decompressive hemicraniectomy . P01375 REA alpha ( P01375 REA - α ) is a pro-inflammatory and immunoregulatory cytokine involved in the pathogenesis of several autoimmune disorders . DB00005 SUB , a P01375 REA - α antagonist ( anti - P01375 REA - α ) acting as a soluble P01375 REA - 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 REA - 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 SUB is an anti - P01375 REA 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 SUB is a soluble tumor necrosis factor ( P01375 REA ) 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 AVG 01 ( trade name AVENT ™ ) , using a novel expression vector-based technology . Here we show , by extensive analytical characterization , that AVG 01 is highly similar to the reference product Enbrel ® and demonstrates similar efficacy in pre-clinical studies .

DB00005 SUB . Soluble tumour necrosis factor receptor , P01375 REA receptor fusion protein , TNFR-Fc , Q92752 REA 001 , Enbrel .

Role of tumor necrosis factor ( P01375 REA ) receptor-associated factor 2 ( TRAF 2 ) in distinct and overlapping P25942 REA and P01375 REA receptor 2 / DB00005 SUB - 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 REA . P25942 REA signals stimulate B cell P01375 REA secretion , which subsequently signals via P20333 REA ( DB00005 SUB ) to enhance B cell activation . Although the function of the pro-apoptotic and pro-inflammatory receptor P19438 REA ( CD120a ) has been the subject of much research , less is understood about the distinct contributions of DB00005 SUB 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 REA and DB00005 SUB bind Q12933 REA ( TRAF 2 ) upon ligand stimulation . Wild type and TRAF 2 - deficient B cells expressing P25942 REA or the hybrid molecule ( human ) P25942 REA ( mouse ) - DB00005 SUB were examined . P25942 REA - and DB00005 SUB - mediated IgM secretion were partly TRAF 2 - dependent , but only P25942 REA required TRAF 2 for c-Jun N-terminal kinase activation . P25942 REA and DB00005 SUB used primarily divergent mechanisms to activate NF-kappaB , exemplifying how TNFR family members can use diverse mechanisms to mediate similar downstream events .

P01375 REA receptors ( Tnfr ) in mouse fibroblasts deficient in Tnfr 1 or Tnfr 2 are signaling competent and activate the mitogen-activated protein kinase pathway with differential kinetics . To dissect tumor necrosis factor receptor ( Tnfr ) - 1 ( CD120a ) and Tnfr 2 ( DB00005 SUB ) - dependent signal transduction pathways , primary fibroblasts isolated from inguinal adipose tissue of wild type ( wt ) , tnfr 1 ( o ) , tnfr 2 ( o ) , and tnfr 1 ( o ) / tnfr 2 ( o ) mice were studied . The mitogen-activated protein kinases Erk 1 and Erk 2 were found to be tyrosine-phosphorylated and activated by Tnf treatment in all wt , tnfr 1 ( o ) , and tnfr 2 ( o ) fibroblasts ; the activation was down-regulated 60 min after the start of steady state Tnf treatment . Distinct kinetics of Erk 1 and Erk 2 activation were detected ; the Tnfr 1 - mediated activation of Erk 1 and Erk 2 started more slowly and persisted for more prolonged times as compared with Tnfr 2 activation . P04049 REA , 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 Tnfr 1 and Tnfr 2 mediated independently the activation of the transcription factor Ap - 1 albeit with parallel activation kinetics . In contrast , Tnfr 1 exclusively mediated activation of NF-kappaB and fibroblast proliferation ; however , Tnfr 2 enhanced proliferation triggered through Tnfr 1 . These findings indicate distinct but also overlapping roles of Tnfr 1 and Tnfr 2 in primary mouse fibroblasts and suggest different regulation mechanisms of signal transduction pathways under the control of both Tnf receptors .

DB00005 SUB 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 REA - α ) inhibitors were the first biologic drug class licensed for the treatment of rheumatoid arthritis . DB00005 SUB is a fusion protein composed of two P01375 REA 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 SUB is an attractive therapeutic option given the excellent safety profile , reduced immunogenicity and ease of administration .

DB00005 SUB reduces acute tissue injury and mortality associated to zymosan-induced multiple organ dysfunction syndrome . It has been well demonstrated that P01375 REA 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 REA - 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 SUB 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 REA receptor 1 ( P19438 REA ) - deficient animals were used as control . Treatment of mice with DB00005 SUB and P19438 REA gene deletion decreased the peritoneal exudation and the migration of neutrophils caused by zymosan . In addition , pharmacological and genetic neutralization of P01375 REA attenuated pancreas and ileum injury ( histology ) , the increase in myeloperoxidase activity in the ileum and in the lung , and the formation of P01375 REA and IL - 1beta . Immunohistochemical analysis for P01375 REA , 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 REA knockout mice . Furthermore , P01375 REA 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 ( CDH 1 , Q8NCT1 , P37231 REA , and Q9UL33 ) or LTR retroelements ( P08253 REA , CDKN 2A , Q13950 REA , and Q13761 REA ) and eight stomach-specific genes ( Q03403 , P20142 , P51164 REA , P04155 REA , Q07654 REA , Q9UBU3 , DB00158 , and P20648 REA ) . 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 REA and Q14116 REA plasma levels . P10145 REA and P01375 REA production by purified PMN was higher in the three patient groups than in the healthy controls , but the oxidative burst and Q14116 REA production were normal . No autoantibodies were detected in SAPHO patients . Induction of PMN P10145 REA and P01375 REA 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 REA and P01375 REA production was down-regulated and P01375 REA 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 SUB modulation of PMN activation status emphasizes these new immunological findings .

P15056 REA inhibitors suppress apoptosis through off-target inhibition of JNK signaling . DB08881 MEN and dabrafenib selectively inhibit the P15056 REA ( P15056 REA ) 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 REA activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX 4720 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 REA activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 REA 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 REA - activated endothelial cells by Q9UNN8 and P25116 REA dependent mechanisms . INTRODUCTION : Thrombin and tumor necrosis factor ( P01375 REA ) - alpha up-regulate the expression of proinflammatory molecules in human umbilical vein endothelial cells ( HUVECs ) . However , activated protein C ( P25054 REA ) 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 REA and thrombin on the expression of sPLA ( 2 ) - IIA and extracellular signal-regulated kinase ( P29323 REA ) 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 REA in the absence and presence of the phosphatidylinositol 3 - kinase ( P19957 REA - 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 REA potently induced its expression . The prior treatment of cells with P25054 REA inhibited expression of sPLA ( 2 ) - IIA through the Q9UNN8 - dependent cleavage of P25116 REA . Further studies revealed that if HUVECs were pretreated with the zymogen protein C to occupy Q9UNN8 , thrombin also inhibited the P01375 REA - mediated expression of sPLA ( 2 ) - IIA through the cleavage of P25116 REA . The Q9UNN8 - dependent cleavage of P25116 REA by both P25054 REA and thrombin increased the phosphorylation of P29323 REA 1/2 . Pretreatment of cells with either LY294002 or MbetaCD abolished the inhibitory activity of both P25054 REA and thrombin against sPLA ( 2 ) - IIA expression , suggesting that the protein C occupancy of Q9UNN8 confers a P19957 REA - kinase dependent protective activity for thrombin such that its cleavage of the lipid-raft localized P25116 REA inhibits the P01375 REA - mediated expression of sPLA ( 2 ) - IIA in HUVECs .

Spotlight on etanercept in plaque psoriasis and psoriatic arthritis . DB00005 SUB ( Enbrel ) , a tumor necrosis factor ( P01375 REA ) - 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 SUB 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 REA converting enzyme activation through stimulation of P41595 REA and alpha 1D 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 REA 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 REA ( P01375 REA - Converting Enzyme ) , a member of a disintegrin and metalloproteinase ( ADAM ) family , as a downstream target of the P41595 REA and 1D receptor-NADPH oxidase signaling pathways . Upon P41595 REA or 1D receptor stimulation , ROS fully govern P01375 REA - shedding in the surrounding milieu of 1C115 - HT or 1C11NE cells . Third , P41595 REA and 1Dreceptor couplings to the NADPH oxidase - P78536 REA cascade are strictly restricted to 1C11 - derived progenies that have implemented a complete serotonergic or noradrenergic phenotype . Overall , these observations suggest that P41595 REA 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 SUB attenuates traumatic brain injury in rats by reducing brain P01375 REA - 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 REA - 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 REA - 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 REA - 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 REA - 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 REA ) - 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 REA - 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 REA - α antagonists were administered included rheumatologic disorders ( 4 ) , sarcoidosis ( 3 ) , psoriasis ( 1 ) and Crohn ' s disease ( 1 ) . DB00005 SUB , 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 REA - 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 REA - α antagonists are relatively rare but important potential complications of these drugs . Determining if the relationship between the neurological deficits and P01375 REA - 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 REA ) 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 SUB 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 REA 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-S 4 and MnSOD - P28222 REA ) . 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 REA 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 REA - 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 MEN ) have been used as anti-inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-alpha ( P01375 REA ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage-colony stimulating factor ( GM - P04141 REA ) . 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 MEN exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer . Signaling pathways that activate P42345 REA ( mammalian target of rapamycin ) are altered in many human cancers and these alterations are associated with prognosis and treatment response . P42345 REA 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 ( RAD 001 ) 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 REA 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 MEN ± 5 Gy suppressed endothelin 1 and lactate dehydrogenase expression and increased P15692 REA , P38936 REA , hypoxia-inducible factor - 1α and P11166 REA ( facilitated glucose transporter 1 ) . P42345 REA mRNA levels were unaffected while P01375 REA - 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 REA - selective antagonistic mutant P01375 REA . Blocking the binding of P01375 REA to P01375 REA receptor subtype - 1 ( P19438 REA ) is an important strategy for the treatment of rheumatoid arthritis ( RA ) . We recently succeeded in developing a P19438 REA - selective antagonistic P01375 REA 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-R 1antTNF ) . In prophylactic protocols , PEG-R 1antTNF clearly improved the incidence , and the clinical score of arthritis due to its long plasma half-life . Although , the effect of PEG-R 1antTNF on the incidence and production of IL1 - beta was less than that of the existing P01375 REA - blocking drug DB00005 SUB , its effect on severity was almost as marked as DB00005 SUB . Interestingly , in therapeutic protocols , PEG-R 1antTNF showed greater therapeutic effect than DB00005 SUB . These data suggest that the anti-inflammatory effects of PEG-R 1antTNF depend on the stage of arthritis . Recently , there has been much concern over the reactivation of viral infection caused by P01375 REA blockade . Unlike DB00005 SUB , PEG-R 1antTNF did not reactivate viral infection . Together , these results indicate that selective inhibition of P01375 REA / P19438 REA could be effective in treating RA and that PEG-R 1antTNF could serve as a promising anti-inflammatory drug for this purpose .

Rheumatoid arthritis in pregnancy : successful outcome with anti - P01375 REA agent ( DB00005 SUB ) .

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 REA 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 REA 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 REA ) - alpha production were evaluated . The knockdown of P01375 REA mRNA was obtained with the use of selective small interfering RNA . RESULTS : We show that the P21554 REA receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor . The activation of the P21554 REA 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 REA mRNA abrogated the ceramide increase and , therefore , the apoptotic effect induced by cannabinoid receptor activation . CONCLUSIONS : The present study shows that either P21554 REA or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells . Our data unveiled , for the first time , that P01375 REA 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 REA ) 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 REA antagonists include infliximab and etanercept . DB00065 is a chimeric P01375 REA 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 SUB is a human P01375 REA 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 REA antagonists in the development of infection , malignancy and autoimmune disease remains unknown .

DB00005 SUB attenuates short-term cigarette-smoke-exposure-induced pulmonary arterial remodelling in rats by suppressing the activation of P01375 REA / NF-kB signal and the activities of P08253 REA and P14780 REA . The pathogenesis of cigarette-smoke-exposure-induced pulmonary vasculature impairment is unclear . Cigarette-smoke-exposure-induced the accumulation of tumour necrosis factor-alpha ( P01375 REA - 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 REA - α antagonist DB00005 SUB is an anti-inflammatory drug with a potential role in regulating MMP expression . To determine the effect of DB00005 SUB 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 SUB . Cigarette-smoke-exposure-induced elevation of mean pulmonary artery pressures and medial hypertrophy of pulmonary arterioles were partially reduced by DB00005 SUB . Up-regulation of the expression and activities of P08253 REA and P14780 REA , induced by cigarette-smoke , were also suppressed significantly by DB00005 SUB . Furthermore , DB00005 SUB treatment significantly attenuated cigarette-smoke-induced TNFα accumulation and activation of nuclear factor NF-kB signal . These results suggest that DB00005 SUB have the protective effects in cigarette-smoke-induced pulmonary vascular remodelling , with the attenuation of the up-regulated expression and activities of P08253 REA and P14780 REA and activation of P01375 REA - 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 REA 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 MENMAX DB01281 MEN , a protein that blocks the costimulation of autoreactive T cells . The addition of P60568 REA could reverse the inhibition seen in vitro with DB01281 MEN . The effects of inhibition of P33681 REA costimulation were also examined by an analysis of cytokine responses and P60568 REA receptor on T cells . DB01281 MEN treatment in vitro reduced the expression of P60568 REA receptor on T cells , enhanced T cell apoptosis and decreased the synthesis of P60568 REA , P01579 REA and P01375 REA . DB01281 MEN treatment had no effect on P22301 REA synthesis by T cells , a cytokine implicated in the functions of regulatory T cell subsets . Overall , our studies support the rationale of P33681 REA 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 REA - 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 SUB 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 REA - alpha and interleukin - 1beta were expressed by infiltrated cells shortly after KLH injection . P01375 REA - 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 REA expression was minimal during the response . Based on this observation , animals were treated with systemic injection of DB00005 SUB , 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 REA - 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 MEN ( ® ) ) . 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 REA / P01375 REA signaling . Marrow stromal cells ( MSCs ) are capable of differentiating into various cell types including endothelial cells . Microenvironment is important in cell fate determination . P01375 REA - alpha converting enzyme ( P78536 REA ) , 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 REA ) . 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 REA / P01375 REA 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 REA and P01375 REA as well as P78536 REA protein expression were significantly upregulated in direct , but not in indirect , coculture condition . Addition of human recombinant P78536 REA promoted gene expression of endothelial specific markers including P04275 REA , CD31 , P33151 REA , Flk - 1 , and Flt - 1 in the differentiating MSCs . Furthermore , inhibition of P78536 REA with TAPI - 2 or inhibition of P01375 REA with DB00005 SUB 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 REA / TNFalpha signaling .

Pulmonary Sarcoidosis following DB00005 SUB Treatment . Tumour necrosis factor ( P01375 REA ) is an important cytokine involved in the pathology of a number of inflammatory conditions , and thus blockade with anti - P01375 REA 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 REA - 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 SUB 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 REA ) agents . We recommend caution in the use of anti - P01375 REA agents in elderly RA patients with preexisting ILD .

DB00005 SUB : long-term clinical experience in rheumatoid arthritis and other arthritis . DB00005 SUB is a dimeric fusion protein based on the p75 P01375 REA receptor . It binds to P01375 REA 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 SUB 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 REA 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 REA 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 SUB therapy in juvenile-onset BD patients , characterized by refractory multiorgan involvement .

Immune function in patients with rheumatoid arthritis treated with etanercept . DB00005 SUB , a recombinant human tumor necrosis factor ( P01375 REA ) inhibitor that binds both soluble and cell-bound P01375 REA , has been shown to reduce disease activity and inhibit joint destruction when administered to patients with rheumatoid arthritis ( RA ) . Because P01375 REA 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 REA 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 REA inhibitors in Switzerland . 106 patients ( 68 female / 38 male ) were included . 61 patients were treated with DB00005 SUB ( 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 REA 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 REA inhibitors seems to be safe and effective for children and adolescents with rheumatologic diseases .

A new role for the P40763 REA inhibitor , Q9Y6X2 REA : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 REA ) 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 REA gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 REA inhibitor , Q9Y6X2 REA . Q9Y6X2 REA is a transcriptional inhibitor that acts by specifically inhibiting P40763 REA ' s DNA binding activity . We found that it can directly associate with O75030 REA using an in vitro pull-down assay . Immunoprecipitation of O75030 REA from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co-immunoprecipitation of Q9Y6X2 REA . Co-transfection of O75030 REA with Q9Y6X2 REA in NIH 3T3 fibroblasts containing an mMCP - 6 promoter-luciferase reporter demonstrated up to 94 % inhibition of O75030 REA - mediated transcriptional activation . Using a gel-shift assay , it was shown that Q9Y6X2 REA can block DNA binding activity . It was also found that P40763 REA does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 REA and O75030 REA . These data suggest that Q9Y6X2 REA functions in vivo as a key molecule in supressing the transcriptional activity of O75030 REA , 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 REA ) - 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 REA significantly suppressed basal and GH-releasing hormone ( P01148 REA ) - stimulated GH release . P01375 REA also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0.1- 10 nM ) . Whereas P01375 REA reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 REA 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 REA 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 REA on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 REA . These results demonstrate a direct effect of P01375 REA on anterior pituitary hormone release , which is cell-type specific and age dependent .

Photoacoustic tomography of joints aided by an DB00005 SUB - 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 REA drug delivery . After the contrast agent composed of gold nanorods conjugated with DB00005 SUB molecules was produced , ELISA experiments were performed to prove the conjugation and to show that the conjugated anti - P01375 REA - 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 REA antagonist pharmaceutical preparations with gold nanorods , preservation of the mechanism of action of P01375 REA 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 REA - α in vitiligo : direct correlation between tissue levels and clinical parameters . BACKGROUND : Experimental evidences have shown that tumor necrosis factor ( P01375 REA ) - α may play a role in the pathogenesis of nonsegmental vitiligo , and successful cases of vitiligo treated with P01375 REA - α inhibitors have been recently reported . MATERIALS AND METHODS : Two cases of refractory generalized vitiligo , which showed high tissue levels of P01375 REA - α , were commenced anti - P01375 REA - α antibody etanercept 50 mg weekly . A retrospective study , considering chart review and immunohistochemical staining for P01375 REA - α , was then carried out on eight additional patients affected by untreated vitiligo . RESULTS : DB00005 SUB achieved improvement of vitiligo in two patients at 6 - month follow-up . Five out of eight specimens showed a strong cytoplasmic staining for P01375 REA - α . Considering all 10 cases , patients with a strong P01375 REA - 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 REA - α in the pathogenesis of vitiligo . The intensity of P01375 REA - α staining in vitiligo lesions may be worth to be further studied as a biomarker for potentially successful anti - P01375 REA - 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 REA 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 SUB , 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 REA ) antagonist etanercept as a treatment for psoriatic disease , including the failure of traditional therapies to meet patient needs , evidence that P01375 REA 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 SUB prevents initiation of the proinflammatory cascade by competitively binding P01375 REA . First indicated for RA , etanercept is also approved for the treatment of psoriatic arthritis , juvenile RA , ankylosing spondylitis , and most recently psoriasis . DB00005 SUB 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 SUB 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 REA ) 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 REA ( 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 REA ) alpha inhibitor can be the favourable treatment for rheumatoid arthritis when the first TNFalpha blocker has been withdrawn because of adverse events .

DB00005 SUB 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 SUB was started , based on the observation of increased serum levels of tumor necrosis factor-alpha ( P01375 REA ) in patients with P04201 . Her condition improved following etanercept , suggesting that etanercept might have a therapeutic role in resistant P04201 .

DB00005 SUB : a review of its use in the management of rheumatoid arthritis . DB00005 SUB ( Enbrel ) , a soluble fusion protein that binds specifically to the cytokine human tumour necrosis factor ( P01375 REA ) , 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 SUB 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 REA negatively regulates O14788 REA - 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 REA ) - mediated osteoclast differentiation from monocyte / macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction . Protein inhibitor of activated P40763 REA ( Q9Y6X2 REA ) was initially identified as a molecule that inhibits DNA binding of P40763 REA and regulates many transcription factors through distinct mechanisms . To analyze Q9Y6X2 REA function in osteoclasts in vivo , we have generated transgenic mice in which Q9Y6X2 REA is specifically expressed in the osteoclast lineage using the tartrate-resistant acid phosphatase ( TRAP ) gene promoter . Q9Y6X2 REA transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation . Overexpression of Q9Y6X2 REA in RAW 264.7 cells suppressed O14788 REA - induced osteoclastogenesis by inhibiting the expression of c-Fos and O95644 REA . Interestingly , Q9Y6X2 REA inhibits the transcriptional activity of microphthalmia-associated transcription factor ( O75030 REA ) independent of sumoylation . Down-regulation of Q9Y6X2 REA markedly enhances O14788 REA - mediated osteoclastogenesis in RAW 264.7 cells . Furthermore , overexpression of Q9Y6X2 REA in mouse primary osteoblast ( DB00925 ) , down-regulates O14788 REA expression induced by interleukin - 6 ( P05231 REA ) cytokine family , and inhibits osteoclast formation from bone marrow macrophages ( BMMs ) in vitro coculture system . Down-regulation of Q9Y6X2 REA leads to the accelerated expression of O14788 REA in DB00925 stimulated with P05231 REA and soluble P05231 REA receptor ( sIL - 6R ) . Taken together , our results clearly indicate that Q9Y6X2 REA negatively regulates O14788 REA - mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts .

DB00005 SUB for the treatment of psoriasis : combination therapy with other modalities . DB00005 SUB is a self-administered medication that has FDA approval for the treatment of rheumatoid arthritis , juvenile rheumatoid arthritis , psoriatic arthritis , and ankylosing spondylitis . DB00005 SUB is a human fusion protein of the tumor necrosis factor receptor ( TNFR ) and the Fc region of IgG 1 that binds to and presumably inhibits the pro-inflammatory and pro-proliferative activity of the tumor necrosis factor ( P01375 REA ) . 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 MEN , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 REA trafficking . DB00338 MEN is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 REA , 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 MEN topically applied to the skin of UV-irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . DB00338 MEN had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel 17 , or O75030 REA mRNA levels . Although melanocytes do not express P20648 REA , they do express Q04656 REA , a copper transporting P-type ATPase in the trans-Golgi network that is required for copper acquisition by tyrosinase . Q04656 REA relocalization from the trans-Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . DB00338 MEN 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 REA 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 REA pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin-releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . DB00007 MEN ( 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 REA - induced synaptic potentiation was blocked by 1 microM [ Acetyl -3,4- dehydro-Pro 1 , D-p-F-Phe 2 , D-Trp 3,6 ] - P01148 REA , a specific P30968 REA antagonist . Furthermore , P30968 REA - 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 MEN ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 REA , P28222 REA , Q8IWU9 , P09172 REA , P21917 REA , P21964 REA , and P60880 REA ) in the response to DB00422 MEN 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 MEN responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of DB00422 MEN among adults with ADHD .

P01375 REA alpha inhibition as treatment modality for certain rheumatologic and gastrointestinal diseases . With the development of biologicals that specifically target tumor necrosis factor ( P01375 REA ) alpha , our therapeutic approach to inflammatory diseases has dramatically changed . There are currently three anti-TNFalpha drugs available : etanercept , infliximab , and adalimumab . DB00005 SUB 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 REA therapies .

DB00005 SUB attenuates the development of cerulein-induced acute pancreatitis in mice : a comparison with P01375 REA genetic deletion . P01375 REA plays a pivotal role in the pathogenesis of acute pancreatitis . Recent studies have shown that P01375 REA inhibition significantly ameliorates the course of experimental acute pancreatitis , but in this context , the effects of DB00005 SUB , a novel anti - P01375 REA agent , have not been investigated so far . The aims of the present study are ( i ) to assess the effects of pharmacological inhibition of P01375 REA by means of DB00005 SUB 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 REA receptor 1 knockout ( P19438 REA - KO ) mice . Necrotizing acute pancreatitis was induced in P01375 REA wild type for P19438 REA ( WT ) and P19438 REA - KO mice by intraperitoneal injection of cerulein ( hourly x5 , 50 microg / kg ) . In another group of WT mice , DB00005 SUB 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 SUB - treated and P19438 REA - KO mice . Likewise , in these two groups , immunohistochemical stainings and terminal deoxynucleotidyltransferase-mediated UTP nick-end labeling assay were found negative . P01375 REA receptor 1 gene deletion and DB00005 SUB administration ameliorate the course of experimental acute pancreatitis in a similar degree . Future studies on clinical applications of DB00005 SUB in pancreatitis seem promising .

[ Anti - P01375 REA 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 REA drugs DB00065 ( Remicade ) and DB00005 SUB ( 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 SUB in the treatment of rheumatoid arthritis . DB00005 SUB ( DB01613 ) is the first anti-tumor necrosis factor ( P01375 REA ) 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 ) .