interacts_with DB08904?
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 . Evaluation of pharmacokinetics and pharmacodynamics and clinical efficacy of certolizumab pegol for Crohn 's disease . INTRODUCTION : P01375 -α antagonists have transformed the treatment of patients with Crohn 's disease ( CD ) . DB08904 ( CZP ) is the third P01375 -α antagonist to be approved for use in the United States but is not currently approved in Europe . AREAS COVERED : This review evaluates the pharmacokinetics , pharmacodynamics and efficacy of CZP in CD . Safety , immunogenicity and its use in pregnancy have also been assessed . A literature search was conducted using Pub Med ( 2004 - 2014 ) for the terms ' Crohn 's disease ' and ' certolizumab pegol ' or ' certolizumab ' or ' cimzia ' . Additional studies were identified from other sources including citation . EXPERT OPINION : As a Fab ' fragment , CZP is effective in binding P01375 -α , but does not cause Fc-mediated effects . PEGylation has improved its pharmacokinetic profile and allowed for an increased half-life of 2 weeks . Benefit for inducing response ( an improvement in symptoms ) and maintenance of remission has been shown . However , the benefit is less clear for the more stringent end-points of inducing remission and mucosal healing . There may be an advantage from the PEGylated formulation of CZP in terms of reduced injection-site reactions , reduced placental transfer in pregnancy and as a treatment option in patients who are unable to tolerate infliximab . The use of P01375 blocking agents in rheumatoid arthritis : an update . P01375 has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis ( RA ) . Drugs targeting P01375 have been developed to neutralise the deleterious effects of this inflammatory cytokine . There are , at present , three drugs available for the treatment of RA patients with active disease who are refractory to conventional treatments including methotrexate : 2 monoclonal antibodies , infliximab and adalimumab , and a fusion protein with p75 receptors , etanercept . These three agents have proved to be effective and safe in large placebo-controlled trials enrolling patients with established or early disease and showed effectiveness in controlling signs and symptoms of the disease , improving quality of life and in slowing and even arresting the progression of radiographic damage . With the long-term surveillance of these drugs were described serious adverse events , particularly infections such as tuberculosis , especially with infliximab . The risk for malignancies under P01375 antagonists , especially lymphoma , remains controversial . Specific recommendations are given by international experts for selecting and monitoring RA patients with P01375 antagonists . Other drugs targeting P01375 such as PEGylated molecules ( DB08904 or certolizumab ) are in development . These new biological therapies blocking P01375 undoubtedly constitute a considerable advancement in the management of RA , but careful evaluation at the initiation of the treatment and long-term surveillance of the patients receiving such drugs remains necessary . P01375 and its inhibitors in cancer . P01375 ( P01375 ) -alpha is implicated in the same time in apoptosis and in cell proliferation . P01375 not only acts as pro-inflammatory cytokine conducing to wide spectrum of human diseases including inflammatory diseases , but can also induce tumor development . The molecular mechanisms of P01375 functions have been intensively investigated . In this review we covered P01375 , the molecule , its signaling pathway , and its therapeutic functions . We provide a particular insight in its paradoxical role in tumor promotion and in its use as anti-tumor agent . This review considers also the recent findings regarding P01375 inhibitors , their pharmacokinetics , and their pharmacodynamics . Six P01375 inhibitors have been considered here : DB00065 , DB00051 , Golimumab , DB08904 , CDP571 , DB00005 , and Thalidomide . We discussed the clinical relevance of their functions in treatment of several diseases such as advanced inflammatory rheumatic and bowel disease , with a focus in cancer treatment . Targeting P01375 by these drugs has many side effects like malignancies development , and the long-term sequels are not very well explored . Their efficacy and their safety were discussed , underscoring the necessity of close patients monitoring and of their caution use . P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1. P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] -doxepin . 2 . (+)- DB01114 , a selective and classical antihistamine , occupied 76.8 +/- 4.2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)-chlorpheniramine almost completely abolished the binding of [ 11C ] -doxepin to H1 receptors ( H1 receptor occupancy : 98.2 +/- 1.2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17.2 +/- 14.2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea-pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea-pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second-generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively . Profile of certolizumab and its potential in the treatment of psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic inflammatory arthropathy associated with psoriasis ( PsO ) . PsA could be considered an enthesal disease because of the link between mechanical stress ( entheses ) and immunologically active tissue ( synovium ) . Evidence of efficacy of anti-tumor necrosis factor alpha ( P01375 -α ) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment . DB08904 ( CZP ) is a polyethylene glycolylated ( PEGylated ) Fab ' fragment of a humanized monoclonal antibody that binds and neutralizes human P01375 -α . The PEG moiety of the Fab fragment , markedly increases the half-life of CZP and confers to the drug a unique structure that differs from the other anti- P01375 -α agents tested for the treatment of Crohn 's disease , rheumatoid arthritis , ankylosing spondylitis , axial spondyloarthritis , nonradiographic spondyloarthritis , PsO , and PsA . In contrast to other anti- P01375 -α agents , CZP did not mediate increased levels of apoptosis , suggesting that these mechanisms are not essential for the anti- P01375 -α efficacy in Crohn 's disease . As CZP , infliximab , and adalimumab , but not etanercept , almost completely inhibited lipopolysaccharide-induced interleukin-1 beta release from monocytes , this cytokine-production inhibition may be relevant for drug efficacy . Due to these characteristics , it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO , with a safety profile similar to rheumatoid arthritis . This drug can be considered as a valid treatment in patients affected by PsA . The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA . P01375 as a therapeutic target in inflammatory diseases , ischemia-reperfusion injury and trauma . P01375 -alpha ( P01375 ) is a central regulator of inflammation , and P01375 antagonists may be effective in treating inflammatory disorders in which P01375 plays an important pathogenetic role . Recombinant or modified proteins are an emerging class of therapeutic agents . To date , several recombinant or modified proteins which acts as P01375 antagonists have been disclosed . In particular , antibodies that bind to and neutralise P01375 have been sought as a means to inhibit P01375 activity . Inhibition of P01375 has proven to be an effective therapy for patients with rheumatoid arthritis and other forms of inflammatory disease including psoriasis , psoriatic arthritis , and ankylosing spondylitis , inflammatory bowel disease . Additionally , the efficacy of preventing septic shock and AIDS has been questioned as a result of recent research . The currently available therapies include a soluble p75 P01375 receptor:Fc construct , etanercept , a chimeric monoclonal antibody , infliximab , and a fully human monoclonal antibody , adalimumab . DB08904 is a novel P01375 inhibitor which is an antigen-binding domain of a humanized P01375 antibody coupled to polyethylene glycol ( PEG ) to increase half-life , and thus is Fc-domain-free . In this review , we discuss briefly the present understanding of P01375 -mediated biology and the current therapies in clinical use , and focus on some of the new therapeutic approaches with small-molecule inhibitors . Moreover , we examine recent reports providing important insights into the understanding of efficacy of thalidomide and its analogs , as P01375 activity inhibitories , especially in therapies of several inflammatory diseases within the nervous system . [ DB08904 ] . DB08904 is a new anti- P01375 drug formed by the Fab ' fragment of a humanized mouse monoclonal antibody bound to two molecules of polyethylene glycol . DB08904 recognizes and binds to human P01375 -α , both in its soluble and membrane bound form , and has shown clinical efficacy in controlled trials for the treatment of RA and Crohns ' disease . In this review we summarize the structural characteristics and clinical efficacy data , as well as safety data of this anti- P01375 agent in patients with RA . DB08904 -- what role does this new P01375 inhibitor have in the treatment of RA ? The efficacy and safety of a new tumor necrosis factor inhibitor , certolizumab pegol , in active rheumatoid arthritis has now been assessed in three phase III , multicenter , randomized , double-blind , placebo-controlled clinical trials . This commentary focuses on the paper by Keystone et al. , in which patients were followed for the longest duration . This study , which compared two doses of subcutaneous certolizumab pegol with placebo in patients with active RA receiving methotrexate , showed no advantage of 400 mg over 200 mg certolizumab pegol over 52 weeks , after induction with 400 mg . The nature of the patients enrolled in this study , trial design and possible safety issues are discussed , as is whether this trial can teach us anything about tumor necrosis factor inhibitors in general . On the basis of the results from this study , certolizumab pegol does not represent a major addition to our armamentarium , but because of the slightly different mechanism of action and structure of this drug , and the apparently acceptable therapeutic effects over one year , it is , nevertheless , welcome . The regulation of rotenone-induced inflammatory factor production by DB00171 -sensitive potassium channel expressed in BV-2 cells . Our previous studies have demonstrated that activating DB00171 -sensitive potassium channel ( K( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson 's disease ( PD ) . In this study , it was first shown that the subunits of K( DB00171 ) channels are expressed in BV-2 cells , and then it was investigated whether K( DB00171 ) channel was involved in regulating inflammatory factor production from BV-2 cells activated by rotenone . It was found that K( DB00171 ) channel was expressed in BV-2 cell and formed by the combination of Kir 6.1 and Q09428 2A/2B . K( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone-induced morphological alterations of BV-2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5-hydroxydecanoate acid ( a selective mitochondrial K( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K( DB00171 ) channels , especially mitochondrial DB00171 -sensitive potassium channels ( mitoK( DB00171 ) channels ) , played a crucial role in preventing the activation of BV-2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders . The efficacy and safety of certolizumab pegol ( CZP ) in the treatment of active rheumatoid arthritis ( RA ) : a meta-analysis from nine randomized controlled trials . OBJECTIVE : DB08904 ( CZP ) is a novel anti- P01375 agent that is used for patients with moderate to severe active rheumatoid arthritis ( RA ) . However , the efficacy of CZP in RA remains controversial . Thus , we performed this meta-analysis to assess the efficacy and safety of CZP in the treatment of RA patients . METHODS : Eligible studies were randomized controlled trials ( RCTs ) that evaluated the efficacy and safe of CZP in the patients with active RA . The primary outcome was American College of Rheumatology 20 % ( ACR20 ) , and secondary outcome were ACR50 , ACR70 , disease activity , patient-reported outcomes ( PROs ) , and adverse events . A fixed-effect model or random-effect model was used to pool the estimates , depending on the absence or presence of heterogeneity among the included studies . RESULTS : Nine RCTs with a total of 5228 patients were included in this meta-analysis , and all of the patients were administered CZP or placebo . The pooled results showed that CZP significantly improved the ACR20 , ACR50 , ACR70 response rates , and physical function . CZP was associated with a statistically significant reduction in Disease Activity Score in 28 joints-Erythrocyte sedimentation rate , arthritis pain , and fatigue . Patients who received CZP treatment did not have a higher incidence of treatment-related adverse events , no matter in any intensity . CONCLUSIONS : CZP 200 or 400mg in the treatment of active RA significantly reduced the RA signs and symptoms , and improved physical function as compared with the placebo . More large-scale RCTs are needed to evaluate the long-term efficacy and safety of CZP in the treatment of active RA . DB08904 in rheumatoid arthritis : current update . INTRODUCTION : The development of P01375 -α inhibitors ( P01375 -is ) represents a major advancement in the treatment of rheumatoid arthritis ( RA ) . Currently , there are five agents licensed for moderate-to-severely active RA . DB08904 ( CZP ) is a novel PEGylated , constant fragment-free P01375 -i therapy , which is the focus of this review . AREAS COVERED : Data from Phase III randomised controlled trials in terms of clinical efficacy , radiographic progression , patient-reported outcomes and safety profile are reviewed . These include long-term data from open-label extension studies . EXPERT OPINION : The advantages of CZP include rapid reduction of disease activity , low rates of injection-site reaction and may be safe for use in pregnancy . The long-term data strengthen the position of CZP for use either as monotherapy or preferably in combination with disease modifying anti-rheumatic drugs ( DMARDs ) , in moderate-to-severely active RA , comparable to other P01375 -is . Notably , prolonged CZP exposure is not associated with increased risk of severe infection compared to general population , contrasting with preliminary analysis of short-term data . Over the next few years , evidence will be available on the use of CZP in combination with methotrexate for remission induction in DMARD-naïve patients , biomarkers and the development and licensing of P01375 -i biosimilars . The cytotoxic effects of certolizumab pegol and DB06674 mediated by transmembrane tumor necrosis factor α . BACKGROUND : Anti-tumor necrosis factor α ( anti- P01375 -α ) agents have been successfully applied for the treatment of rheumatoid arthritis , Crohn 's disease , and other chronic inflammatory diseases . Not only the neutralization of soluble P01375 -α but also the effect on transmembrane P01375 -α is important mechanisms of action of anti- P01375 -α agents . This study investigated the cytotoxic effects of new anti- P01375 -α agents , certolizumab pegol and DB06674 , which are mediated by transmembrane P01375 -α . METHODS : Transmembrane P01375 -α-expressing Jurkat T cells that did not express P01375 receptors were used . The binding ability of each anti- P01375 -α agent to transmembrane P01375 -α , antibody-dependent cell-mediated cytotoxicity , complement-dependent cytotoxicity , and the apoptotic effect were examined . RESULTS : DB08904 and DB06674 bound to transmembrane P01375 -α . Golimumab induced antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity , which was comparable to infliximab and adalimumab . However , certolizumab pegol did not induce antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity . DB08904 directly induced nonapoptotic cell death in transmembrane P01375 -α-expressing cells . Golimumab induced a weaker apoptotic effect than infliximab and adalimumab . CONCLUSIONS : The cytotoxic effects of anti- P01375 -α agents on P01375 -α-expressing cells are considered to be associated with the clinical effect of these agents on granulomatous diseases . The direct cytotoxic effect of certolizumab pegol on P01375 -α-producing cells may contribute to its clinical efficacy in Crohn 's disease . Golimumab may be less effective for granulomatous diseases . DB08904 in Crohn 's disease . DB08904 is a humanized Fab ' fragment monoclonal antibody to tumor necrosis factor alpha ( P01375 ) . PEGylation increases its half-life , and it is administered subcutaneously to treat immune-mediated inflammatory diseases such as Crohn 's disease and rheumatoid arthritis . DB08904 improves quality of life and reduces clinical disease activity . Inflammatory markers such as P02741 ( CRP ) also decrease after administration of certolizumab pegol . The dose for induction of remission is 400 mg subcutaneously at weeks 0 , 2 and 4 . The dose for maintenance of remission is 400 mg sc given every four weeks . The safety profile is comparable with other anti- P01375 agents , and the major adverse events are related to infections . This article reviews the published data regarding the efficacy and safety of certolizumab pegol . DB08904 for the treatment of Crohn 's disease . DB08904 is a polyethylene glycolated FAb ' fragment of a humanized anti- P01375 monoclonal antibody . This pegylated molecule binds with circulating P01375 and forms an inactive complex that is then eliminated from the body . The drug has been shown to be better than placebo in the treatment of Crohn 's disease and maintaining a clinical response in adult patients with moderate-to-severe active disease who have had an inadequate response to conventional therapy , and the treatment of adults with moderately to severely active rheumatoid arthritis . Comparative trials with an active control group are lacking . The most common adverse reactions include abdominal pain , diarrhea , injection site reactions and infection . All necessary live and attenuated vaccines should be given prior to the initiation of certolizumab pegol therapy , patients should be evaluated for TB risk factors and tested for latent TB prior to initiating therapy , and the initiation of therapy should be avoided if the patient has an active infection . Concomitant use with anakinra is not recommended because of the increased risk of serious infections and neutropenia . Therapy should be discontinued if the patient develops a serious infection during therapy . Pulmonary infectious complications of tumor necrosis factor blockade . The understanding of the infection risks posed by tumor necrosis factor ( P01375 ) antagonists has continued to evolve in the 10 years since these drugs first were introduced . Recent prospective studies have confirmed the risk of tuberculosis ( TB ) reactivation posed by P01375 antibodies to be several fold greater than soluble P01375 receptor . DB08904 , a monovalent anti- P01375 Fab ' fragment , appears to share this risk , despite its lack of Fc and its inability to cross-link transmembrane P01375 or activate complement . Two-step ( boosted ) tuberculin skin test screening and initiation of treatment for latent TB infection can greatly reduce the TB risk of anti- P01375 treatment in western countries . Current recommendations for withdrawal of anti- P01375 therapy when TB is diagnosed place patients at risk for paradoxical worsening due to recovery of P01375 -dependent inflammation . Further research is needed to determine how best to prevent and manage their infectious complications and to determine their potential adjunctive therapeutic role in chronic infectious diseases . [ Treatment of patients with destructive arthritis with certolizumab pegol ] . DB08904 is a new anti- P01375 inhibitor which has been approved for the treatment of rheumatoid arthritis since October 2009 . Due to the modification of the antibody fragment by the adherence of polyethylene glycol ( PEG ) a sufficient distribution in inflammatory tissue was found in animal experiments . In two individual case reports a remission of therapy refractive arthritis was achieved by administration of certolizumab pegol . [ Biologic therapies in chronic inflammatory bowel diseases ] . Crohn 's disease and ulcerative colitis are chronic inflammatory bowel diseases which can be difficult to control with conventional therapies . Thanks to a better knowledge of their physiopathology , new therapies aimed at specific targets of the inflammatory cascade were developed . Three monoclonal anti- P01375 antibodies were produced . DB00065 and adalimumab , currently widely used , can induce sustained remission in Crohn 's disease . DB00065 is also efficacious in UC . DB08904 provides good short term results ; its long term efficacy , however , remains to be assessed by further clinical trials . Therapies targeting leucocyte trafficking ( anti-integrine ) have also been provided and are associated with good clinical responses in Crohn 's disease . DB00108 ( anti-alpha4 ) is responsible for significant side effects and is no longer in use in gasrtoenterology in Europe whereas MLN02 ( anti-alpha417 ) has a good profile in terms of efficacy and safety . Monoclonal anti bodies targeting other cytokines are under development , mainly ustekinumab which inhibits IL12 and IL23 . Ustekinumab generates favourable clinical responses in Crohn 's disease . The development of biologic therapies in inflammatory bowel disease has dramatically altered the course and management of these disorders . DB08904 and rheumatoid arthritis . Just another P01375 alpha antagonist , no therapeutic advantage . No comparison with other P01375 alpha antagonists ; possible bleeding risk . Current directions of biologic therapies in inflammatory bowel disease . Crohn 's disease ( CD ) and ulcerative colitis ( UC ) are chronic inflammatory bowel diseases which can be difficult to control with conventional therapies . A greater understanding of their pathophysiology has led to new therapies that target specific molecules of the inflammatory cascade . Three anti-tumor necrosis factor ( P01375 ) monoclonal antibodies have been developed . DB00065 and adalimumab can induce clinical response and sustained remission in CD . DB00065 is also effective in UC . DB08904 gives good short-term results but long-term efficacy has yet to be determined in other clinical trials . Therapies that target leucocyte trafficking ( anti-integrins ) have also been developed and are associated with good clinical response in CD . DB00108 ( anti-α4 integrin antibody ) is associated with important side effects and is not used anymore in gastroenterology in Europe but is still used in the USA . DB09033 ( MLN0002 ) , an anti-α4β7 integrin antibody , has a good efficacy and safety profile . Monoclonal antibodies targeting other cytokines are also under development . For example , ustekinumab ( CNTO 1275 ) inhibits interleukins 12 and 23 . It is associated with a good clinical response in CD . Prefilled certolizumab pegol ( Cimzia(®) ) syringes for self-use in the treatment of rheumatoid arthritis . A new anti-tumor necrosis factor alpha ( P01375 -α ) inhibitor with a novel mechanism of action has entered phase 3 trials in rheumatoid arthritis ( RA ) . DB08904 ( Cimzia(®) ) is a humanized Fab ' antibody fragment against P01375 -α with a polyethylene glycol tail that prevents complement-dependent and antibody-dependent cell-mediated cytotoxicity or apoptosis . Four randomized clinical trials have been published so far . Reported results are similar to those published in previous studies with other P01375 -α inhibitors , with ACR20 , ACR50 , and ACR70 responses of around 60 % , 40 % , and 20 % , respectively , when combined with methotrexate and slightly lower when used as monotherapy . Safety was shown to be similar to that seen with P01375 -α blockers and some cases of tuberculosis were seen in the trials , stressing the importance of a complete screening in these patients . Although we still need effectiveness and safety data in larger numbers of patients and longer follow-up , this new P01375 inhibitor is a welcome addition to our current armamentarium for the treatment of RA . DB08904 compared to natalizumab in patients with moderate to severe Crohn 's disease : results of a decision analysis . INTRODUCTION : A significant proportion of patients with Crohn 's disease ( CD ) lose response to antibodies directed against tumor necrosis factor α ( P01375 ) . Prior P01375 -antagonist failure is associated with lower rates of response to subsequent P01375 -antagonist therapy . In patients failing two anti- P01375 agents , a choice exists between using a third-anti- P01375 therapy or natalizumab ( NAT ) , an α-4 integrin inhibitor . A cost-effectiveness analysis comparing these competing strategies has not been performed . METHODS : A decision analytic model was constructed to compare the performance of certolizumab pegol ( CZP ) versus NAT in patients with moderate to severe CD . Previously published estimates of efficacy of third-line anti- P01375 therapy and NAT were used to inform the model . Costs were expressed in 2010 US dollars . A 1-year time frame was used for the analysis . RESULTS : In the base case estimate , use of NAT was only marginally more effective [ 0.71 vs. 0.70 quality adjusted life-years ( QALYs ) ] than CZP but was expensive with an incremental cost-effectiveness ratio ( Q03060 ) of $ 381,678 per QALY gained . For CZP 2 months response rate of at least 24 % , NAT had an Q03060 above the willingness-to-pay ( WTP ) threshold . The model was sensitive to the costs of both therapies ; for all CZP costs below $ 2,300 per dose , NAT had higher Q03060 than the WTP threshold . Substituting adalimumab for CZP resulted in similar Q03060 estimates and thresholds for NAT use . CONCLUSIONS : In patients with moderate to severe CD failing two P01375 -antagonists , using a third P01375 -antagonist therapy appears to be a cost-effective strategy without significantly compromising treatment efficacy . New concepts in anti-tumor necrosis factor therapy for inflammatory bowel disease . Crohn 's disease is a T helper type 1 response immune disease characterized by increased production of interleukin-12 tumor necrosis factor-a ( P01375 ) , and interferon-g . Clinical trials have demonstrated that inhibition of P01375 is effective for the treatment of Crohn 's disease . Adverse events reported in patients treated with anti- P01375 agents include immunogenicity , acute infusion reactions , delayed hypersensitivity-type reactions , autoimmune diseases including drug-induced lupus and demyelination , and infection . This article reviews new concepts in the treatment of Crohn 's disease and ulcerative colitis with a variety of anti- P01375 biologic therapies : infliximab , adalimumab , DB08904 , CDP571 , etanercept , and onercept . Anti- P01375 therapy in Crohn 's disease . Anti-tumour necrosis factor ( P01375 ) strategies , the most studied of biological therapies , include chimeric monoclonal ( infliximab ) , humanized monoclonal ( CDP571 and the PEGylated DB08904 ) and fully human monoclonal ( adalimumab ) antibodies , p75 fusion protein ( etanercept ) , p55 soluble receptor ( onercept ) and small molecules such as MAPkinase inhibitors . The principal use of infliximab is in treating active Crohn 's disease patients not responding to or intolerant of conventional therapies . DB00065 is steroid sparing . The development of antibodies against infliximab is associated with an increased risk of infusion reactions , and a reduced duration of response to treatment , and concomitant immunosuppressive therapy reduces the immunogenic response . The demonstration of the efficacy of maintenance therapy every 8 weeks with infliximab in the randomised , controlled , ACCENT I trial opened up the strategy for regular maintenance . In patients who have failed therapy with cortocosteroids and immunosuppressive therapy and are poor surgical candidates , and patients with fistulizing disease , where infliximab therapy is chosen , regular maintenance therapy with infliximab is likely to be required . On the other hand , patients with severely active , steroid-refractory disease in whom immunosuppressive therapy and infliximab are initiated together , may respond adequately and be continued on long-term immunosuppressive therapy alone . In ulcerative colitis the role of infliximab remains uncertain . Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc. are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq/ P49842 signaling , PI3K , MAPK pathways , Na/H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK/ P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations . The clinical efficacy and safety of certolizumab pegol in rheumatoid arthritis . IMPORTANCE OF THE FIELD : The treatment of rheumatoid arthritis has changed dramatically over the past 25 years , first with the introduction of methotrexate and then the introduction of biologic therapy . These agents have provided patients with multiple treatment options to try to achieve disease remission . Unfortunately , no one single agent is fully effective in every patient ; different patients respond to different therapies , even those with the same mechanism of action , in different ways . Another medication , such as certolizumab pegol , is a welcome addition to our treatment armamentarium of rheumatoid arthritis . AREAS COVERED IN THIS REVIEW : The basis of this review is all the peer-reviewed manuscripts found in PubMed and Medline searches from 1990 to 2009 and abstracts on certolizumab pegol presented at the American College of Rheumatology and European League Against Rheumatism within the past 5 years . WHAT THE READER WILL GAIN : This review should enable the reader to fully understand the benefit:risk ratio of certolizumab pegol in the treatment of rheumatoid arthritis . TAKE HOME MESSAGE : DB08904 is an effective agent either in combination with methotrexate or as monotherapy in the treatment of rheumatoid arthritis with a safety profile similar to other approved P01375 inhibitors . Infectious complications of tumor necrosis factor blockade . PURPOSE OF REVIEW : Our understanding of the infection risks posed by tumor necrosis factor ( P01375 ) antagonists has continued to evolve in the 10 years since these drugs were first introduced . This review summarizes recent data regarding infection risk , examines potential structure-function relationships that may account for the differences , and discusses their implications with regard to tuberculosis prevention and management . RECENT FINDINGS : Recent prospective studies have confirmed the risk of tuberculosis reactivation posed by P01375 antibodies to be several fold greater than soluble P01375 receptor . DB08904 , a monovalent anti- P01375 Fab ' fragment appears to share this risk , despite its lack of Fc and its inability to cross-link transmembrane P01375 . Screening and initiation of treatment for latent tuberculosis ( TB ) infection can greatly reduce the TB risk of anti- P01375 treatment in western countries . However , alternative strategies to prevent TB because of new transmission may be required as these therapies become available worldwide . Current recommendations for withdrawal of anti- P01375 therapy when TB is diagnosed place patients at risk for paradoxical worsening because of recovery of P01375 -dependent inflammation . Recent case reports suggest reinstitution of P01375 blockade may be safe and effective adjunctive treatment in such cases , but prospective studies are needed to confirm these observations . SUMMARY : P01375 blockers have transformed treatment of several chronic inflammatory conditions . Further research is needed to determine how best to prevent and manage their infectious complications and to determine their potential adjunctive therapeutic role in chronic infection diseases . DB08904 for the treatment of rheumatoid arthritis . INTRODUCTION : Improved understanding of the pathogenesis of rheumatoid arthritis ( RA ) , and subsequent development of targeted therapies , have greatly advanced the management of this chronic inflammatory disease . The aim of treatment is a state of clinical remission . DB08904 ( CZP ) is a novel pegylated P01375 alpha inhibitor ( TNFi ) therapy and is the focus of this review . AREAS COVERED : CZP is different from other TNFi as it contains a polyethylene glycol ( PEG ) moiety , and lacks the constant fragment ( Fc ) of immunoglobulin ; therefore it does not activate complement . In this review in addition to clinical efficacy of CZP , effects on radiographic and patient-reported outcomes , are discussed . Adverse event data from clinical trials and extension studies are also reviewed . EXPERT OPINION : The addition of novel TNFi therapies to treat RA is welcomed . As well as displaying clinical efficacy , there is evidence to suggest that CZP has unique characteristics , including reduced transfer across the placenta and reduced frequency of injection site reactions . Furthermore , randomised controlled trials ( RCTs ) of CZP have demonstrated rapid improvements in workplace and home productivity in patients contributing to reducing the significant socioeconomic burden of RA . Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol-A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER-labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER-labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER-labelled neurons in the VMH . EE and Q03001 increased ER-labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats . The PRECiSE 2 trial of certolizumab pegol , a new PEGylated anti- P01375 agent , in the treatment of Crohn 's disease : An interview with David A Schwartz , 13 June 2007 . DB08904 ( CDP 870 ) is a new anti-tumor necrosis factor ( P01375 ) therapy currently in development for the treatment of Crohn 's disease , rheumatoid arthritis , and psoriasis . DB08904 is the first PEGylated biologic anti- P01375 agent and has a high binding affinity for P01375 . Dr. Schwartz was an investigator of the PRECiSE ( PEGylated Antibody Fragment Evaluation in Crohn 's Disease Safety and Efficacy ) 2 trial of certolizumab pegol in patients with Crohn 's disease . Pegylation of biological molecules and potential benefits : pharmacological properties of certolizumab pegol . PEGylation of biological proteins , defined as the covalent conjugation of proteins with polyethylene glycol ( PEG ) , leads to a number of biopharmaceutical improvements , including increased half-life , increased solubility and reduced aggregation , and reduced immunogenicity . Since their introduction in 1990 , PEGylated proteins have significantly improved the management of various chronic diseases , including rheumatoid arthritis ( RA ) and Crohn 's disease . DB08904 is the only PEGylated anti-tumour necrosis factor ( P01375 ) -α agent . It is a PEGylated , humanised , antigen-binding fragment of an anti- P01375 monoclonal antibody . Unlike other anti- P01375 agents , it has no crystallisable fragment ( Fc ) domain . Because of its novel structure , certolizumab pegol may have a different mechanism of action to the other anti- P01375 agents , and also has different pharmacodynamic properties , which could possibly translate to a different safety profile . Pharmacodynamic studies have shown that certolizumab pegol binds to P01375 with a higher affinity than adalimumab and infliximab . DB08904 is also more potent at neutralising soluble P01375 -mediated signalling than adalimumab and infliximab , and has similar or lesser potency to etanercept . DB08904 does not cause detrimental in vitro effects such as degranulation , loss of cell integrity , apoptosis , complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity . DB08904 may also penetrate more effectively into inflamed arthritic tissue than other anti- P01375 agents , and is not actively transported across the placenta during pregnancy . Pharmacokinetic studies in healthy volunteers demonstrated that single intravenous and subcutaneous doses of certolizumab pegol had predictable pharmacokinetics . The pharmacokinetics of certolizumab pegol in patients with RA and Crohn 's disease were consistent with pharmacokinetics in healthy volunteers . Randomised clinical trial : improvement in health outcomes with certolizumab pegol in patients with active Crohn 's disease with prior loss of response to infliximab . BACKGROUND : Crohn 's disease ( CD ) is associated with impaired health-related quality of life ( HRQoL ) . DB08904 , administered either every 2 weeks ( q2w ) or q4w , maintains efficacy in patients previously failing on the anti- P01375 agent infliximab ( WELCOME study ) . AIM : To investigate the impact of certolizumab pegol administered q2w and q4w on work productivity and HRQoL in the WELCOME study . METHODS : Patients with loss of response to infliximab received open-label certolizumab pegol induction and were randomised to receive double-blind maintenance treatment with certolizumab pegol 400 mg either q4w or q2w through week 24 , with a final evaluation at week 26 . Work productivity and HRQoL were assessed using the Work Productivity and Activity Impairment:CD questionnaire and Inflammatory Bowel Disease Questionnaire respectively . RESULTS : Baseline HRQoL burden was representative of moderately to severely active CD . HRQoL , daily activity and work productivity improved in both treatment groups as early as week 6 and were maintained through week 26 . Treatment benefits to HRQoL , daily activity and work productivity were similar between the certolizumab pegol q2w vs. q4w groups . CONCLUSIONS : DB08904 therapy results in meaningful improvements in work productivity , daily activities and HRQoL in patients with active CD who previously responded to but either lost response or could not tolerate infliximab ( ClinicalTrials.gov number : NCT00308581 ) . Optimizing anti-tumor necrosis factor strategies in inflammatory bowel disease . The introduction of infliximab , a mouse/human chimeric monoclonal antibody to tumor necrosis factor ( P01375 ) , is an important advance in the treatment of Crohn 's disease . DB00065 is effective for induction and maintenance of remission in patients with inflammatory luminal and fistulizing disease . The development of human antichimeric antibodies ( HACAs ) has led to infusion reactions and loss of efficacy in patients treated with infliximab . Strategies to reduce the frequency of HACA formation include induction of immunologic tolerance with a three-dose regimen at 0 , 2 , and 6 weeks followed by systematic maintenance dosing every 8 weeks ; concomitant immunosuppressive therapy with azathioprine , 6-mercaptopurine , or methotrexate ; and premedication with intravenous corticosteroids . Humanized or fully human anti- P01375 biotechnologic agents , including CDP571 , DB08904 , etanercept , adalimumab , and onercept , are theoretically less immunogenic than the chimeric antibody infliximab . DB00005 is not effective for Crohn 's disease . CDP571 is not effective in unselected patients with active Crohn 's disease , but it may be effective in patients with elevated P02741 . The efficacy of DB08904 , adalimumab , and onercept is under investigation . The different mechanisms of action of these anti- P01375 agents may account for their variable efficacy . Their benefits , however , must be considered in the context of their risks , including infusion reaction ; delayed hypersensitivity-like reaction ; new onset of autoimmunity , with rare cases of drug-induced lupus and new-onset demyelination ; and the potential for rare but serious infections . DB08904 in the treatment of Crohn 's disease . INTRODUCTION : The introduction of antibodies directed against tumour necrosis factor ( anti- P01375 ) has dramatically changed the concept of treating patients with Crohn 's disease ( CD ) . Unfortunately , the long-term efficacy of anti- P01375 agents may be hampered by immunogenicity . The availability of more anti- P01375 agents in the therapeutic armamentarium would therefore be of great benefit in patients loosing response to another anti- P01375 . In this review , the authors will focus on the efficacy of certolizumab pegol ( CZP ) . AREAS COVERED : A literature search to January 2013 was performed to identify all trials studying CZP in patients with CD . The authors first focused on the mechanism of action of CZP . Second , they evaluated the efficacy of an induction and maintenance therapy with CZP and the impact of CZP on mucosal healing and fistula closure . Next , they explored the influence of previous anti- P01375 exposure and baseline P02741 levels . Finally , they analysed the safety data on CZP , including the development of antibodies against CZP and the use of CZP during pregnancy . EXPERT OPINION : Based on the provided literature , CZP could be a good alternative in patients with moderate-to-severe CD failing another anti- P01375 agent . More data are required to conclude on its impact on the long-term outcome of CD . Treatment of Crohn 's disease with certolizumab pegol . Biologic therapies have revolutionized the treatment of Crohn 's disease ( CD ) . Targeting P01375 with monoclonal antibodies has changed the therapeutic landscape for tackling refractory and complicated CD . Intravenous use of infliximab , a chimeric monoclonal antibody to P01375 is , however , limited by the occurrence of adverse events , infusion reactions , infectious complications , aggravation of heart failure , the occurrence of neurological demyelinating conditions and induction of rare malignancies . The incremental development of next-generation P01375 antibodies and binding proteins through antibody-engineering techniques has followed , with the aim of producing efficacious drugs that are less expensive to produce , have a convenient route of administration and have fewer side effects . DB08904 ( DB08904 , Cimzia ) is an engineered humanized anti- P01375 antibody Fab fragment that minimizes the protein component and is conjugated to polyethylene glycol . Clinical studies have demonstrated efficacy in the treatment of moderate-to-severe active CD . Reported adverse events in the clinical trial program have been largely of mild-to-moderate severity , and occurred at similar frequencies in the active-treatment and placebo groups . DB08904 will be a useful addition to the armamentarium of biologic agents that can be used for the long-term treatment of CD . The use of P01375 blocking agents in rheumatoid arthritis : an overview . P01375 has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis ( RA ) . The overexpression of P01375 in RA synovium , the data from in vitro synovial cell cultures with the use of anti- P01375 antibody and the results from P01375 blockade in animal models of arthritis argued for the importance of this cytokine in RA . Drugs targeting P01375 have been developed to neutralise the deleterious effects of this inflammatory cytokine . There are currently three drugs available in the treatment of RA patients with active disease , which was refractory to conventional treatments including methotrexate , infliximab ( a chimeric mouse/human monoclonal antibody ) , etanercept ( a fusion protein combining 2 p75 P01375 receptors with a Fc fragment of human IgG ( 1 ) ) and adalimumab ( a fully human monoclonal antibody ) . These three drugs have proved to be effective and safe in appropriate and well conducted clinical trials and showed effectiveness in slowing and even arresting the progression of radiographic damage . With the long-term surveillance of these drugs serious adverse events were described , particularly intracellular organism infections such as tuberculosis . Other drugs targeting P01375 are in development and include monoclonal antibody ( CDP571 ) , pegylated molecules ( DB08904 and PEG-r-Hu-sTNF-RI ) or soluble p55 P01375 receptor construct ( lenercept ) . These new biological therapies blocking P01375 undoubtedly constitute a considerable advance in the management of RA , but careful evaluation at the initiation of the treatment and long-term surveillance of the patients receiving such drugs remains necessary . Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis . BACKGROUND : Psoriasis is an immune-mediated chronic inflammatory disease triggered and maintained by inflammatory mediators , including P01375 . OBJECTIVE/METHODS : To summarize the role of anti- P01375 agents psoriasis therapy , focusing on the mechanisms and biological pathways involved , by reviewing relevant literature . RESULTS/CONCLUSIONS : The three P01375 antagonists currently available ( etanercept , infliximab and adalimumab ) are effective in the therapy of psoriasis and psoriatic arthritis . DB08904 and DB06674 are P01375 inhibitors not approved for therapy of psoriasis yet . In addition to neutralizing soluble P01375 , P01375 blockers bind to membrane P01375 and change the behavior of P01375 -expressing cells , resulting in hastened cell cycle arrest and apoptosis , and suppression of cytokine production . P01375 blockers may also affect adaptive immune responses by reducing T helper cell (Th)1 and Th17 responses , and favoring the development of T-regulatory cells . P01375 antagonists can regulate differentiation and activation of osteoclasts , thus reducing bone destruction in psoriatic arthritis . Anti- P01375 agents differ in their pharmacokinetics and pharmacodinamic properties , which is reflected in their therapeutic and safety profiles . The safety of P01375 antagonists has been established , and patient selection and monitoring allow risk minimization . Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c-Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen-presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 -mediated NF-ĸB signaling of DCs remain poorly defined . METHODS : Bone-marrow ( BM ) -derived DCs ( BM-DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 -mediated signaling . The crosstalk of P35367 -mediated signaling and the NF-ĸB pathway was examined by NF-ĸB cellular activity using a luciferase reporter assay , NF-ĸB subunit analysis using Western blotting and P01375 -α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 -α and P05231 production of BM-DCs . P35367 -specific agonists were able to enhance P01375 -α production , but this overexpression was significantly inhibited by NF-ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF-ĸB activity , suggesting crosstalk between P35367 and NF-ĸB signaling in DCs . After comprehensive analysis of NF-ĸB subunits , c-Rel protein expression was significantly down-regulated in ketotifen-treated BM-DCs , which led to inhibition of the promoter activity of P01375 -α . Finally , adoptive transfer of the ketotifen-treated BM-DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c-Rel controls P35367 -mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 -mediated signaling and NF-ĸB pathway crosstalk in allergic inflammation . Meta-analysis : the efficacy and safety of certolizumab pegol in Crohn 's disease . BACKGROUND : DB08904 is the third anti- P01375 agent approved by the Food and Drug Administration of the United States . AIM : To provide a comprehensive up-to-date review of the efficacy and safety of certolizumab in Crohn 's disease ( CD ) . METHODS : Electronic databases , including PubMed , EMBASE , the Cochrane library and the Science Citation Index , were searched to retrieve relevant trials . In addition , meeting abstracts and the reference lists of retrieved articles were reviewed for further relevant studies . RESULTS : Three trials , enrolling a total of 1040 patients , are included in the meta-analysis to evaluate the short-term efficacy of certolizumab , which is effective for rapid induction and long-term maintenance of clinical response or remission and can improve quality of life in patients with Crohn 's disease . Certolizumab is also effective for patients who have lost response to infliximab . However , its efficacy in infliximab-exposed patients is probably less than in infliximab-naive patients . Re-induction with certolizumab in patients who have flared on maintenance therapy can rescue a significant proportion of patients . There is no significant association between the efficacy of certolizumab and the baseline P02741 level . In comparison with placebo , certolizumab does not increase the risk of serious adverse events . CONCLUSIONS : Certolizumab is effective and safe in treating Crohn 's disease . Further studies are still required to assess its full safety profile . DB00278 -coupled Affi-Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . DB00278 has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba(2+) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan-snake ( Oxyuranus scutellatus ) venom and bound to the argatroban-coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days . NSA9 , a human prothrombin kringle-2-derived peptide , acts as an inhibitor of kringle-2-induced activation in EOC2 microglia . In neurodegenerative diseases , such as Alzheimer 's and Parkinson 's , microglial cell activation is thought to contribute to CNS injury by producing neurotoxic compounds . P00734 and kringle-2 increase levels of NO and the mRNA expression of P35228 , IL-1beta , and P01375 in microglial cells . In contrast , the human prothrombin kringle-2 derived peptide NSA9 inhibits NO release and the production of pro-inflammatory cytokines such as IL-1beta , P01375 , and P05231 in LPS-activated EOC2 microglia . In this study , we investigated the anti-inflammatory effects of NSA9 in human prothrombin- and kringle-2-stimulated EOC2 microglia . Treatment with 20-100 muM of NSA9 attenuated both prothrombin- and kringle-2-induced microglial activation . NO production induced by MAPKs and NF-kappaB was similarly reduced by inhibitors of P29323 ( PD98059 ) , p38 ( SB203580 ) , NF-kappaB ( DB06151 ) , and NSA9 . These results suggest that NSA9 acts independently as an inhibitor of microglial activation and that its effects in EOC2 microglia are not influenced by the presence of kringle-2 . The role of atorvastatin in regulating the immune response leading to vascular damage in a model of Kawasaki disease . Superantigens have been implicated in a number of diseases including Kawasaki disease ( KD ) , a multi-system vasculitis resulting in coronary artery aneurysms . We have characterized a murine disease model in which coronary arteritis is induced by a novel superantigen found in Lactobacillus casei cell wall extract ( LCWE ) . Using this animal model of KD , we have identified three pathogenic steps leading to coronary artery aneurysm formation . These steps include T cell activation and proliferation , production of the proinflammatory cytokine tumour necrosis factor ( P01375 ) -α and up-regulation of matrix metalloproteinase 9 ( P14780 ) , an elastolytic protease . In addition to their cholesterol-lowering effects , 3-hydroxy-3-methylglutaryl ( HMG ) coenzyme A ( DB01992 ) reductase inhibitors ( statins ) have pleotropic immunomodulatory properties . Thus , we examined the effect of atorvastatin in modulating each of these three critical pathogenic processes leading to aneurysm formation in the disease model . DB01076 inhibited lymphocyte proliferation in response to superantigen stimulation in a dose-dependent manner . This inhibition was also observed for production of soluble mediators of inflammation including interleukin ( IL ) -2 and P01375 -α . The inhibitory effect on proliferation was rescued completely by mevalonic acid , confirming that the mechanism responsible for this inhibitory activity on immune activation was inhibition of P04035 . Similarly , P01375 -α-induced P14780 production was reduced in a dose-dependent manner in response to atorvastatin . Inhibition of extracellular-regulated kinase ( P29323 ) phosphorylation appears to be the mechanism responsible for inhibition of P14780 production . In conclusion , atorvastatin is able to inhibit critical steps known to be important in the development of coronary aneurysms , suggesting that statins may have therapeutic benefit in patients with KD . A review and expert opinion of the use of certolizumab for Crohn 's disease . INTRODUCTION : Crohn 's disease ( CD ) is a chronic , idiopathic , inflammatory bowel disease with no known cure . In those patients with moderate to severe disease , the result is often a clinically debilitating condition . In the last decade , one of the most significant developments in therapy has been a class of biological agents that neutralize TNFa . DB08904 ( CZP ) is the most recently FDA approved anti- P01375 agent for the induction and maintenance of moderate to severely active Crohn 's disease . AREAS COVERED : The currently available evidence regarding the use of CZP in CD , the expected efficacy and possible adverse events associated with this population . EXPERT OPINION : CZP is a TNFa inhibitor that is a safe and effective agent for treatment of CD . It has several unique features which make it useful in patients with moderate to severe disease . Synthesis and evaluation of ( S ) -2-(2-[18F]fluoroethoxy)-4- ( [ 3-methyl-1-(2-piperidin-1-yl-phenyl)-butyl-carbamoyl ] -methyl ) -benzoic acid ( [18F]repaglinide ) : a promising radioligand for quantification of pancreatic beta-cell mass with positron emission tomography ( PET ) . 18F-labeled non-sulfonylurea hypoglycemic agent ( S ) -2-(2-[(18)F]fluoroethoxy)-4- ( ( 3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl ) -methyl ) -benzoic acid ( [(18)F]repaglinide ) , a derivative of the sulfonylurea-receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non-invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta-cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [(18)F] DB00912 could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2-[(18)F]fluoroethyltosylate . Specific activity was in the range of 50-60 GBq/micromol . Labeling was conducted by exchanging the ethoxy-moiety into a 2-[(18)F]fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non-radioactive (19)F-compound for binding to the human Q09428 isoform was assessed . [(19)F] DB00912 induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1.03 ) yielding a dissociation constant ( K(D) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [(18)F]repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i.v. injection . Pancreatic tissue displayed a stable accumulation of approximately 0.12 % of the injected dose from 10 min to 30 min p.i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [(18)F]repaglinide might be suitable for in vivo investigation with PET . Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e.g. olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5-HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5-HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : DB00734 ( 1.0 mg/kg , s.c. ) , given alone , significantly increased 5-HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg/kg , s.c. ) , by itself , produced a significant increase in 5-HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5-HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0.2 mg/kg , s.c. ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment-resistant depression may be due , at least in part , to potentiation of SSRI-induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5- Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed . DB08904 for the treatment of Crohn 's disease . In this article we provide a contemporary overview of available clinical data on certolizumab pegol , a pegylated anti-tumor necrosis factor ( P01375 ) alpha agent that comprises a uniquely small protein , and its emerging role as a therapy for Crohn 's disease ( CD ) . The results from a comprehensive clinical trial program suggest that certolizumab pegol offers rapid and sustained remission of moderate to severe CD . DB08904 is an effective and well-tolerated therapy both in patients who have already received biologics and in patients who are anti- P01375 naïve . Benefits of therapy include a stable dosing regimen , which allows for rapid induction of a clinical response followed by long-term maintenance of response and remission under one fixed dose . Treatment with certolizumab pegol has been shown to improve function and quality of life in patients with CD , and insights into the potential mechanisms by which certolizumab pegol effects a response in CD suggest that this agent may have the potential to slow or even modify disease progression . Early therapy is particularly effective and could help control CD progression and lessen the burden of disease on patients . DB08904 : a new biologic targeting rheumatoid arthritis . The past decade has been an exciting period for clinical research and patient care in rheumatoid arthritis . This is mostly due to targeted biologic agents that have changed the outcome of this disease . DB08904 ( Cimzia(®) , UCB Inc. , GA , USA ) , which targets P01375 -α with a different mechanism of action than widely used biologics , was initially investigated for Crohn 's disease but has now been shown to be effective for rheumatoid arthritis . There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis ; two with combination methotrexate and one with monotherapy . This article will summarize the data from those trials and compare some of the characteristics of certolizumab pegol to conventional disease-modifying antirheumatic drugs and other biologic agents . Treatment recommendations are beyond the scope of this review ; however , with many options available , there will be annotations on current trends in the care of this chronic disease . DB08904 : an evidence-based review of its place in the treatment of Crohn 's disease . INTRODUCTION : Crohn 's disease ( CD ) is a chronic inflammatory bowel disease characterized by a relapsing/remitting course with transmural inflammation of potentially any section of the digestive tract . DB08904 ( CZP ) is a pegylated Fc-free Fab ' fragment of a humanized anti- P01375 -alfa monoclonal antibody that is in development for clinical use in CD . AIMS : To review the available data with CZP in CD , to investigate its possible place in therapy . EVIDENCE REVIEW : Available studies suggest that CZP has the potential to achieve and maintain clinical response and remission in moderate to severe CD , and to improve quality of life compared with placebo . Further studies with CZP are also ongoing . PLACE IN THERAPY : Although only suggested by currently available studies , successive clinical practice and further ongoing trials may confirm a positive role for CZP as a new anti- P01375 treatment in CD . The impact on clinical management or on resources can not be estimated until the results from all phase III clinical trials are available and the price is determined . 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 . DB00171 -sensitive potassium channels ( K( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3- , lethal 20- and 40-min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K( DB00171 ) channel blockade on IPC protection were studied by treatment with 0.01 % glipizide . IPC was mimicked by injection of K( DB00171 ) channel openers of 0.01 % (-)cromakalim or 0.01 % P1060 72 h before 20-min ischemia . Co-expression of K( DB00171 ) channel subunits Kir6.2/ Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20- or 40-min ischemia , a 3-min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20-min ischemia had a significant improvement of the ERG . (-)Cromakalim and P1060 mimicked the effect of IPC . DB01067 significantly suppressed the protective effects of preconditioning . In conclusion , activation of K( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult . Efficacy and safety of certolizumab pegol in rheumatoid arthritis : meeting rheumatologists ' requirements in routine clinical practice . DB08904 , a pegylated Fab ' anti-tumour necrosis factor ( P01375 ) -α agent , has shown efficacy in patients with rheumatoid arthritis ( RA ) unresponsive to previous treatment . In key randomised controlled trials involving patients with moderate to severe RA and an inadequate response to methotrexate or one or more disease-modifying antirheumatic drug ( DMARD ) , the efficacy of certolizumab pegol , as monotherapy or with methotrexate , was similar to that reported in other anti- P01375 clinical studies , with 60 % or fewer of patients achieving American College of Rheumatology 20 % improvement in RA . Rapid clinical response was also seen , with significant differences evident at week 1 , and efficacy maintained at study end and in open-label extensions . Adding certolizumab pegol to non-biological DMARDs is efficacious in other RA populations . In the CERTAIN study , certolizumab increased remission rates , prevented disease worsening and improved work productivity and daily activity in patients with low to moderate RA . In the REALISTIC study , rapid and consistent clinical responses were observed in a diverse group of anti- P01375 -eligible RA patients representing those seen in clinical practice . In the RAPID studies , rapid and sustained reduction in RA signs and symptoms , inhibition of structural joint damage progression , and improved physical function were seen with certolizumab pegol plus methotrexate versus methotrexate alone in RA patients with an incomplete response to methotrexate . DB08904 was generally well-tolerated in clinical trials , although long-term observational data are not yet available . Current data suggest that certolizumab pegol suits a ' treat to target ' approach , providing rapid and sustained improvements in RA signs and symptoms , and beneficial effects on workplace and home productivity in patients with RA . Targeting nanomedicines in the treatment of Crohn 's disease : focus on certolizumab pegol ( DB08904 ) . A variety of targets for therapeutic intervention are based upon advances in understanding of the immunopathogenesis of Crohn 's disease . Crohn 's disease is initiated by an innate immune response , which eventuates in a T-cell driven process , characterized by a T-helper cell 1 type cytokine profile . Several new treatments now focus on suppressing T-cell differentiation or T-cell inflammation . Since inflammatory bowel disease ( Q9UKU7 ) represents a state of dysregulated inflammation , drugs that augment the anti-inflammatory response have the potential to downregulate inflammation and thereby hopefully modify the disease . Tumour necrosis factor ( P01375 ) is a major target of research and clinical investigation . P01375 has proinflammatory effects in the intestinal mucosa and is a pivotal cytokine in the inflammatory cascade . DB08904 ( DB08904 ) is a PEGylated , Fab ' fragment of a humanized anti- P01375 monoclonal antibody . PEGylation increases the half-life , reduces the requirement for frequent dosing , and possibly reduces antigenicity as well . Certolizumab has been shown in Phase III trials to achieve and maintain clinical response and remission in Crohn 's disease patients . It improves the quality of life . DB08904 will be indicated for moderately to severely active Crohn 's disease , but it is not yet licensed in Europe or the US . It is not possible to construct an algorithm for treatment , but when compared with infliximab the two principal advantages are likely to be lower immunogenicity ( as shown by anti-drug antibodies , absence of infusion reactions , and low rate of antinuclear antibodies ) , and a subcutaneous route of administration . These two factors may be sufficient to promote it up the pecking order of anti- P01375 agents . Recommendations for the treatment of Crohn 's disease with tumor necrosis factor antagonists : an expert consensus report . BACKGROUND : Symptom relief is the traditional treatment goal in Crohn 's disease ( CD ) . New goals including mucosal healing and bowel preservation are now achievable with tumor necrosis factor ( P01375 ) antagonists . DB00065 and adalimumab are approved as second-line treatments for severe , active CD . DB08904 is approved only in the U.S. and Switzerland as second-line treatment for moderate-to-severe , active CD . Data from trials of infliximab suggest that high-risk patients and patients with active inflammation ( CRP elevation and/or ileocolonic ulcers ) may benefit from earlier use of this drug . METHODS : A Delphi survey was used to obtain consensus on issues surrounding bowel preservation and use of P01375 antagonists . At the time of this survey , infliximab was the only P01375 antagonist approved for the treatment of CD in Europe , Canada , and Australia . An expert panel of 12 gastroenterologists with substantial clinical experience using infliximab in clinical practice and trials in these areas participated . RESULTS : The experts agreed that bowel preservation and mucosal healing are relevant and achievable goals , and form a rationale for using P01375 antagonists in CD patients . Control of inflammation and induction of mucosal healing were considered essential for bowel preservation . Consensus areas : 1 ) mucosal healing is predictive of improved long-term disease course and increases the likelihood of steroid-free remission ; 2 ) infliximab induces sustained mucosal healing , promotes bowel preservation , and reduces hospitalizations and surgeries ; 3 ) benefits of infliximab in relation to mucosal healing , bowel preservation , and clinical remission increase when therapy is initiated earlier . CONCLUSIONS : Treatment with P01375 antagonists helps preserve the bowel in CD patients . DB08904 attenuates the pro-inflammatory state in endothelial cells in a manner that is atheroprotective . OBJECTIVES : Rheumatoid arthritis ( RA ) is associated with accelerated atherosclerosis and premature cardiovascular death . Anti- P01375 therapy is thought to reduce clinical cardiovascular disease risk and improve vascular function in RA patients . However , the specific effects of P01375 inhibitors on endothelial cell function are largely unknown . Our aim was to explore the effects of certolizumab pegol ( CZP ) on P01375 -activated human aortic endothelial cells ( HAoECs ) . METHODS : HAoECs were cultured in vitro and exposed to i ) P01375 alone , ii ) P01375 plus CZP , or iii ) neither agent . Microarray analysis and quantitative polymerase chain reaction were used to analyse gene expression . Activation of NF-κB was investigated using immunocytochemistry , high content analysis and western blotting . Flow cytometry was performed to detect microparticle release from HAoECs . RESULTS : P01375 alone had strong effects on endothelial gene expression , while P01375 and CZP together produced a global gene expression pattern similar to untreated controls . In particular , genes for P16581 , P19320 and P05362 were significantly up-regulated by P01375 treatment . Notably , the P01375 /CZP cocktail prevented the up-regulation of these genes . P01375 -induced nuclear translocation of NF-κB was abolished by treatment with CZP . In addition the increased production of endothelial microparticles in P01375 -activated HAoECs was prevented by treatment with CZP . CONCLUSIONS : We have found at cellular level , that a clinically available P01375 inhibitor , CZP i ) reduces adhesion molecule expression ; ii ) prevents P01375 -induced activation of the NF-κB pathway and iii ) prevents the production of microparticles by activated endothelial cells . This could be central to the prevention of inflammatory environments underlying these conditions . How future tumor necrosis factor antagonists and other compounds will meet the remaining challenges in Crohn 's disease . The chimeric monoclonal antibody to tumor necrosis factor ( P01375 ) , infliximab , is an effective therapy for Crohn 's disease . However , the formation of human anti-chimeric antibodies to infliximab ( immunogenicity ) can lead to loss of efficacy as well as acute infusion reactions and delayed hypersensitivity reactions . The fully human monoclonal antibody adalimumab and the pegylated humanized monoclonal antibody fragment DB08904 are biologic therapies against P01375 that might be effective for Crohn 's disease and less immunogenic than infliximab . Other potential alternatives to infliximab for Crohn 's disease include the humanized anti-adhesion molecule antibodies natalizumab and DB05802 , the humanized anti-interleukin 12 antibody ABT-874 , the humanized anti-interferon g antibody fontolizumab , the humanized anti-interleukin 6 receptor antibody DB06273 , and human recombinant granulocyte macrophage colony stimulating factor ( sargramostim ) . Some , or all , of these therapies will likely represent important treatments for Crohn 's disease in the future . DB08904 : a review of its use in the management of rheumatoid arthritis . DB08904 ( Cimzia(®) ) is a recombinant , polyethylene glycolylated , antigen-binding fragment of a humanized monoclonal antibody that selectively targets and neutralizes tumour necrosis factor ( P01375 ) -α . The drug is indicated for subcutaneous use every 2 or 4 weeks ( q2w or q4w ) for the treatment of adults with moderate to severe active rheumatoid arthritis ( RA ) . The efficacy of subcutaneous certolizumab pegol in adults with active RA has been investigated in several well designed , placebo-controlled trials . In four pivotal studies of ≤52 weeks duration , patients with moderate to severe disease receiving recommended dosages of certolizumab pegol ( 200 mg q2w or 400 mg q4w ) , either as monotherapy ( after failing prior disease-modifying anti-rheumatic drug [ DMARD ] therapy ) or in combination with methotrexate ( after responding inadequately to methotrexate alone ) , experienced rapid clinical improvement , with some combination trials also demonstrating inhibition of radiographic progression . The beneficial effects of certolizumab pegol therapy were generally maintained for up to ≈5 years in clinical trial extensions in which the drug was administered at dosages of 400 mg q4w or q2w . Additional studies suggest certolizumab pegol is also effective in patients who are Asian or have low to moderate disease activity , as well as more clinically representative patient populations . The tolerability profile of certolizumab pegol was acceptable , with infections/infestations the most common adverse events . Thus , certolizumab pegol is an effective option for the management of active RA in adults , although additional long-term and comparative efficacy and tolerability data are needed to help definitively position certolizumab pegol relative to other biological DMARDs , particularly other anti- P01375 agents . 8-OH-DPAT ( P08908 agonist ) Attenuates 6-Hydroxy- dopamine-induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE(S) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8-OH-DPAT on 6-OHDA-induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6-OHDA ( 8 μg/2 μl/rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar-test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8-OH-DPAT ( P08908 receptor agonist ; 0.25 , 0.5 and 1mg/kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8-OH-DPAT administration and analyzed by ELISA method to measure levels of P01375 -α , IL-1β and P05231 . RESULTS : Chronic injection of 8-OH-DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti-cataleptic effect was observed at the dose of 1 mg/kg of 8-OH-DPAT . Levels of P01375 -α in P04141 increased three weeks after 6-OHDA injection while there was a significant decrease in P01375 -α level of parkinsonian animals treated with 8-OH-DPAT ( 1 mg/kg , IP for 10 days ) . IL-1β and P05231 decreased and increased in parkinsonian rats and in 8-OH-DPAT-treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8-OH-DPAT improves catalepsy in 6-OHDA-induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines . DB08904 for the treatment of psoriatic arthritis . DB08904 ( CZP ) is a P01375 -α inhibitor approved for the treatment of psoriatic arthritis in 38 countries , including many European countries and the USA . It is a pegylated humanized anti- P01375 -α antigen-binding fragment , administered subcutaneously . As other P01375 -α antibodies , CZP binds to and neutralizes both soluble and membrane P01375 -α . In contrast to whole antibodies and etanercept , CZP does not activate antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity , as it does not have an Fc piece . CZP showed efficacy in improving skin scores and patient reported outcomes in a Phase II study of 176 adults with moderate-to-severe plaque psoriasis . In a Phase III study of CZP in 409 psoriatic arthritis patients , CZP treatment resulted in improvements in peripheral arthritis , as well as dactylitis , enthesitis , nail disease and quality of life . The safety profile of CZP appears to be similar to that of other P01375 -α inhibitor . DB08904 in axial spondyloarthritis . The axial spondyloarthritis ( SpA ) classification criteria cover both patients with ankylosing spondylitis and non-radiographic axial SpA . After failure of NSAIDs P01375 -α-inhibitors ( P01375 -blockers ) can be given to patients with active axial SpA . Until recently , the P01375 -blockers infliximab , adalimumab , etanercept and DB06674 are labeled for the treatment of active ankylosing spondylitis while for active nr-axSpA only adalimumab has been approved in Europe . The P01375 -blocker certolizumab pegol has recently been evaluated in the RAPID-axSpA trial which is the first placebo-controlled randomized-controlled trial in the entire group of axial SpA . An elevated P02741 and/ or evidence of bone marrow edema on Q9BWK5 of the sacroiliac joints were required for inclusion in RAPID-axSpA , and patients could have been preexposed to P01375 -blockers . The interesting data of this important trial in the context of the emerging therapeutic field of non-radiographic axial SpA therapy is discussed in this review . Strategies for targeting tumour necrosis factor in Q9UKU7 . Tumour necrosis factor ( P01375 ) plays an important role in mediating the inflammation of inflammatory bowel disease , in particular , Crohn 's disease . Strategies aimed at reducing tumour necrosis factor in patients with inflammatory bowel disease include the mouse/human chimeric monoclonal antibody infliximab , the humanized monoclonal antibody CDP571 , the human soluble P01375 p55 receptor onercept , the human monoclonal antibody D2E7 ( adalimumab ) , the anti- P01375 human antibody Fab ' fragment-polyethelene glycol ( PEG ) conjugate DB08904 , and the small molecules thalidomide and CNI-1493 ( Q96HU1 -kinase inhibitor ) . DB00065 is effective for treating active Crohn 's disease , maintaining remission , closing fistulas , maintaining fistula closure , and treating ankylosing spondylitis . DB00065 is also being investigated for the treatment of ulcerative colitis . Side-effects occurring in patients treated with infliximab include human anti-chimeric antibodies , infusion reactions , delayed hypersensitivity reactions , formation of autoantibodies , and , in rare circumstances , drug-induced lupus and serious infections , including tuberculosis . CDP571 is effective for treating active Crohn 's disease , steroid sparing , and possibly for closing fistulas and maintaining remission . Side-effects occurring in patients treated with CDP571 include anti-idiotype antibodies , infusion reactions and the formation of autoantibodies . A controlled trial of etanercept in patients with Crohn 's disease was negative . Pilot studies with onercept , thalidomide , and CNI-1493 have suggested benefit for Crohn 's disease . There are no published data on the efficacy of adalimumab ( D2E7 ) or DB08904 for either Crohn 's disease or ulcerative colitis . Anti-tumour necrosis factor therapies are effective for the treatment of Crohn 's disease and are being investigated for ulcerative colitis . 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 .