MH_dev_108

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 REA . OBJECTIVE / METHODS : To summarize the role of anti - P01375 REA agents psoriasis therapy , focusing on the mechanisms and biological pathways involved , by reviewing relevant literature . RESULTS / CONCLUSIONS : The three P01375 REA antagonists currently available ( etanercept , infliximab and adalimumab ) are effective in the therapy of psoriasis and psoriatic arthritis . DB08904 and DB06674 SUB are P01375 REA inhibitors not approved for therapy of psoriasis yet . In addition to neutralizing soluble P01375 REA , P01375 REA blockers bind to membrane P01375 REA and change the behavior of P01375 REA - expressing cells , resulting in hastened cell cycle arrest and apoptosis , and suppression of cytokine production . P01375 REA 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 REA antagonists can regulate differentiation and activation of osteoclasts , thus reducing bone destruction in psoriatic arthritis . Anti - P01375 REA agents differ in their pharmacokinetics and pharmacodinamic properties , which is reflected in their therapeutic and safety profiles . The safety of P01375 REA antagonists has been established , and patient selection and monitoring allow risk minimization .

Treatment of ankylosing spondylitis with P01375 REA blockers : a meta-analysis . Biological agents directed against tumor necrosis factor ( P01375 REA ) represent therapeutic options for patients with ankylosing spondylitis with high disease activity despite use of non-steroidal anti-inflammatory drugs . To evaluate the efficacy and safety of the anti - P01375 REA agents infliximab , etanercept , adalimumab , DB06674 SUB , and certolizumab for the treatment of ankylosing spondylitis , we performed a systematic review of randomized clinical trials on adult patients with ankylosing spondylitis using articles culled from the EMBASE , MEDLINE , Cochrane Controlled Trials Register and LILACS databases ( September / 2012 ) , manual literature search , and the gray literature . Study selections and data collection were performed by two independent reviewers , with disagreements solved by a third reviewer . The following outcomes were evaluated : ASAS 20 response , disease activity , physical function , vertebral mobility , adverse events , and withdraws . The meta-analysis was performed using the Review Manager ( ® ) 5.1 software by applying the random effects model . Eighteen studies were included in this review . No study of certolizumab was included . Patients treated with anti - P01375 REA agents were more likely to display an ASAS 20 response after 12/14 weeks ( RR 2.21 ; 95 % CI 1.91 ; 2.56 ) and 24 weeks ( RR 2.68 ; 95 % CI 2.06 ; 3.48 ) compared with controls , which was also true for several other efficacy outcomes . Meta-analysis of safety outcomes and withdraws did not indicate statistically significant differences between treatment and control groups after 12 or 30 weeks . DB00051 , infliximab , etanercept , and DB06674 SUB can effectively reduce the signs and symptoms of the axial component of ankylosing spondylitis . Safety outcomes deserve further study , especially with respect to long-term follow-ups .

[ Genetic polymorphisms and cancer risk ] . While hereditary disease genes have a high lifelong cumulative incidence rate ( penetrance ) , the penetrance for polymorphism genotypes is not high . Polymorphisms relating to cancer incidence are classified into 1 . carcinogen metabolizing enzymes ( CYPs , GSTs , P15559 REA , etc . ) , 2 . DNA repair enzymes ( O15527 REA , P18887 REA , P18074 REA , etc . ) , 3 . DNA synthesis and methylation ( P42898 REA , MS , etc . ) , 4 . cytokines and inflammation-related enzymes ( IL - 1B , P01375 REA - A , P05164 REA , etc . ) , and 5 . sex hormone metabolizing enzymes and the receptors ( P11511 REA , P31213 REA , ER , etc . ) . Since genotypes can not be manipulated , they are not the factors subject to prevention . However , the finding that the strength of association between lifestyle and disease occurrence is influenced by genotypes ( gene-environment interaction ) , opens the door to genotype applications for disease prevention practice .

Current therapies in rheumatoid arthritis : a Latin American perspective . Rheumatoid arthritis ( RA ) is a systemic inflammatory disease affecting the synovium of joints , tendons , and some extra-articular sites . RA prevalence in Latin America ranges from 0.4 to 1.6 % . Early treatment of RA translates into a substantial reduction in the cost to society . In light of this , early disease clinics are being established in some countries . Barriers to RA management , such as delay in referral to rheumatologists and limited access to therapy , have been identified . Evidence-based treatment guidelines have been adapted by countries according to their own situations . The need for keeping accurate records of biologics prescribed has been addressed by biologic registries , thereby contributing toward a better understanding of rheumatic diseases and their treatment . Current biologics include the tumor necrosis factor ( P01375 REA ) - α inhibitors ( etanercept , infliximab , and adalimumab ) , B-cell depletion agent ( rituximab ) , interleukin - 6 receptor blocker ( tocilizumab ) , and T-cell co-stimulatory blocker ( abatacept ) . Future therapies include kinase inhibitors ( tofacitinib and fostamatinib ) , alternative P01375 REA - α inhibitors ( DB06674 SUB and certolizumab ) , and biosimilars .

Golimumab for the treatment of ulcerative colitis . The introduction of therapeutic antibodies against tumor necrosis factor ( P01375 REA ) had a major impact on the treatment of ulcerative colitis ( UC ) . DB00065 and adalimumab are powerful agents that are used for remission induction and maintenance therapy in UC and have an acceptable safety profile . However , a proportion of UC patients for whom therapy with anti - P01375 REA agents is indicated fail or become intolerant to treatment with infliximab or adalimumab . Hence , there remains an unmet need for novel anti - P01375 REA agents . Golimumab ( Simponi ® ) , a human anti - P01375 REA antibody that is administered by monthly subcutaneous injections , is the most recently introduced P01375 REA blocker for the treatment of UC . Here , we will discuss recent literature on clinical efficacy and safety of DB06674 SUB induction and maintenance treatment in patients with UC . Furthermore , we will discuss the positioning of DB06674 SUB for UC in current treatment algorithms .

A functional polymorphism in the P32297 REA gene and risk of chronic obstructive pulmonary disease in a Korean population . A genome-wide association study has identified the 15q25 region as being associated with the risk of chronic obstructive pulmonary disease ( P48444 REA ) in Caucasians . This study intended as a confirmatory assessment of this association in a Korean population . The rs6495309C > T polymorphism in the promoter of nicotinic acetylcholine receptor alpha subunit 3 ( P32297 REA ) gene was investigated in a case-control study that consisted of 406 patients with P48444 REA and 394 healthy control subjects . The rs6495309 CT or TT genotype was associated with a significantly decreased risk of P48444 REA when compared to the rs6495309 CC genotype ( adjusted odds ratio = 0.69 , 95 % confidence interval = 0.50- 0.95 , P = 0.023 ) . The effect of the rs6495309C > T on the risk of P48444 REA was more evident in moderate to very severe P48444 REA than in mild P48444 REA under a dominant model for the variant T allele ( P = 0.024 for homogeneity ) . The P32297 REA rs6495309C > T polymorphism on chromosome 15q25 is associated with the risk of P48444 REA in a Korean population .

New biologics for psoriasis and psoriatic arthritis . The prevalence of psoriasis is estimated to be 2.2 % in the United States , and 6-39 % of patients with psoriasis also develop psoriatic arthritis . New advances have been made in developing treatment options . A new human tumor necrosis factor ( P01375 REA ) - alpha antibody , DB06674 SUB , has been shown to significantly improve symptoms of psoriatic arthritis . In addition , clinical trials of certolizumab pegol , a PEGylated Fab ' fragment of an anti - P01375 REA monoclonal antibody , show promising results for treating rheumatoid arthritis and suggest that it may be applicable for treating psoriasis and psoriatic arthritis in the future . New biologic therapies also include antibodies to interleukin - 12 and interleukin - 23 . Phase II studies suggest that ustekinumab is effective in alleviating symptoms of psoriasis and psoriatic arthritis . However , longer studies with radiographic evaluation will be required before their impact on joint destruction can be assessed .

P01375 REA - alpha antagonists : differential clinical effects by different biotechnological molecules . Inhibitors of tumor necrosis factor-alpha have deeply changed the therapy of several inflammatory human diseases . For instance , clinical management of rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis have profoundly benefited after the introduction of new therapeutic tools , such as antagonist of P01375 REA molecule . These drugs include etanercept , a soluble P01375 REA receptor antagonist , three anti - P01375 REA antibodies , adalimumab , infliximab , DB06674 SUB and certolizumab a humanized Fab fragment combined with polyethylene glycol . These compounds efficiently inhibit several P01375 REA biological-mediated effects , however , they have also shown differential clinical efficacy in several trials from different autoimmune diseases . It is of clinical relevance that non-responders to one of these drugs often positively responded to another . Different mechanisms of action and diversity in pharmacokinetics of these three compounds may partially explain different clinical effects . However , partially diverse pathogenetic mechanisms in different diseases also contribute to differential therapeutic responses . Therefore , these apparently homogeneous agents can not be considered equivalent in their clinically efficacy . Differential therapeutic actions of these drugs may be advantageously used in clinical practice and further improve the great potential of individual P01375 REA inhibitors .

Safety and efficacy of ustekinumab or DB06674 SUB in patients with chronic sarcoidosis . Sarcoidosis is characterised by non-caseating granulomas that secrete pro-inflammatory cytokines , including interleukin ( IL ) - 12 , IL - 23 , and tumour necrosis factor ( P01375 REA ) - α . Ustekinumab and DB06674 SUB are monoclonal antibodies that specifically inhibit IL - 12 / IL - 23 and P01375 REA - α , respectively . Patients with chronic pulmonary sarcoidosis ( lung group ) and / or skin sarcoidosis ( skin group ) received either 180 mg ustekinumab at week 0 followed by 90 mg every 8 weeks , 200 mg DB06674 SUB at week 0 followed by 100 mg every 4 weeks , or placebo . Patients underwent corticosteroid tapering between weeks 16 and 28 . The primary end-point was week 16 change in percentage predicted forced vital capacity ( ΔFVC % pred ) in the lung group . Major secondary end-points were : week 28 for ΔFVC % pred , 6 - min walking distance , St George ' s Respiratory Questionnaire ( lung group ) , and Skin Physician Global Assessment response ( skin group ) . At week 16 , no significant differences were observed in ΔFVC % pred with ustekinumab ( -0.15 , p = 0.13 ) or DB06674 SUB ( 1.15 , p = 0.54 ) compared with placebo ( 2.02 ) . At week 28 , there were no significant improvements in the major secondary end-points , although a nonsignificant numerically greater Skin Physician Global Assessment response was observed following DB06674 SUB treatment ( 53 % ) when compared with the placebo ( 30 % ) . Serious adverse events were similar in all treatment groups . Although treatment was well tolerated , neither ustekinumab nor DB06674 SUB demonstrated efficacy in pulmonary sarcoidosis . However , trends towards improvement were observed with DB06674 SUB in some dermatological end-points .

The use of biologic therapies in the treatment of rheumatoid arthritis . The use of biologic agents has revolutionized the management of rheumatoid arthritis ( RA ) in the past two decades . These biologic agents directly target molecules and cells involved in the pathogenesis of RA . Biologic agents indeed lead to a better prognosis and clinical remission in patients with RA , especially in patients who are not well-controlled with traditional disease-modifying anti-rheumatic drugs ( DMARDs ) . Currently , five P01375 REA inhibitors ( infliximab , etanercept , adalimumab , DB06674 SUB and certolizumab pegol ) , an P05231 REA receptor antagonist ( tocilizumab ) , an IL - 1 receptor antagonist ( anakinra ) , a B cell depleting agent ( rituximab ) and a T cell co-stimulation inhibitor ( abatacept ) have been approved for the treatment of RA . With the increased understanding of the pathogenic mechanisms of RA and advantages in manufacturing biotechnology of pharmaceutical companies , a series of novel biologic therapeutic approaches are being developed . In the present paper , we will summarize the biologic agents currently available to treat RA , and the prospective biologic therapies that might be used in the management of RA in future .

P01375 REA - alpha antagonists twenty years later : what do Cochrane reviews tell us ? In 1998 , the U . S . Food and Drug Administration granted regulatory approval to the first tumor necrosis factor-α antagonist , infliximab , for the treatment of moderately to severely active Crohn ' s disease . As of 2013 , there were 3 additional tumor necrosis factor-α antagonists commercially available for the treatment of inflammatory bowel disease in the United States : adalimumab , certolizumab pegol , and DB06674 SUB . Despite a vast literature describing both clinical trial and clinical practice experience with these agents , there remain important questions regarding the efficacy and safety of tumor necrosis factor-α antagonists for the treatment of inflammatory bowel disease . These questions and the best available evidence to answer them were discussed during a Cochrane Collaboration session held at the 2013 Digestive Diseases Week annual meeting . This article reviews the data from that session .

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 REA 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 REA 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 REA ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 REA ) . 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 .

Pharmacogenetics and future therapeutic scenarios : what affects the prediction of response to treatment with etanercept ? There are five tumor necrosis factor alpha ( P01375 REA - α ) inhibitors available for clinical use that have demonstrated efficacy as monotherapy or in combination with other anti-inflammatory or disease-modifying anti-rheumatic drugs ( DMARDs ) in the treatment of immune-mediated diseases . These include the anti - P01375 REA - α monoclonal antibodies infliximab , adalimumab , DB06674 SUB , and certolizumab pegol , and the fusion protein , etanercept . The use of pharmacogenetic testing has the potential to increase drug efficiency by identifying genetic factors responsible for a lack of response to , or toxicities from , P01375 REA - α inhibitors , and could be used to individualize therapy . Several studies have reported associations between genetic polymorphisms and the response to etanercept , but most are small and insufficiently powered to detect effect , and markers tend to be more prognostic than predictive of therapeutic response . Limitations of pharmacogenetic studies include the use of single nucleotide polymorphisms ( SNPs ) , genes in linkage with other loci , interaction of environmental factors , and cohort heterogeneity , all of which can complicate the relationship between genetic polymorphisms and treatment response . Further studies are needed for pharmacogenetics to become a routine part of daily clinical therapeutic practice .

[ Genetic aspects of occupational chronic obstructive lung disease under exposure to various risk factors ] . The article deals with data on association of SNP rs1828591 of Q96QV1 gene with COLD development under exposure to dust and chemical factors . SNP rs1800470 of TGFbeta 1 gene is associated with occupational COLD under exposure to dust and did not show connection with COLD under exposure to chemical aerosols . No association was seen between SNP rs4129267 of IL - 6R gene and SNP rs1051730 of P32297 REA gene with occupational COLD under exposure to the studied factors . SNP rs1828591 of Q96QV1 gene is associated with occupational COLD development under exposure to dust and chemical factors . Study of association of genotype and phenotypic features of COLD revealed the following trends : " dust " COLD patients with genotype AA SNP rs1800470 of TGFbeta 1 gene show lower level of P02741 REA and P01375 REA , if compared with other genotypes .

A latent variable approach for modeling categorical endpoints among patients with rheumatoid arthritis treated with DB06674 SUB plus methotrexate . The need for accurate exposure-response modeling is critical in the drug development process . Few methods are available for linking discrete endpoints , especially ordered categorical variables , to mechanistic ( e . g . , indirect response ) models . Here we describe a latent-variable approach that is proposed in conjunction with an inhibitory indirect response model to link the placebo / comedication effect and drug exposure to the endpoints . The model is parsimonious , with desirable characteristics at initial timepoints , and allows simultaneous modeling of multiple endpoints that are categorically ordered . Application of the model is demonstrated with data from a phase 3 clinical trial of DB06674 SUB , a human IgG 1kappa monoclonal antibody that binds with high affinity and specificity to tumor necrosis factor ( P01375 REA ) - alpha , in patients with rheumatoid arthritis . The efficacy endpoints were 20 , 50 , and 70 % improvement in the American College of Rheumatology criteria ( ACR 20 , ACR 50 , and ACR 70 , respectively ) as measures of improvement in disease severity . The modeling results were shown to be consistent by using either a sequential or simultaneous pharmacokinetic / pharmacodynamic modeling approach . The suitability of likelihood profiling and proper use of bootstrap methods in assessing parameter estimation precision are also presented . More accurate , parsimonious models with appropriately quantified uncertainty can facilitate better drug development decisions .

Efficacy and safety of P01375 REA - α inhibitors in refractory primary complex aphthosis : a patient series and overview of the literature . BACKGROUND : Otherwise healthy patients with severe recurrent mucocutaneous aphthous ulcerations ( complex aphthosis ) may require systemic immunomodulatory therapy . However , a subset of patients remain resistant or intolerant to recommended therapeutic agents . Recently , case reports have described that tumor necrosis factor-α ( P01375 REA - α ) inhibitors may induce remission in these patients . METHODS : Data on efficacy and safety of various P01375 REA - α inhibitors used as monotherapy in a case series of 18 patients with refractory primary complex aphthosis are presented . RESULTS : A total of 16 patients ( 89 % ) obtained complete or almost clearance of orogenital aphthous ulcerations rapidly after onset of therapy either with etanercept , adalimumab , infliximab or DB06674 SUB . Duration of treatment ranged between 3 and 77 months . Nine patients ( 50 % ) received more than one P01375 REA - α inhibitor during the course of treatment . Five ( 28 % ) patients experienced side effects that could be related to treatment with P01375 REA - α inhibitors . CONCLUSION : P01375 REA - α inhibitors are an effective and safe treatment option for patients with severe complex aphthosis who do not respond sufficiently to standard therapy as recommended by existing guidelines . However , the final position of P01375 REA - α inhibitors in the therapeutic armamentarium awaits randomized controlled trials .

P01375 REA antagonist mechanisms of action : a comprehensive review . During the past 30 years , elucidation of the pathogenesis of rheumatoid arthritis , Crohn ' s disease , psoriasis , psoriatic arthritis and ankylosing spondylitis at the cellular and molecular levels has revealed that these diseases share common mechanisms and are more closely related than was previously recognized . Research on the complex biology of tumor necrosis factor ( P01375 REA ) has uncovered many mechanisms and pathways by which P01375 REA may be involved in the pathogenesis of these diseases . There are 3 P01375 REA antagonists currently available : adalimumab , a fully human monoclonal antibody ; etanercept , a soluble receptor construct ; and infliximab , a chimeric monoclonal antibody . Two other P01375 REA antagonists , certolizumab and DB06674 SUB , are in clinical development . The remarkable efficacy of P01375 REA antagonists in these diseases places P01375 REA in the center of our understanding of the pathogenesis of many immune-mediated inflammatory diseases . The purpose of this review is to discuss the biology of P01375 REA and related family members in the context of the potential mechanisms of action of P01375 REA antagonists in a variety of immune-mediated inflammatory diseases . Possible mechanistic differences between P01375 REA antagonists are addressed with regard to their efficacy and safety profiles .

One target , different effects : a comparison of distinct therapeutic antibodies against the same targets . To date , more than 30 antibodies have been approved worldwide for therapeutic use . While the monoclonal antibody market is rapidly growing , the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders . Moreover , antibodies against only five targets ( P01375 REA - α , P04626 REA , P11836 , P00533 REA , and P15692 REA ) account for more than 80 percent of the worldwide market of therapeutic antibodies . The shortage of novel , clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets , based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another . For example , four antibodies against P01375 REA - α have been approved by the FDA - - infliximab , adalimumab , DB06674 SUB , and certolizumab pegol - - with many more in clinical and preclinical development . The situation is similar for P04626 REA , P11836 , P00533 REA , and P15692 REA , each having one or more approved antibodies and many more under development . This review discusses the different binding characteristics , mechanisms of action , and biological and clinical activities of multiple monoclonal antibodies against P01375 REA - α , HER - 2 , P11836 , and P00533 REA and provides insights into the development of therapeutic antibodies .

Emerging drugs for the treatment of axial and peripheral spondyloarthritis . INTRODUCTION : The topic under discussion is of strong relevance to the field of spondyloarthritis ( SpA ) because , in addition to established biological , there are new promising compounds . The reason for the review is to put all available data together to allow for an overview on recent developments and to especially inform readers about emerging drugs , biologics and small molecules in the field of SpA . AREAS COVERED : This review on new therapies in axial and peripheral SpA comprising psoriatic arthritis ( PsA ) shows , that , in addition to the established anti - P01375 REA agents infliximab , etanercept , adalimumab , DB06674 SUB , certolizumab and the first biosimilar approved in the EU , there are at least two emerging biologics in the field of SpA : ustekinumab , a compound targeting IL12 / IL - 23 via the p40 subunit of both cytokines works for psoriasis and PsA and probably also for Crohn ' s disease , and the anti - Q16552 REA antibody secukinumab which has also been shown to work in psoriasis , both compounds seem to also work in ankylosing spondylitis . In addition , the potential of two small molecules , apremilast a phoshodiesterase 4 inhibitor and tofacitinib , a januskinase inhibitor is discussed . EXPERT OPINION : Since , in contrast to rheumatoid arthritis , the therapeutic array in SpA is currently limited to P01375 REA - blockers , and since there is still an unmet need because some patients do not respond to anti - P01375 REA therapy at all or they loose response , new agents with a different mechanism of action are eagerly awaited .

aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 REA resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 REA ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy-Nine consecutive elderly patients , 31 late onset AD and 48 non-demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2.200 , p = 0.036 for MMSE and t = 2.724 , p= 0.011 for IADL , respectively ) . DB00989 MEN was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 REA with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long-term studies on this issue are needed .

Antagonism by salvianolic acid B of lipopolysaccharide-induced disseminated intravascular coagulation in rabbits . The aim of the present study was to investigate the effects of salvianolic acid B on lipopolysaccharide ( LPS ) - induced disseminated intravascular coagulation ( DIC ) in rabbits . Continuous infusion of LPS was used to induce a DIC model in rabbits . Treatment with salvianolic acid B ( 1 , 3 or 6 mg / kg ) was started simultaneously with LPS infusion ( 0.5 mg / kg LPS in 60 mL saline ; 10 mL / h over a period of 6 h ) through the contralateral marginal ear vein . Activated partial thromboplastin time ( APTT ) , prothrombin time ( PT ) , platelet count and fibrinogen concentration were determined , as were plasma levels of fibrin-fibrinogen degradation products ( Q9NRC9 ) , alanine aminotransferase ( ALT ) , blood urea nitrogen ( BUN ) , protein C activity , antithrombin III ( P01008 REA ) and tumour necrosis factor ( P01375 REA ) - α concentration . The gradual impairment of haemostatic parameters was induced by continuous infusion of LPS . There were marked increases in APTT , PT , BUN , ALT and plasma P01375 REA - α and marked decreases in the platelet count , fibrinogen , Q9NRC9 , protein C and P01008 REA . The intravenous administration of 1 , 3 or 6 mg / kg salvianolic acid B attenuated the increases in APTT , PT , BUN , ALT and plasma P01375 REA - α and the decreases in fibrinogen , platelet , Q9NRC9 , protein C and P01008 REA induced by LPS infusion . These observations indicate that salvianolic acid B has an effect against LPS-induced DIC in rabbits .

Update upon efficacy and safety of P01375 REA - α inhibitors . The ongoing progresses in the knowledge of the pathogenic mechanisms of various immune-mediated and inflammatory diseases as well as the availability of innovative biotechnological approaches have led to the development of new drugs that add to conventional treatments . Among these , tumor necrosis factor ( P01375 REA ) - α inhibitors , that is , infliximab , adalimumab , etanercept , DB06674 SUB and certolizumab pegol , are now available for clinical use . This editorial discusses the recent indications of P01375 REA - α inhibitors , the pretreatment considerations , the reported adverse events and , finally , the recommendations for its use in pregnancy .

Therapy with a synthetic retinoid - - ( Ro 10-1670 ) etretin - - increases the cellular retinoic acid-binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 REA ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , DB00459 MEN ( Ro 10-1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 REA levels were not altered during therapy . The results show that P09455 REA and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .

Selective P01375 REA - α inhibitor-induced injection site reactions . INTRODUCTION : During the last decade , many new biological immune modulators entered the market as new therapeutic principles . P01375 REA - α is a pro-inflammatory cytokine known to a have a key role in the pathogenic mechanisms of various immune-mediated or inflammatory diseases . P01375 REA - α blockers have demonstrated efficacy in large , randomized controlled clinical trials either as monotherapy or in combination with other anti-inflammatory or disease-modifying anti-rheumatic drugs . AREAS COVERED : Although generally well tolerated and safe , potential adverse events may be associated with P01375 REA - α inhibitor treatment . The authors will briefly review the potential adverse drug reactions and the immunological mechanisms of injection site reactions ( ISRs ) in patients treated with etanercept and adalimumab . EXPERT OPINION : Patients treated with P01375 REA - α inhibitors can develop ISR around the sites of injections . ' Type IV delayed type reaction ' or ' recall ISRs ' . Eosinophilic cellulitis or ' Wells syndrome ' , ' type III ' and ' type I ' reactions are reported . Long-term studies are necessary to determine the durability of response and the real risk of ISRs with DB06674 SUB and certolizumab pegol . Further studies are also necessary to evaluate the immunogenicity of these drugs .

Basal cell carcinoma and variants in genes coding for immune response , DNA repair , folate and iron metabolism . Basal cell carcinoma ( BCC ) is one of the most common neoplasms in the world and its incidence has been increasing worldwide in recent years . BCCs are caused by an interplay between genetic and environment factors . We conducted a case-control association study in BCC patients and controls from Sweden and Finland . Fifteen single nucleotide polymorphisms ( SNPs ) , P05231 REA - 174G / C , - 634G / C , and - 597G / A ; P22301 REA - 1082G / A and - 592C / A ; IL - 1beta - 511C / T ; NBS 1 exon 5 Glu 185Gln ; Q01831 REA exon 15 Lys 939Gln ; P18074 REA exon 23 Lys 751Gln ; P18887 REA exon 10 Arg 399Gln ; O43542 REA exon 7 Thr 241Met ; cyclin D1 exon 4 G870A ; P42898 REA exon 4 Ala 222Val and exon 7 Glu 429Ala ; Q30201 exon 4 C282Y were performed by Pyrosequencing and RFLP techniques . Most of the genotype distributions were in accordance with the Hardy-Weinberg equilibrium ( HWE ) , except for P22301 REA - 1082G / A , where cases with BCC showed a significant deviation from HWE ( P = 0.04 ) . Linkage disequilibrium was observed between the - 174 and - 597 alleles in the P05231 REA gene in the present populations . No difference between BCC and controls appeared in any of the SNPs analyzed . Only the combined distributions of TT / AA genotypes in P42898 REA exon 4 ( C / T ) and exon 7 ( A / C ) showed slight increase in BCC compared to controls ( P < 0.07 , OR : 1.94 ; 95 % CI : 0.96- 3.89 ) .

The role of P01375 REA in insulin resistance . P01308 REA resistance is an important component of the metabolic syndrome associated with obesity . Early-stage insulin-resistance and related mild glucose intolerance may be compensated by increased insulin secretion . When combined with impaired insulin secretion , insulin resistance plays an important role in type 2 diabetes ( 1 ) . P01308 REA - resistance is also associated with a variety of pathological conditions , including trauma , infection , and cancer . Obesity and type 2 diabetes are the most common metabolic diseases in Western societies , together affecting as much as half of the adult population ( 2 ) . The prevalence of these conditions is not only high , but continues to increase . We have only recently come to appreciate the role of fat , especially visceral fat , as an endocrine organ . Visceral fat is the source of a number of substances which might play a role in the development of insulin resistance . Among the latter are tumor necrosis factor-alpha ( P01375 REA ) , adiponectin , P05231 REA , resistin and free fatty acids . This review will discuss the regulation of insulin responses by P01375 REA and evidence supporting the hypothesis that over expression of P01375 REA plays a role in the pathophysiology of insulin resistance .

Chemotherapeutic drugs and human tumor cells cytokine network . The ability of human tumor cell lines to produce various cytokines , chemokines , angiogenic and growth factors was investigated using Luminex multiplex technology . Media conditioned by tumor cells protected tumor cells from drug-induced apoptosis and stimulated tumor cell proliferation . Antibodies neutralizing P05231 REA , P10145 REA , P13500 REA and P13501 REA blocked this stimulation . Treatment of tumor cells with doxorubicin and cisplatin resulted in a substantial increase in the production of P05231 REA , P10145 REA , P13500 REA , P13501 REA , BFGF , G - P04141 REA and P15692 REA . This stimulation was associated with drug-induced activation of NF-kappaB , AP - 1 , P05549 REA , CREB , Q9BYW2 , P35610 - 1 , P35610 - 3 , P35610 - 5 and P39905 REA - 2 transcription factors and upregulation of P05231 REA , P10145 REA , P09038 REA , P04141 REA - 3 and P13501 REA gene expression . Treatment of tumor cells with doxorubicin and antibodies neutralizing DB00099 , P13500 REA or P13501 REA had higher inhibitory effects than each modality used alone . These results indicate that chemokines and growth factors produced by tumor by binding to the cognate receptors on tumor and stroma cells could provide proliferative and antiapoptotic signals helping tumor to escape drug-mediated destruction . Clinical studies showed that antibodies neutralizing P15692 REA ( DB00112 / DB00112 ) or blocking P04626 REA / neu signaling ( Herceptin / DB00072 MEN ) could increase the efficacy of chemotherapy , although these beneficial effects have been limited . It is possible that drug-stimulated production of growth and proangiogenic factors could counterbalance the effects of antibody therapy . In addition , numerous growth factors and chemokines share angiogenic and growth-stimulating properties , and thus reduction of a single factor is insufficient to completely block tumor growth . Thus , a broad disruption of tumor cytokine network is needed to further increase the efficacy of cancer therapy .

Golimumab in unresponsive ulcerative colitis . Ulcerative colitis ( UC ) is a chronic inflammation mainly affecting the colon mucosa . It predominantly occurs in younger patients . Until recently , the main goals in the treatment of UC were to temper the symptoms , such as diarrhea , pain , and weight loss , by using mesalazine and steroids . With newer medications , such as immunomodulators ( thiopurines ) and the biologics providing blockade of tumor necrosis factor ( P01375 REA ) , the goals of the therapy in UC have changed to long-term remission and mucosal healing . The first available anti - P01375 REA therapy in UC included infusion therapy with infliximab every few weeks . In 2012 , subcutaneously administered adalimumab gained approval for the treatment of UC in Germany . In patients with a mild disease , therapy with mesalazine , orally or topically , can be sufficient . In patients with moderate to severe disease , therapy with azathioprine or anti - P01375 REA is often required to reach disease control ; however , this is only efficient in about two-thirds of patients . Some patients either show no response or a lost response while on treatment . So , further medical options are warranted in the treatment of UC . With DB06674 SUB , a new approach in the treatment of mild to moderate UC recently became available in Germany and is a promising new option in the therapy regimen for patients with UC .

Clinically relevant advances in rheumatoid arthritis therapy . Owing to the success of biologics in the treatment of rheumatoid arthritis ( RA ) , several novel drugs have been introduced in the therapeutic armamentarium , although not all of them have been approved in all countries worldwide . Among the drugs are tumour necrosis factor ( P01375 REA ) inhibitors such as certolizumab pegol and DB06674 SUB ( the latter of which was the first P01375 REA blocker shown to be effective in patients who had been unsuccessfully treated with other P01375 REA blockers and which can be applied only once a month ) , and the interleukin - 6 receptor antagonist tocilizumab , which not only opens up a completely new field of anti-inflammatory modulation of RA pathophysiology , but also highlights the challenge of novel potential side effects . Moreover , aside from clinical studies showing efficacy in the inhibition of osteoclast activation by the anti - O14788 REA ( receptor activator of nuclear factor-kappa B ligand ) antibody denosumab , an improved form of steroid application known as slow-release ' tempus tablet ' for treatment of RA and several developments in the small-molecule area have been addressed by clinical trials .

Anti-allergic effects of nilotinib on mast cell-mediated anaphylaxis like reactions . DB04868 MEN is a new orally bioavailable potent tyrosine kinase inhibitor that is used for the treatment of P11274 REA - P00519 REA - positive chronic myelogenous leukemia . However , its effect on mast cell-mediated anaphylactic reaction is still not known . The present study aimed to investigate the effect of nilotinib on the anaphylactic allergic reaction and study its possible mechanism ( s ) of action . DB04868 MEN administration prevented systemic anaphylaxis in mice , mediated by compound 48/80 , in a dose - and time-dependent manner . Also , nilotinib significantly inhibited ( P < 0.05 ) allergic paw edema in rats . Furthermore , nilotinib significantly decreased ( P < 0.05 ) the IgE-mediated passive cutaneous anaphylaxis in a dose dependent manner . In addition , nilotinib dose-dependently reduced histamine release from the rat peritoneal mast cells activated either by compound 48/80 or by ovalbumin . Moreover , nilotinib attenuated the secretion of pro-inflammatory cytokine , tumor necrosis factor ( P01375 REA ) - α expression in the rat peritoneal mast cells . These findings provide evidence that nilotinib inhibits mast cell-derived immediate-type allergic reactions and so it could be a candidate as an anti-allergic agent .

Safety issues and concerns of new immunomodulators in rheumatology . INTRODUCTION : The development of biologic therapies has been an enormous leap in the management of patients with rheumatoid and psoriatic arthritis . Since the first anti - P01375 REA - α therapies , numerous molecules have been identified as targets of immunomodulatory therapies , such as IL - 1 ( anakinra , canakinumab ) , P05231 REA ( tocilizumab ) , P11836 ( + ) B cells ( rituximab ) , P16410 REA ( abatacept ) and two additional anti - P01375 REA - α therapies ( certolizumab pegol , DB06674 SUB ) . AREAS COVERED : In the present review , we will describe the safety issues related to the immunosuppressive action of these biologic drugs that are mainly represented by infection and malignancy . The risk of infection should be identified before initiating a biologic treatment and markers checked over time , in particular for tuberculosis and hepatitis B and C viruses . Other infections ( bacterial , viral , parasitic ; opportunistic ; surgery-related ) and safety issues may require temporary interruption of the treatment until complete resolution . No significantly increased risk of malignancy , both hematological and solid , has been associated with the use of biologic agents . In all cases , it is difficult to dissect the risks related to biologics from those related to baseline treatments . EXPERT OPINION : Detailed medical history and laboratory screening should be performed before starting biologic therapies . Clinicians should be aware of the different safety profiles associated with different molecules and they should follow up data coming out of the existing registries for biologics in regard to new or old side effects .

P01375 REA inhibitors - state of knowledge . P01375 REA ( P01375 REA ) is considered a major proinflammatory cytokine , affecting various aspects of the immune reaction . All five P01375 REA inhibitors currently available on the market ( i . e . , etanercept , infliximab , adalimumab , certolizumab and DB06674 SUB ) are top sellers , although indicated only in autoimmune diseases , including rheumatoid arthritis , Crohn ' s disease and psoriasis . This article briefly discusses the background and place for P01375 REA inhibitors in modern therapy . The main safety aspects of P01375 REA inhibitor administration are described in particular , with special consideration of the available meta-analyses . Finally , perspectives on the next-generation P01375 REA inhibitors and their use in the clinic are given .

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 Kir 6.2 / Q09428 REA 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 MEN 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 .

[ Safety in the diagnosis and treatment of inflammatory bowel disease ] . The presentations at Digestive Disease Week 2013 emphasized treatment safety . Anti-tumor necrosis factor ( P01375 REA ) agents and thiopurines are reasonably safe in breastfeeding and pregnancy . Several studies indicate that controlling the risk of tuberculosis when anti - P01375 REA agents are planned presents several problems , both in the initial diagnosis of latent tuberculosis and in subsequent patient follow-up , given that cases of tuberculosis continue to occur , despite recommendations . Thiopurines increase the risk of lymphoma , but there is no residual risk when these drugs are withdrawn . Despite increasing knowledge of the risks and recommendations on how to avoid them , there remain considerable shortfalls in the application of preventive measures and , more specifically , in vaccinations . DB00065 and cyclosporin produce similar results when used to treat severe outbreaks of ulcerative colitis . Thromboembolism prevention continues to be deficient , and the barriers to effective prevention concern not only physicians but can also involve nursing staff , for example . There is still a wide margin for improvement in safety . New drugs under study ( vedolizumab , DB06674 SUB ) have not shown any hitherto unknown signs of significant toxicity .

Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing P04626 REA . In an attempt to treat cancer patients with P04626 REA overexpressing tumors , we developed a chimeric antigen receptor ( CAR ) based on the widely used humanized monoclonal antibody ( mAb ) DB00072 MENMAX DB00072 MEN ( Herceptin ) . An optimized CAR vector containing P10747 REA , 4-1 BB , and CD3zeta signaling moieties was assembled in a gamma-retroviral vector and used to transduce autologous peripheral blood lymphocytes ( PBLs ) from a patient with colon cancer metastatic to the lungs and liver , refractory to multiple standard treatments . The gene transfer efficiency into autologous T cells was 79 % CAR ( + ) in CD3 ( + ) cells and these cells demonstrated high-specific reactivity in in vitro coculture assays . Following completion of nonmyeloablative conditioning , the patient received 10 ( 10 ) cells intravenously . Within 15 minutes after cell infusion the patient experienced respiratory distress , and displayed a dramatic pulmonary infiltrate on chest X-ray . She was intubated and despite intensive medical intervention the patient died 5 days after treatment . Serum samples after cell infusion showed marked increases in interferon-gamma ( P01579 REA ) , granulocyte macrophage-colony stimulating factor ( GM - P04141 REA ) , tumor necrosis factor-alpha ( P01375 REA ) , interleukin - 6 ( P05231 REA ) , and P22301 REA , consistent with a cytokine storm . We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of P04626 REA on lung epithelial cells .

Combination systemic therapies in psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic , progressive , and debilitating disorder . When monotherapy fails , combination therapy is necessary for the long-term management of these patients . There is currently no review on this subject , and the purpose of this study was to investigate and describe the current literature on combination therapy in PsA . A PubMed MeSH search was performed for psoriatic arthritis and combination therapy , which yielded at total of 83 articles . After excluding reviews and commentaries , and pursuing relevant citations , a total of 21 articles on the subject were found : one study of NSAIDs and methotrexate , three studies of cyclosporine and methotrexate , three studies of non - P01375 REA biologic inhibitors ( alefacept , ustekinumab ) and methotrexate , and 14 studies of anti - P01375 REA - inhibitors ( etanercept , adalimumab , infliximab , DB06674 SUB ) and methotrexate . The combination of cyclosporine and methotrexate reduces the dosages and also the side effects of each agent , allowing better disease control with less toxicity . DB00563 in combination with biologic agents , either non - P01375 REA inhibitors or anti - P01375 REA inhibitors , may have a role in decreasing side effects , but it does not appear to improve clinical symptoms beyond those attained by biologic monotherapy .

Treatment of ulcerative colitis . PURPOSE OF REVIEW : Ulcerative colitis is a chronic inflammatory disease of the colon of unknown cause that is characterized by alternating intervals of active and inactive disease in 80-90 % of patients . The primary goal of treatment is to induce and maintain remission using therapy tailored to the individual patient . The purpose of this review was to describe the management of ulcerative colitis with emphasis on the use of anti-tumor necrosis factor ( P01375 REA ) agents . RECENT FINDINGS : Recent research has shown that new anti - P01375 REA agents , adalimumab ( P00813 REA ) and DB06674 SUB , are effective in induction of remission and maintenance of remission in patients with extensive ulcerative colitis . In a recent study , infliximab was found to have comparable efficacy to cyclosporine in treatment of acute severe refractory to corticosteroids ulcerative colitis . SUMMARY : Anti - P01375 REA therapy should be initiated in patients with acute severe refractory to corticosteroids ulcerative colitis and in patients with moderate-to-severe ulcerative colitis who are not responsive to conventional treatment with aminosalicylates , corticosteroids and immune modulators . Alternatives to infliximab are P00813 REA and DB06674 SUB . Future research is needed to further assess the long-term efficacy and safety of P00813 REA and DB06674 SUB in ulcerative colitis .

Tailored therapy for severe asthma . Patients with severe asthma or P48444 REA have often a suboptimal symptom control due to inadequate treatment . A better understanding of pathogenetic mechanisms , phenotypes , endotypes and the new technologies available in the fields of molecular biology and immunogenetics have made it possible to synthesize specific monoclonal antibodies virtually able to interact with any target antigen , or to open a way for new therapeutic target options . At the moment , the only biologic drug available in clinical practice is omalizumab . To overcome the limits of omalizumab , the research has focused on new monoclonal antibodies presenting higher avidity for IgE ( e . g . ligelizumab and lumiximab ) and ability to interact also with low affinity IgE receptor ( FcϵRII ) . At present , many new biological drugs with different mechanisms of action and targets are matter of research . It is very important to identify the asthmatic phenotype in order to select the most appropriate drug for the individual patient . The most promising agents are targeted against cytokines of Th2 pattern and related receptors , such as P60568 REA ( daclizumab ) and P35225 REA ( lebrikizumab ) or P05113 REA in patients with hypereosinophilia ( mepolizumab , reslizumab and benralizumab ) . Other interesting drugs have as a target P01375 REA - α or its soluble receptor ( infliximab , DB06674 SUB and etanercept ) or IL - 1 ( canakinumab ) , a cytokine with an important systemic proinflammatory action . Finally , the discovery of increased levels of C5a in the airways of asthmatic patients has led to the synthesis of a specific monoclonal antibody ( eculizumab ) . Further help should come from the identification of biomarkers that can guide in choosing the best treatment for the individual patient , such as IgE for omalizumab or periostin for lebrikizumab .

New treatments for inflammatory rheumatic disease . As our understanding of the pathogenesis of autoimmune diseases is growing , new therapies are being developed to target disease-specific pathways . Since the introduction of etanercept in 1998 , several biotechnological agents have been developed , most of them indicated in the treatment of rheumatoid arthritis , but also psoriatic arthritis . Most currently available molecules target P01375 REA - alfa with different strategies ( i . e . , etanercept , infliximab , adalimumab , DB06674 SUB , and certolizumab pegol ) , P05231 REA ( tocilizumab ) , P16410 REA ( abatacept ) , and B cells ( rituximab , belimumab ) as they are key mediators in the cascade of inflammation . Further , small molecules have been recently developed to target intracellular signaling , such as Janus Kinases for tofacitinib , the first FDA-approved small molecule for rheumatoid arthritis . Most novel treatments are being developed for arthritis with specific differences between rheumatoid and psoriatic arthritis , as well as for systemic lupus erythematosus , following the approval of belimumab . Finally , biologic therapies are effective also in gout , mainly targeting interleukin - 1 to block the inflammasome . This review article describes the new and upcoming treatment options for rheumatoid arthritis , psoriatic arthritis , systemic lupus erythematosus , and gout to dissect what we should be aware of when discussing these new and promising molecules .

[ Functional characteristics of calcium-sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0.2- 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20-100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . DB00477 MEN , another calmodulin antagonist , reduced Ca2 + - stimulated AC activity only at the concentrations of 200-1000 microM . AC stimulating effects of serotonin , P01133 REA and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 REA , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D-glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium-sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 REA , DB02527 , insulin , and serotonin .

Biologic monotherapy as initial treatment in patients with early rheumatoid arthritis . Although biologic agents are most well established as part of combination regimens in patients with RA , biologic monotherapy is common in clinical practice . To date , few double-blind , randomized clinical trials have compared biologic monotherapy with MTX monotherapy . Five randomized double-blind trials evaluating the P01375 REA antagonists etanercept ( ERA and TEMPO ) , adalimumab ( PREMIER ) and DB06674 SUB ( GO-BEFORE ) and the P05231 REA receptor antagonist tocilizumab ( AMBITION ) were identified . We noted considerable variation in patient characteristics ( i . e . disease duration and disease severity ) in the five trials . Studies involving monotherapy with P01375 REA inhibitors found no clear clinical efficacy advantage over MTX monotherapy . In the two trials that included a P01375 REA inhibitor / MTX combination arm , combination therapy was superior to monotherapy with either agent alone . In contrast , the AMBITION trial demonstrated that tocilizumab monotherapy was superior to MTX in terms of clinical response , disease activity , remission and functionality . Although results can not be compared across clinical trials , tocilizumab was the only biologic agent to demonstrate superiority to MTX as monotherapy in patients with RA with limited / no exposure to MTX .

anti - P01375 REA agents as therapeutic choice in immune-mediated inflammatory diseases : focus on adalimumab . The complex pathogenesis of immune-mediated inflammatory diseases ( IMIDs ) has been extensively investigated and dysregulation of cytokines , such as tumour necrosis factor ( P01375 REA ) has been shown to play a dominant role in the pathogenesis of various IMIDs , such as rheumatoid arthritis , ankylosing spondylitis , Crohn ' s disease , ulcerative colitis , psoriasis and psoriatic arthritis . The subsequent development of biological agents capable of blocking P01375 REA has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with P01375 REA having a predominant role . Five P01375 REA inhibitors have currently been approved for treatment of one or more IMIDs ; these include infliximab , etanercept , adalimumab , DB06674 SUB and certolizumab pegol . Given the similarities in the pathogenic background of IMIDs , one could expect that anti - P01375 REA agents be similarly effective and with comparable tolerability profiles ; however , this may not be the case . Structural and pharmacological differences among the anti - P01375 REA drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs , together with differences in potency , therapeutic dose ranges , dosing regimens , administration routes , and propensity for immunogenicity . Among the five P01375 REA inhibitors approved for treatment of IMIDs , adalimumab has the widest range of indications . Data from controlled clinical trials of adalimumab , showing its excellent efficacy and tolerability in a wide range of indications , are supported by real-world long-term data from observational studies , which confirm the value of adalimumab as a suitable choice in the management of IMIDs .

Temporal network based analysis of cell specific vein graft transcriptome defines key pathways and hub genes in implantation injury . Vein graft failure occurs between 1 and 6 months after implantation due to obstructive intimal hyperplasia , related in part to implantation injury . The cell-specific and temporal response of the transcriptome to vein graft implantation injury was determined by transcriptional profiling of laser capture microdissected endothelial cells ( EC ) and medial smooth muscle cells ( SMC ) from canine vein grafts , 2 hours ( H ) to 30 days ( D ) following surgery . Our results demonstrate a robust genomic response beginning at 2 H , peaking at 12-24 H , declining by 7 D , and resolving by 30 D . Gene ontology and pathway analyses of differentially expressed genes indicated that implantation injury affects inflammatory and immune responses , apoptosis , mitosis , and extracellular matrix reorganization in both cell types . Through backpropagation an integrated network was built , starting with genes differentially expressed at 30 D , followed by adding upstream interactive genes from each prior time-point . This identified significant enrichment of P05231 REA , P10145 REA , NF-κB , dendritic cell maturation , glucocorticoid receptor , and Triggering Receptor Expressed on Myeloid Cells ( Q9NP99 ) signaling , as well as PPARα activation pathways in graft EC and SMC . Interactive network-based analyses identified P05231 REA , P10145 REA , IL - 1α , and P01308 REA Receptor ( P06213 REA ) as focus hub genes within these pathways . Real-time PCR was used for the validation of two of these genes : P05231 REA and P10145 REA , in addition to Collagen 11A1 ( P12107 REA ) , a cornerstone of the backpropagation . In conclusion , these results establish causality relationships clarifying the pathogenesis of vein graft implantation injury , and identifying novel targets for its prevention .

Golimumab , the newest P01375 REA - α blocker , comes of age . Golimumab , a fully human monoclonal antibody against tumour necrosis factor-α ( P01375 REA - α ) is one of the newest biologics that has become available for the treatment of rheumatoid arthritis , ankylosing spondylitis and psoriatic arthritis . Following the initial randomised double-blind placebo-controlled clinical trials , which demonstrated the efficacy and safety of the drug in the context of a limited patient sample and a relatively short time frame , DB06674 SUB has been the focus of continuous investigation through the extensions of the above-mentioned trials , new clinical trials and registries of biologic drug use in daily clinical practice . The review of this data and their inclusion in meta-analyses and indirect comparisons across P01375 REA - α blockers suggest that DB06674 SUB possesses similar properties regarding efficacy and safety as the older monoclonal anti - P01375 REA - α antibodies . The novelty of DB06674 SUB is perhaps its dosing regimen , i . e . subcutaneous self-administration once monthly , which allows for the least disturbance in the life of patients .

Tuberculosis risk in patients treated with non-anti-tumor necrosis factor-α ( P01375 REA - α ) targeted biologics and recently licensed P01375 REA - α inhibitors : data from clinical trials and national registries . This review aimed to evaluate the risk of active tuberculosis ( TB ) occurrence in patients with rheumatic disorders receiving non-anti-tumor necrosis factor ( P01375 REA ) targeted biologics anakinra ( ANK ) , tocilizumab ( TCZ ) , rituximab ( RTX ) , abatacept ( ABA ) , and recently approved anti - P01375 REA DB06674 SUB ( GOL ) , and certolizumab pegol ( P53007 REA ) . In recent findings , no cases of active TB were recorded in patients with rheumatoid arthritis ( RA ) and other rheumatic conditions treated with anti - P11836 + RTX and anti - P10747 REA ABA . No patient receiving anti-interleukin 1 ( IL - 1 ) ANK developed active TB , and an increased risk was excluded in a Canadian database . In contrast , 8 active TB cases were observed in 21 trials of patients with RA receiving anti - P05231 REA TCZ , while no increased TB risk resulted from Japanese postmarketing surveillance . Among GOL-treated and P53007 REA - treated patients , 8 and 10 active TB cases occurred , respectively , while no data are available from registries . However , all but 1 TB case recorded in patients treated with TCZ , GOL , and P53007 REA occurred in TB-endemic countries . No TB risk resulted for ANK , RTX , and ABA , suggesting pretreatment screening procedures for latent TB infection detection are unnecessary . Because all TB cases occurred in countries at high risk for TB , where TB exposure could have occurred during treatment , no definitive conclusions can be drawn for TCZ , GOL , and P53007 REA .

Effects of subcutaneous and intravenous DB06674 SUB on inflammatory biomarkers in patients with rheumatoid arthritis : results of a phase 1 , randomized , open-label trial . OBJECTIVE : To evaluate the effects of the anti - P01375 REA - α monoclonal antibody DB06674 SUB , administered by s . c . injection or i . v . infusion , on markers of inflammation in patients with RA . METHODS : In this phase 1 , open-label study , patients with active RA were randomized to receive s . c . DB06674 SUB 100 mg at baseline and every 4 weeks through week 20 ( n = 33 ; group 1 ) or i . v . DB06674 SUB 2 mg / kg at baseline and week 12 ( n = 16 ; group 2 ) . Serum levels of CRP , P05231 REA , serum amyloid A ( P0DJI8 ) , P01375 REA receptor II ( TNFRII ) , P08254 REA , hyaluronic acid , haptoglobin , ferritin and haemoglobin and serum / urine hepcidin were measured at various time points . Associations between the biomarkers were assessed with Spearman ' s correlations . RESULTS : In both groups 1 and 2 , decreases in mean serum levels of CRP , P05231 REA , P0DJI8 , TNFRII , P08254 REA , haptoglobin , ferritin and hepcidin , and mean urine levels of hepcidin occurred within 1 week and were sustained through week 8 . Decreases in concentrations of serum CRP , P05231 REA , P0DJI8 , P08254 REA , hepcidin , ferritin and haptoglobin and urine hepcidin were maintained through week 24 in group 1 , but began to reverse after week 8 in group 2 . Among all patients , decreases in serum hepcidin correlated significantly with decreases in serum CRP and ferritin . CONCLUSION : Decreases in serum and urine concentrations of markers of inflammation occurred as early as 24 h after treatment with DB06674 SUB , and most of these improvements were sustained through week 24 in group 1 .

DB00227 - stimulated superinduction of P16581 REA , P05362 REA and P19320 REA in P01375 REA activated human vascular endothelial cells . Inhibitors of P04035 REA ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 REA , intercellular cell adhesion molecule - 1 ( P05362 REA ) and vascular cell adhesion molecule - 1 ( P19320 REA ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 REA . This effect is potentiated by 100-200 % when the cells are pretreated with 0.1- 2.5 microM lovastatin . The lovastatin-mediated increase in the cytoplasm and at the cell surface is dose-dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin-potentiated increase of P16581 REA and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .

Tumour necrosis factor α antagonists in the treatment of rheumatoid arthritis : an immunological perspective . Rheumatoid arthritis ( RA ) is one of the most prevalent autoimmune conditions , affecting approximately 1 % of the adult population . It is associated with decreased quality of life and considerable morbidity and mortality . Various inflammatory cells , including macrophages , neutrophils , mast cells , natural killer cells , B and T cells and stromal cells play key pathophysiological roles in joint inflammation and RA progression . Several cytokines , including interleukin ( IL ) - 1α and / or IL - 1β , and tumour necrosis factor ( P01375 REA ) - α , are involved at each stage of RA pathogenesis ; namely , by augmenting autoimmunity , sustaining long-term inflammatory synovitis and promoting joint damage . Different cell types are involved in RA pathogenesis through upregulation of several cytokine and soluble pro-inflammatory mediators . As early as the late 1980s , P01375 REA had been identified as a potential target in RA . Five anti - P01375 REA drugs , infliximab , adalimumab , certolizumab pegol , etanercept and DB06674 SUB , are now approved for the treatment of RA in various countries . All are bivalent monoclonal antibodies , with the exception of the monovalent certolizumab and etanercept , which is an engineered dimeric receptor . Although all react with and neutralise soluble P01375 REA in vitro , structural differences in the molecules may contribute to differences in their therapeutic effects and the occurrence of side effects . Pegylated certolizumab permits once-monthly dosing . Other mechanisms of action proposed to be important for the efficacy of anti - P01375 REA agents are as follows : induction of apoptosis of both monocytes and T cells ; neutralization of membrane P01375 REA ; antibody-dependent cell-mediated and complement-dependent cytotoxicity ; and reverse signaling via membrane P01375 REA .

The emergence of DNA methylation as a key modulator of aberrant cell death in prostate cancer . It is now well established that cancer cells exhibit a number of genetic defects in the machinery that governs programmed cell death and that sabotage of apoptosis is one of the principal factors aiding in the evolution of the carcinogenic phenotype . A number of studies have implicated aberrant DNA methylation as a key survival mechanism in cancer , whereby promoter hypermethylation silences genes essential for many processes including apoptosis . To date , studies on the methylation profile of apoptotic genes have largely focused on cancers of the breast , colon and stomach , with only limited data available on prostate cancer . Here we discuss the major developments in the field of DNA methylation and its role in the regulation of aberrant apoptosis in prostate cancer . The most significant advances have involved the discovery of apoptotic gene targets of methylation , including Q6GPH4 , ( fragile histidine triad ( P49789 ) , cellular retinol binding protein 1 ( P09455 REA ) , decoy receptor 1 ( O14798 REA ) , decoy receptor 2 ( Q9UBN6 ) , target of methylation-induced silenceing 1 ( Q9ULZ3 ) , P01375 REA receptor superfamily , member 6 ( FAS ) , Reprimo ( Q9NS64 ) and P08151 REA pathogenesis-related 1 ( P48060 REA ) . These genes are reported to be hypermethylated in prostate cancer and some offer potential as diagnostic and prognostic markers . We also introduce the concept of an ' apoptotic methylation signature ' for prostate cancer and evaluate its potential in a diagnostic , prognostic and therapeutic setting .

New therapies in the management of rheumatoid arthritis . PURPOSE OF REVIEW : The therapeutic landscape in the management of rheumatoid arthritis ( RA ) has witnessed significant changes over the past decade . The ambition to improve outcomes further , minimize safety concerns and provide more convenient means of administration are all factors that continue to drive continued drug development . This review summarizes novel therapies that have been most recently under investigation . RECENT FINDINGS : More refined drug technology has seen the development of subcutaneous forms of existing therapies ( abatacept , tocilizumab ) , as well as newer-generation monoclonal antibodies ( e . g . B-cell-depleting agents , ocrelizumab and ofatumumab and the P01375 REA - inhibitors certolizumab and DB06674 SUB ) . Alternative methods of targeting critical pathways , for example Blys inhibition ( atacicept ) and P05231 REA as opposed to P05231 REA receptor antagonism , have also been evaluated . Finally , small molecules are receiving increasing attention , with some of the protein kinases inhibitors particularly promising . SUMMARY : The new emerging therapies for the management of RA illustrate much diversity , in terms of both drug technology as well as the immunological target . Although not all may succeed in reaching the market , important insights can still be gained . Challenging and exciting times lie ahead as these new technologies are embraced and efforts are made to determine how best to implement in practice .

Tumor necrosis factors blocking agents : analogies and differences . Five anti - P01375 REA agents , infliximab , adalimumab , etanercept , DB06674 SUB and certolizumab pegol are approved worldwide for the treatment of RA . Anti - P01375 REA agents , bind to and neutralize soluble P01375 REA , but exert different effects on transmembrane P01375 REA - expressing cells ( P01375 REA - producing cells ) . Differences on affinity and avidity for soluble and transmembrane P01375 REA were showed . Different activity on cells apoptosis , complement-dependent cytotoxicity ( CDC ) antibody dependent cell-mediated cytotoxicity ( Q15848 REA ) were described . Some dramatic changes in gene expression were seen with all the anti-TNFs . Reviewing the biology of transmembrane P01375 REA and its interaction with anti - P01375 REA agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities .

Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II-dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 REA ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , DB06271 MEN ( SLX ) which catalyzes thrombin inhibition by P01008 REA and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti-thrombin U / kg , respectively . SLX ( 16 anti-thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti-thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 REA and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .

Current and emerging biologics for ulcerative colitis . Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy . Hence , different biological agents that target specific immunological pathways are be-ing investigated for treating ulcerative colitis . Anti-tumor necrosis factor ( P01375 REA ) agents were the first biologics to be used for treating inflammatory bowel disease . For example , infliximab and adalimumab , which are anti - P01375 REA agents , are be-ing used for treating ulcerative colitis . Recently , DB06674 SUB , another anti - P01375 REA agent , and vedolizumab , an anti-adhesion therapy , have been approved for ulcerative colitis by the U . S . Food and Drug Administration . In addition , new medications such as tofacitinib , a Janus kinase inhibitor , and etrolizumab , another anti-adhesion therapy , are emerging as therapeutic agents . Therefore , there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage .

A mixed treatment comparison of the efficacy of anti - P01375 REA agents in rheumatoid arthritis for methotrexate non-responders demonstrates differences between treatments : a Bayesian approach . BACKGROUND : A number of tumour necrosis factor α ( TNFα ) antagonists ( anti-TNFα ) are available to treat rheumatoid arthritis . All of these have demonstrated considerable efficacy in placebo controlled trials , but few head-to-head comparisons exist to date . This work ' s objective is to estimate the relative efficacy among licensed anti-TNFs in patients who have had an inadequate response to methotrexate ( MTX ) . Different outcome measures are used to highlight the advantages of continuous measures in such analyses . METHODS : A systematic review identified randomised controlled trials comparing the efficacy of licensed anti-TNFα agents with placebo at 24 weeks in patients who have had an inadequate response to MTX . Relative efficacy was estimated using Bayesian mixed treatment comparison ( P04629 REA ) models . Three different outcome measures were used : RR of achieving an American College of Rheumatology ( P10323 ) 20 and ACR 50 response and the percentage improvement in Health Assessment Questionnaire ( HAQ ) score . RESULTS : 16 published trials were included in the analysis . All anti-TNFs show considerably improved efficacy over placebo . The P04629 REA results also provide evidence of some differences in efficacy of the TNFα antagonists . DB00005 appears superior to infliximab and DB06674 SUB , and certolizumab to infliximab and adalimumab . P10323 results indicate improved efficacy of certolizumab over DB06674 SUB . On HAQ analysis , adalimumab , certolizumab , etanercept and DB06674 SUB appear superior to infliximab , and etanercept shows improved efficacy compared with adalimumab . CONCLUSIONS : There are differences in efficacy among the TNFα antagonists . In a P04629 REA , a continuous outcome measure has more strength to detect such differences than a binomial outcome measure because of its enhanced sensitivity to change .

[ Research update of anti - P01375 REA - α biologic agents in the treatment of uveitis ] . Uveitis is one of the common sight-threatening eye diseases , which is usually recurrent and refractory to treatment . It is generally considered that the development of uveitis is closely related to the autoimmune response of uvea . P01375 REA ( P01375 REA ) - α is one of the key cytokines involved in the emergence and progression of uveitis . Blocking the production or inhibiting the activity of P01375 REA - α can inhibit the development or progression of uveitis . Presently , the commercially available P01375 REA - α blockers include infliximab , adalimumab , etanercept , and DB06674 SUB . This review describes the clinical studies and adverse effects of P01375 REA - α blockers in the treatment of uveitis , and discusses the principle for clinical use of P01375 REA - α blockers in synergy with other immunosuppressive agents .

DB00184 MEN consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 REA - P30532 REA - P30926 REA cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug-naive α5 ( - / - ) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation . We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 * - nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single-nucleotide polymorphism , the non-synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self-administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake .

P01375 REA alpha antagonists in the treatment of axial spondyloarthritis . INTRODUCTION : The introduction of therapy with tumor necrosis factor antagonists ( aTNF ) was a cornerstone of treatment modalities in patients with ankylosing spondylitis ( AS ) . After > 10 years of using aTNF , the introduction of aTNF therapy was a major step forward in the medical management of patients with spondyloarthritis ( SpA ) , but there are still a number of scientific questions that have not been resolved . AREAS COVERED : This review includes both subtypes of axial spondyloarthritis ( axSpA ) , non-radiographic axial SpA ( nr-axSpA ) , and AS . It covers all five aTNF adalimumab , certolizumab , etanercept , DB06674 SUB , and infliximab , which are approved for patients with active AS . EXPERT OPINION : aTNF are efficacious and effective in reducing signs and symptoms of patients with axSpA . While aTNF reduce spinal inflammation , the effects on new bone formation are less clear . There may be a deceleration of radiographic progression in 4 years . The development of fatty lesions in vertebral edges seems to be relevant for that - especially when inflammation also persists . Reduction of aTNF doses seems to be possible in selected patients over time . In case of failure , switching to another aTNF works in the majority of cases . Long-term data suggest a favorable safety profile of aTNF .

P25116 REA - mediated synovial proliferation in patients with rheumatoid arthritis . Synovial cell proliferation is one of the pathological bases of rheumatoid arthritis ( RA ) . Several cytokines including IL - 1 and P05231 REA and growth factors have been shown to be involved in the synovial cell proliferation in RA . Thrombin is a multifunctional protease and acts as a mitogen for several cell types through its specific receptor . To assess whether thrombin is involved in overproliferation of rheumatoid synovial cells , we measured the concentration of thrombin-anti-thrombin III ( P01008 REA ) complex ( TAT ) in synovial fluid obtained from patients with RA or osteoarthritis ( OA ) . We also examined the effect of thrombin or thrombin receptor agonist peptide ( TRAP ) on cell growth of synovial cell clones ( SCCs ) established from an RA patient . The concentrations of TAT in the synovial fluid from patients with RA were significantly higher than in those with OA . Moreover , both thrombin and TRAP enhanced proliferation of synovial cells in vitro . We also characterized the expression of thrombin receptor mRNA by reverse transcription-PCR . The expression of mRNA for thrombin receptor was up-regulated by thrombin or TRAP stimulation . P25116 REA antigen was also detected on both SCCs and synovial tissue from RA patients by immunostaining using a monoclonal antibody against thrombin receptor . These findings indicate that thrombin may act as a mitogen for synovial cells through thrombin receptor and may play some role in synovial overproliferation and remodeling in RA .

Characterization of plant P18887 REA and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 REA ( Pol beta ) and P49916 REA ( Lig 3 ) genes . Thus , the plant short-patch base excision repair ( short-patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X-ray repair cross complementing 1 ( P18887 REA ) , a well-known BER protein . The plant P18887 REA lacks the N-terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 REA ( OsXRCC 1 ) protein binds single-stranded DNA ( ssDNA ) as well as double-stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull-down assay . Through immunoprecipitation , we demonstrated that OsXRCC 1 forms a complex with P12004 REA in vivo . OsXRCC 1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV-B . DB00290 MEN also increased the fraction of OsXRCC 1 associated with chromatin . These results suggest that OsXRCC 1 contributes to DNA repair pathways that differ from the mammalian BER system .

Biologic agents for rheumatoid arthritis : 2008 and beyond . Rheumatoid arthritis ( RA ) is a chronic disease with a complex underlying pathology and varied presentation in patients . Several novel biologic disease-modifying antirheumatic drugs have become available for the treatment of RA . Agents in late-stage clinical trials include DB06674 SUB and certolizumab , which are anti-tumor necrosis factor ( P01375 REA ) - alpha agents ; ocrelizumab , an anti - P11836 agent ; and tocilizumab , an inhibitor of interleukin - 6 . As treatment options for RA expand , nursing care will play an increasingly important role in empowering patients through interventions such as patient education and adverse effect management .

The effect of neutralizing antibodies on the sustainable efficacy of biologic therapies : what ' s in it for African and Middle Eastern rheumatologists . Over the last decade , biologic therapeutic proteins have advanced the treatment of diseases such as rheumatoid arthritis ( RA ) . Therapeutic antibodies such as infliximab , adalimumab , rituximab , tocilizumab , DB06674 SUB , certolizumab pegol , the receptor construct etanercept , and abatacept , an anticluster of differentiation ( CD )8 0 / anti - P42081 REA fusion protein , are used as treatment for RA and ankylosing spondylitis ( AS ) . DB00065 , adalimumab , DB06674 SUB , certolizumab pegol , and etanercept are inhibitors of tumor necrosis factor ( P01375 REA ) , a key regulator of inflammation . Left untreated , progression of rheumatic diseases due to inflammation can lead to irreversible joint damage and serious disability . One limitation for the use of therapeutic antibodies is immunogenicity , the induction of antibodies by the adaptive immune system in response to foreign substances . The development of antidrug antibodies ( ADAs ) has a varying impact on the clinical efficacy of biologic agents for the treatment of RA and AS , depending on whether the ADAs are neutralizing or non-neutralizing . Studies have indicated that neutralizing ADAs are associated with a reduced efficacy , decreased drug survival , increased instances of dose escalation , and adverse events . Comparison studies of anti - P01375 REA biologics have demonstrated that each drug has a different sustained efficacy profile depending on immunogenicity . The purpose of this review is to provide rheumatologists with information regarding the effect of neutralizing antibodies on the sustainable efficacy of anti - P01375 REA biologic therapies . This information will be of value to practicing rheumatologists in Africa and the Middle East who should take into account the potential for changes in the efficacy and safety of biologic therapies and closely monitor patients under their care .

Aspects of P01375 REA inhibitor therapy in rheumatoid arthritis . Treatment outcomes in rheumatoid arthritis ( RA ) have improved considerably with the use of biological therapies . Since the discovery of the role of tumor necrosis factor ( P01375 REA ) alpha in the pathogenesis of the disease , three P01375 REA inhibitors , infliximab , etanercept and adalimumab , have become widely used for the treatment of RA . More recently , two newer P01375 REA inhibitors-certolizumab pegol and DB06674 SUB - have become available , increasing the armamentarium of therapy . With improved therapies , treatment strategies have also changed , with the aims now being to achieve and maintain remission . This article addresses some of these aspects of treating RA , reviewing the studies on these two newer P01375 REA inhibitors , certolizumab pegol and DB06674 SUB , and those addressing the induction of remission or low disease activity with P01375 REA inhibitors and maintenance with less intensive treatment .

Biologics in the management of ulcerative colitis - comparative safety and efficacy of P01375 REA - α antagonists . Ulcerative colitis can cause debilitating symptoms and complications such as colonic strictures , colonic dysplasia , colorectal cancer , and toxic megacolon or perforation . Goals of treatment in ulcerative colitis include resolution of gastrointestinal symptoms , healing of colonic mucosa , and prevention of disease complications . Our treatment armamentarium has expanded dramatically over the past 10 years , and we now have multiple biologic agents approved for the treatment of moderate-severe disease , in addition to conventional therapies such as 5 - aminosalicylates , thiopurines , and corticosteroids . In this review , we will provide a detailed discussion of the three tumor necrosis factor-alpha ( P01375 REA - α ) inhibitors currently approved for treatment of ulcerative colitis : infliximab , adalimumab , and DB06674 SUB . All three agents are effective for inducing and maintaining clinical response and remission in patients with ulcerative colitis , and they have comparable safety profiles . There are no head-to-head trials comparing their efficacy , and the choice of agent is most often based on insurance coverage , route of administration , and patient preference . Combination therapy with an immunomodulator is proven to be more effective than anti - P01375 REA monotherapy , and patients who lose response to an anti - P01375 REA agent should undergo dose intensification in order to regain clinical response . Despite therapeutic optimization , a significant percentage of patients will not achieve clinical remission with anti - P01375 REA agents , and so newer therapies are on the horizon .