interacts_with DB00482?
The new P35354 inhibitors : rofecoxib ( Vioxx ) and celecoxib ( DB00482 ) . Tolerability of selective cyclooxygenase inhibitor , celecoxib , in patients with analgesic intolerance . Intolerance reactions to acetyl salicylic acid ( ASA ) and nonsteroidal anti-inflammatory drugs ( NSAIDs ) are common and caused by inhibition of P23219 enzyme . Therefore , drugs that selectively inhibit P35354 enzyme may be safe in these subjects . In this study , we evaluated the tolerability of celecoxib , a selective P35354 inhibitor , in patients with analgesic intolerance . The eligible study population consisted of patients with a history of urticaria/angioedema , naso-ocular symptoms , bronchospasm , and/or anaphylactoid reaction induced by ASA and/or NSAIDs . A single-blind , placebo-controlled oral challenge test was performed in the hospital setting . On 2 separate days , 1/4 and 3/4 divided doses of placebo and celecoxib ( DB00482 200 mg , Pfizer , Turkey ) were given with 2-hour intervals . Seventy-five subjects ( mean age : 38.2 +/- 1.4 years ; F:M : 55:20 ) were included in the study . Twenty-one subjects had asthma . No reaction was observed with placebo or celecoxib provocation . Although celecoxib seems to be a safe alternative drug in our study group , considering its serious adverse events reported in the literature , the drug should be recommended for patients with analgesic intolerance only after being tested by an experienced allergist . 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 . P35354 inhibitors and cancer therapeutics : potential roles for inhibitors of P35354 in combination with cytotoxic therapy : reports from a symposium held in conjunction with the Radiation Therapy Oncology Group June 2001 Meeting . Tumor growth and angiogenesis are interdependent . Cyclooxygenase ( P36551 ) catalyzes the synthesis of prostaglandins ( PGs ) from arachidonic acid . Nonsteroidal antiinflammatory drugs ( NSAIDs ) inhibit P36551 -mediated synthesis of PGs . Although P23219 is constitutively expressed in a wide range of tissues , P35354 is cytokine inducible . Enhanced P35354 expression has been attributed a key role in the development of inflammation and related processes observed in pathologically altered disease states . Two specific P35354 inhibitors , namely , rofecoxib ( Vioxx ) and celecoxib ( DB00482 ) , both oral agents and FDA approved , have been shown preclinically and clinically to have efficacy comparable to that of NSAIDs for relief of pain and inflammation in osteoarthritis , with decreased risk of gastrointestinal damage . Significant preclinical evidence strongly supports the potential role for these inhibitors for the treatment of cancer . On June 29 , 2001 , the Radiation Therapy Oncology Group ( www.rtog.org ) , a National Cancer Institute-sponsored cooperative group , held a 1-day symposium focusing on the potential role of inhibitors of P35354 in the treatment of cancer . This issue of the American Journal of Clinical Oncology contains the summary of those presentations . Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue , 2,5-dimethyl-celecoxib . The proteasome inhibitor bortezomib ( Velcade ) is known to trigger endoplasmic reticulum ( ER ) stress via the accumulation of obsolete and damaged proteins . The selective cyclooxygenase-2 ( P35354 ) inhibitor celecoxib ( DB00482 ) causes ER stress through a different mechanism ( i.e. , by causing leakage of calcium from the ER into the cytosol ) . Each of these two mechanisms has been implicated in the anticancer effects of the respective drug . We therefore investigated whether the combination of these two drugs would lead to further increased ER stress and would enhance their antitumor efficacy . With the use of human glioblastoma cell lines , we show that this is indeed the case . When combined , bortezomib and celecoxib triggered elevated expression of the ER stress markers P11021 / P11021 and P35638 / P35638 , caused activation of c-Jun NH(2)-terminal kinase and ER stress-associated caspase-4 , and greatly increased apoptotic cell death . Small interfering RNA-mediated knockdown of the protective ER chaperone P11021 / P11021 further sensitized the tumor cells to killing by the drug combination . The contribution of celecoxib was independent of the inhibition of P35354 because a non-coxib analogue of this drug , 2,5-dimethyl-celecoxib ( Q6UXB2 ) , faithfully and more potently mimicked these combination effects in vitro and in vivo . Taken together , our results show that combining bortezomib with celecoxib or Q6UXB2 very potently triggers the ER stress response and results in greatly increased glioblastoma cytotoxicity . We propose that this novel drug combination should receive further evaluation as a potentially effective anticancer therapy . Compositions for treatment of cancer and inflammation . Celecoxib ( DB00482 , Pfizer , NY , USA ) is a worldwide top branded P35354 -specific inhibitor . It was shown to provide relief of arthritic pain and inflammation and has recently been under investigation for the prevention and treatment of cancer . However , recent studies showed that long term use of high doses of celecoxib is associated with an increased cardiovascular toxicity . We discovered that the addition of curcumin , a natural P35354 inhibitor , to celecoxib synergistically ( up to 1000 % ) augments the growth inhibitory effects of celecoxib in in-vitro and in-vivo models of arthritis and cancer , thus rendering effective action of the drug at up to tenfold lower dose . This may pave the way for a novel strategy to treat arthritis and cancer because its effect [ 1 ] can be achieved in the serum of patients receiving standard anti inflammatory or anti-neoplastic dosages of celecoxib , and [ 2 ] involves a regimen with a very low profile of side effects . Preliminary data suggest that the combination is not limited only to celecoxib and that addition of curcumin to other NSAIDs such as sulindac , synergistically augments neoplastic cell growth inhibition . Based on these finding we received an IRB approval to evaluate celecoxib+curcumin in patients with osteoarthritis , pancreatic cancer and metastatic CRC . We hope to complete these novel human clinical trials , in 12-18 months . The role of the spinal opioid receptor like1 receptor , the P25103 , and cyclooxygenase-2 in maintaining postoperative pain in the rat . Postoperative incident pain is not easily treated with opioids . Mechanical hyperalgesia induced by skin incision in rats is one of the animal models of postoperative incident pain . It is thought that mechanical hyperalgesia is maintained by the sensitization of spinal dorsal horn neurons . The P25103 , the opioid receptor like1 ( P41146 ) receptor , and cyclooxygenase ( P36551 ) -2 reportedly are involved in the development of spinal sensitization . In this study , we clarified the role of the P25103 , the P41146 receptor , and P35354 in the maintenance of mechanical hyperalgesia induced by skin incision . A 1-cm longitudinal incision was made through skin and fascia of the plantar aspect of the right foot in the rat . Four hours after the skin incision , significant mechanical hyperalgesia developed . An P41146 receptor agonist ( nociceptin ) , P25103 antagonists ( CP-96,345 and FK888 ) , and P35354 inhibitors ( NS398 and JTE522 ) were administered intrathecally 4 h after the skin incision . An P41146 receptor agonist and P25103 antagonists , but not P35354 inhibitors , significantly attenuated the level of mechanical hyperalgesia induced by the skin incision . These findings suggest that the spinal P41146 receptor and the P25103 play an important role in maintaining the mechanical hyperalgesia induced by skin incision . IMPLICATIONS : Intrathecal injection of an P25103 antagonist and an P41146 receptor agonist may be effective for the treatment of postoperative incident pain . P00797 inhibition with aliskiren . 1. Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . DB09026 has a low bioavailability ( between 2.6 and 5.0 % ) compensated by its high potency to inhibit renin ( IC50 : 0.6 nmol/L ) and a long plasma half-life ( 23-36 h ) , which makes it suitable for once-daily dosing . 3 . The once-daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin-nitric oxide-cyclic guanosine monophosphate pathway and possibly the (pro)renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study . P35354 inhibitors and DB00482 : safe or suspect ? Combined preoperative use of celecoxib and gabapentin in the management of postoperative pain . BACKGROUND : In 2005 we reported a study on the efficacy of the preoperative use of the selective P35354 inhibitor celecoxib ( DB00482 ) for reducing both postoperative pain and opioid requirements in patients undergoing bilateral subpectoral breast augmentation . Our findings showed that patients who received 400 mg of celecoxib 30 min before surgery required significantly less postoperative opioid analgesics compared with those given a placebo . DB00996 ( DB00996 ) is an agent commonly used to control neuropathic pain . Here we describe a prospective study assessing the efficacy of preoperative gabapentin in combination with celecoxib for reducing postoperative pain and opioid requirements in elective subpectoral breast augmentation . METHODS : One hundred eighteen patients were given 1200 mg of gabapentin and 400 mg of celecoxib 30-60 min before surgery . From the day of surgery until postoperative day 5 , patients documented any use of analgesics and recorded their degree of pain . Results were then compared with those of our previous study in which only celecoxib was used . RESULTS : The combination of gabapentin and celecoxib was found to be significantly superior ( p < 0.001 ) in reducing postoperative pain and opioid requirements than celecoxib alone in the management of postoperative pain and opioid requirements . CONCLUSION : To decrease postoperative opioid requirements , we recommend 400 mg of celecoxib and 1200 mg of gabapentin taken 30-60 min before surgery by patients undergoing subpectoral breast augmentation or a comparable plastic surgery procedure . P35354 inhibitors : do they have a role in emergency department prescribing ? P35354 selective inhibitors ( COXIB or CSI ) have been released with a fanfare as efficacious and safer alternatives to traditional non-steroidal anti-inflammatory drugs . They purport to offer equivalent degrees of analgesia and an improved safety profile . COXIB currently available in Australasia are celecoxib ( DB00482 ) , rofecoxib ( Vioxx ) and etoricoxib ( Arcoxia ) . This review discusses the pharmacology of these agents and reviews recent literature regarding their effectiveness and safety . It endeavours to answer the question ' Should we be using COXIB in emergency departments in Australasia ' ? P35354 inhibition attenuates antibody responses against human papillomavirus-like particles . Vaccination to generate protective humoral immunity against infectious disease is becoming increasingly important due to emerging strains of virus , poorly immunogenic vaccines , and the threat of bioterrorism . We demonstrate that cyclooxygenase-2 ( Cox-2 ) is crucial for optimal Ab responses to a model vaccine , human papillomavirus type 16 virus-like particles ( HPV 16 VLPs ) . Cox-2-deficient mice produce 70 % less IgG , 50 % fewer Ab-secreting cells , and 10-fold less neutralizing Ab to HPV 16 VLP vaccination compared with wild-type mice . The reduction in Ab production by Cox-2(-/-) mice was partially due to a decrease in class switching . SC-58125 , a structural analog of the Cox-2-selective inhibitor DB00482 reduced by approximately 70 % human memory B cell differentiation to HPV 16 VLP IgG-secreting cells . The widespread use of nonsteroidal anti-inflammatory drugs and Cox-2-selective inhibitory drugs may therefore reduce vaccine efficacy , especially when vaccines are poorly immunogenic or the target population is poorly responsive to immunization . DB00482 offers a small protection from root resorption associated with orthodontic movement . Tooth movement results from alveolar bone resorption/deposition following application of orthodontic forces , and root resorption can be an undesirable complication associated with this process . No treatment for external root resorption is available to date . OBJECTIVE : To determine if P35354 inhibitors like DB00482 are effective in protecting root resorption associated with orthodontic forces . METHODS : A force of 80 grams was applied to the left maxillary first molars of 7-week-old female Wistar rats using nickel titanium closed coil springs attached to the cervical area of the incisors with 0.010 stainless-steel ligature wires . Twenty animals were divided into three experimental groups : one receiving no treatment , the second receiving 25mg/kg , and the third receiving 50 mg/kg of celecoxib ( DB00482 ) in their drinking water . Rats were maintained on a soft diet and euthanized two weeks after initial placement of the force . Paraffin-embedded sections of the right ( control ) and left ( experimental ) maxillae were stained with H & E and the areas of root resorption were examined by counting the number of lacunaes in the roots . RESULTS : No difference in the distance of tooth movement ( 0.5 mm/two weeks ) was seen in all three groups . The rats that received the low dose of DB00482 showed no statistically significant difference in root resorption than that of the rats that received no dose . The rats that received the high dose of DB00482 showed a lower number of lacunaes ( mean = 3.5 ) than that of the control group ( mean 10.2 ; p=0.02 ) . CONCLUSIONS : Administration of DB00482 during the application of orthodontic forces does not interfere with tooth movement and appears to offer some slight protection against root resorption . Current application of selective P35354 inhibitors in cancer prevention and treatment . The multistep process of carcinogenesis , which can take many years , provides many opportunities for intervention to inhibit disease progression . Effective chemoprevention agents may reduce the risk of cancer by inhibiting the initiation stage of carcinoma through induction of apoptosis or DNA repair in cells harboring mutations , or they may act to prevent promotion of tumor growth . Similarly , chemoprevention may entail blocking cancer progression to an invasive phenotype . Over the past decade , in vitro , preclinical , and clinical data have supported the hypothesis that cyclooxygenase ( P36551 ) -2 plays a central role in oncogenesis and that treatment with P35354 inhibitors offers an effective chemoprevention strategy , as exemplified by the activity of celecoxib ( DB00482 ) in familial adenomatous polyposis . These P35354 data have contributed to initiation of clinical trials testing P35354 inhibitors for the chemoprevention of a wide variety of cancers that overexpress P35354 . P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104-115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2+ or Ca2+ to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104-115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2+ or Ca2+ . TnC and P62158 in the presence of either Ca2+ or Mg2+ bound to the TnI peptide 104-115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N-terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2+ but , in the presence of Mg2+ , did not bind to TnC and only bound weakly to P62158 . DB00623 bound to TnC and P62158 only in the presence of Ca2+ . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0.1 M DB00974 compared with the 0.01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins. ( ABSTRACT TRUNCATED AT 250 WORDS ) Antitumor properties of dimethyl-celecoxib , a derivative of celecoxib that does not inhibit cyclooxygenase-2 : implications for glioma therapy . Celecoxib ( DB00482 ) appears to be unique among the class of selective P35354 inhibitors ( coxibs ) , because this particular compound exerts a second function that is independent of its celebrated ability to inhibit P35354 . This second function is the potential to inhibit cell proliferation and stimulate apoptotic cell death at much lower concentrations than any other coxibs . Intriguingly , these two functions are mediated by different moieties of the celecoxib molecule and can be separated . The author , as well as others , have generated and investigated analogs of celecoxib that retain only one of these two functions . One derivative , 2,5-dimethyl-celecoxib ( Q6UXB2 ) , which retains the antiproliferative and apoptosis-inducing function , but completely lacks the P35354 inhibitory activity , is able to mimic faithfully all of the numerous antitumor effects of celecoxib that have been investigated so far , including reduction of neovascularization and inhibition of experimental tumor growth in various in vivo tumor models . In view of the controversy that has recently arisen regarding the life-threatening side effects of this class of coxibs , it may be worthwhile to pursue further the potential benefits of drugs such as Q6UXB2 for anticancer therapy . Because Q6UXB2 is not a coxib yet potently maintains celecoxib 's antitumor potential , one may be inclined to speculate that this novel compound could potentially be advantageous in the management of P35354 -independent cancers . In this summary , the implications of recent findings with Q6UXB2 will be presented and discussed . Membranous glomerulopathy and acute interstitial nephritis following treatment with celecoxib . Both membranous glomerulopathy and acute interstitial nephritis have been reported to occur following treatment with non-steroidal anti-inflammatory drugs . We report the first cases of membranous glomerulopathy and acute interstitial nephritis following treatment with celecoxib ( DB00482 ) , a selective P35354 inhibitor . The rapid and complete resolution of both conditions following discontinuation of DB00482 strongly implicates this agent in disease pathogenesis . These cases enlarge the spectrum of potential renal toxicities of the P35354 -specific non-steroidal anti-inflammatory drugs . Acetylbritannilactone suppresses lipopolysaccharide-induced vascular smooth muscle cell inflammatory response . To investigate the mechanism of action by which a new anti-inflammatory active compound , 1-O-acetylbritannilactone ( P00519 ) isolated from Inula britannica-F. , inhibits inflammatory responses in vascular smooth muscle cells ( VSMCs ) . Enzyme immunoassay was used to measure the levels of prostandin E(2) ( PGE(2) ) production . Immunocytochemistry staining and Western blot analysis were performed to detect the nuclear translocation of nuclear factor-kappaB ( NF-kappaB ) p65 and the expression of IkappaB-alpha , pIkappaB-alpha and cyclooxygenase-2 ( P35354 ) . Electrophoretic mobility shift assays ( EMSA ) were used to detect DNA-binding activity of NF-kappaB in VSMCs . P00519 ( 5 , 10 , 20 micrommol/l ) had several concentration-dependent effects , including inhibition of lipopolysaccharide ( LPS ) -induced PGE(2) production and P35354 expression , and blockade of NF-kappaB activation and translocation . These effects were owing to reductions in IkappaB-alpha phosphorylation and degradation induced by LPS . In addition , P00519 directly inhibited the binding of active NF-kappaB to specific DNA cis-element . These results indicate that P00519 is a potent inhibitor of LPS-stimulated VSMC inflammatory responses through blockade of NF-kappaB activity and inhibition of inflammatory gene P35354 expression . Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer . Genomic copy number aberrations ( CNAs ) are believed to play a major role in the development and progression of human cancers . Although many CNAs have been reported in gastric cancer , their genome-wide transcriptional consequences are poorly understood . In this study , to reveal the impact of CNAs on genome-wide expression in gastric cancer , we analysed 30 cases of gastric cancers for their CNAs by array comparative genomic hybridization ( array CGH ) and 24 of these 30 cases for their expression profiles by oligonucleotide-expression microarray . We found that with the application of laser microdissection , most CNAs were detected at higher frequency than in previous studies . Notably , gain at 20q13 was detected in almost all cases ( 97 % ) , suggesting that this may play an important role in the pathogenesis of gastric cancer . By comparing the array CGH data with expression profiles of the same samples , we showed that both genomic amplification and deletion strongly influence the expression of genes in altered genomic regions . Furthermore , we identified 125 candidate genes , consisting of 114 up-regulated genes located in recurrent regions ( > 10 % ) of amplification and 11 down-regulated genes located in recurrent regions of deletion . Up-regulation of several candidate genes , such as Q99741 , P60059 , Q9BTT0 , Q13895 and P37268 , was confirmed by immunohistochemistry . Interestingly , some candidate genes were localized at genomic loci adjacent to well-known genes such as P00533 , P04626 and Q13485 , and concordantly deregulated by genomic alterations . Based on these results , we propose that our list of candidate genes may contain novel genes involved in the pathogenesis of advanced gastric cancer . The role of celecoxib in Rad51 expression and cell survival affected by gefitinib in human non-small cell lung cancer cells . Celecoxib ( DB00482 ) is a cyclooxygenase-2 ( P35354 ) selective inhibitor and gefitinib ( DB00317 (R) , ZD1839 ) is a selective epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitor for human non-small cell lung cancer ( NSCLC ) . The addition of celecoxib to gefitinib to prolong the survival of patients with NSCLC still remains controversial and needs to be investigated . The Rad51 protein is essential for homologous recombination repair , and is overexpressed in chemo- or radioresistant carcinomas . In this study , we characterize the role of celecoxib in the cytotoxicity , P27361 /2 activation and Rad51 expression affected by gefitinib in NSCLC cells . We show that celecoxib can enhance the cytotoxicity induced by gefitinib in NSCLC cells . Treatment with celecoxib alone has no effect on the P27361 /2 activation , Rad51 mRNA and protein levels , however , combined treatment with gefitinib results in a significant reduction of phospho- P27361 /2 and Rad51 protein levels , and triggers the degradation of Rad51 via a 26S proteasome-dependent pathway . Expression of constitutively active Q02750 /2 vectors ( Q02750 /2-CA ) significantly rescues the decreased P27361 /2 activity , and restores Rad51 protein levels and cell survival under co-treatment with gefitinib and celecoxib . Furthermore , blocking P27361 /2 activation by U0126 ( Q02750 /2 inhibitor ) and knocking down Rad51 expression by transfection with small interfering RNA of Rad51 can enhance the cytotoxicity of celecoxib . P35354 inhibitors -- IBC conference . 12-13 April 1999 , Coronado , CA , USA . The introduction of celecoxib ( DB00482 , Figure 1 ; GD Searle and Co ) as the first cyclooxygenase ( P36551 )2 selective inhibitor in the US and the expected introduction of rofecoxib ( Vioxx ; Merck and Co Inc ) as the first P35354 inhibitor with an acute pain indication , has prompted interest in this class of drugs as a possible therapeutic improvement on dual P23219 / P35354 inhibitor NSAIDs , currently on the market . Recognition that the P35354 enzyme may have a broader role than pain and inflammation has led to studies investigating the efficacy of P35354 inhibitors for Alzheimer 's disease ( AD ) , stroke , cardiovascular disease and colon cancer . Speakers at the second annual conference sponsored by IBC , addressed issues ranging from the basic concepts of P35354 specificity versus selectivity , pathways and regulatory factors related to P35354 expression , the principles underlying the possible broad implications of the P35354 mechanisms , as well as summaries of recently completed clinical trials supporting the clinical efficacy and safety of P35354 inhibitors in humans . The timeliness of this meeting is emphasized by the recent approval of rofecoxib by the FDA Arthritis Advisory panel and the initial reports in the media of toxicity attributed to celecoxib . Preclinical and limited clinical data presented suggest possible therapeutic roles for selective P35354 inhibitors in neurodegeneration due to both AD and stroke , the prevention and treatment of colon cancer , prevention of premature labor , as well as pain and inflammation . Docking studies on NSAID/ P35354 isozyme complexes using contact statistics analysis . The selective inhibition of P35354 isozymes should lead to a new generation of NSAIDs with significantly reduced side effects ; e.g. celecoxib ( DB00482 ) and rofecoxib ( Vioxx ) . To obtain inhibitors with higher selectivity it has become essential to gain additional insight into the details of the interactions between P36551 isozymes-and NSAIDs . Although X-ray structures of P35354 complexed with a small number of ligands are available , experimental data are missing for two well-known selective P35354 inhibitors ( rofecoxib and nimesulide ) and docking results reported are controversial . We use a combination of a traditional docking procedure with a new computational tool ( Contact Statistics analysis ) that identifies the best orientation among a number of solutions to shed some light on this topic . Interactive effect of interleukin-6 and prostaglandin E2 on osteoclastogenesis via the O00300 / O14788 / Q9Y6Q6 system . The O00300 / O14788 / Q9Y6Q6 system regulates osteoclastogenesis . Both cyclooxygenase-2 ( P35354 ) /prostaglandin E2 ( DB00917 ) and interleukin-6 ( P05231 ) are reported to induce osteoclast differentiation . The mechanisms underlying these signaling pathways on the O00300 / O14788 / Q9Y6Q6 system are not fully understood . We herein demonstrate that P35354 and DB00917 stimulated osteoclastogenesis through inhibition of O00300 secretion , stimulation of O14788 production by osteoblasts , and upregulation of Q9Y6Q6 expression in osteoclasts . DB00917 also stimulated P05231 production , and P05231 , in turn , increased DB00917 secretion , P35354 , and EP4/EP2 expression in bone cells . These findings provide evidence of interactive effect of DB00917 and P05231 signaling pathways in osteoclastogenesis via effect on the O00300 / O14788 / Q9Y6Q6 system . Approach to angiogenesis inhibition based on cyclooxygenase-2 . Two cyclooxygenase ( P36551 ) isoforms have been identified : P23219 and P35354 . P23219 is the constitutively expressed form of the enzyme and is ubiquitous in its distribution . P35354 is inducible and is present in inflammatory foci , tumors , and neovasculature . Expression of P35354 appears to be important in tumor promotion , growth , and metastasis . It is up-regulated in a variety of premalignant disorders and malignancies . P36551 inhibitors have a major role in the treatment of inflammation and pain . Epidemiologic evidence in patients who take nonsteroidal anti-inflammatory drugs links P36551 inhibition with decreases in malignant esophageal , stomach , colon , lung , and breast tumors . Nonselective P36551 inhibitors have demonstrated efficacy in control of familial adenomatous polyposis , a disorder associated with the development of thousands of benign intestinal polyps . The selective P35354 inhibitor celecoxib ( DB00482 , Pharmacia ) has been shown to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis as an adjunct to usual care . Celecoxib has recently been approved for this indication and offers the potential for equivalent or greater efficacy than that seen with nonselective P36551 inhibitors but without the gastrointestinal mucosal toxicity and the inhibition of platelet function associated with those agents . Angiogenesis is a feature of both benign and malignant disease . Because P35354 is up-regulated in the neovasculature of the rheumatoid pannus and in malignant tumors and their surrounding stroma , selective P35354 inhibitors may be able to modify the progression of these disorders through the control of angiogenesis . Acute generalized exanthematic pustulosis : a case and an overview of side effects affecting the skin caused by celecoxib and other P35354 inhibitors reported so far . A 55-year-old woman who was treated for periarthritis humeroscapularis with celecoxib ( DB00482 ) developed a generalized pustular exanthema on the head and upper trunk , accompanied by fever , leukocytosis and increased erythrocyte sedimentation rate . The histological findings were subcorneal pustules , necrotic keratinocytes , edema in the upper dermis and polymorphic perivascular infiltrates . Four days after stopping celecoxib , the pustules disappeared without any treatment . Four weeks after disappearance of the skin lesions , celecoxib demonstrated a positive lymphocyte stimulation test . In this article , we present to our knowledge the first case of acute generalized exanthematic pustulosis caused by celecoxib , and we give an overview of the side effects affecting the skin caused by celecoxib and other cyclooxygenase type 2 inhibitors reported so far . Celecoxib-induced upper gastrointestinal hemorrhage and ulceration . P35354 inhibitors are a new class of nonsteroidal anti-inflammatory drugs with a reported benefit of less gastric and duodenal ulceration and hemorrhage . We describe a 67-year-old man taking a higher than usual dose of celecoxib ( DB00482 ) for osteoarthritis with resultant gastric erosions , ulceration , and a significant gastrointestinal ( GI ) hemorrhage . Efficacy and safety of repeated dosing of netupitant , a neurokinin-1 receptor antagonist , in treating overactive bladder . AIM : NK-1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double-blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( -13.85 for placebo to -16.17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . DB09048 was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks . Steatohepatitis in laboratory opossums exhibiting a high lipemic response to dietary cholesterol and fat . Plasma VLDL and LDL cholesterol were markedly elevated ( > 40-fold ) in high-responding opossums , but moderately elevated ( 6-fold ) in low-responding opossums after they had consumed a high-cholesterol and high-fat diet for 24 wk . In both high- and low-responding opossums , plasma triglycerides were slightly elevated , threefold and twofold , respectively . Dietary challenge also induced fatty livers in high responders , but not in low responders . We studied the lipid composition , histopathological features , and gene expression patterns of the fatty livers . Free cholesterol ( 2-fold ) , esterified cholesterol ( 11-fold ) , and triglycerides ( 2-fold ) were higher in the livers of high responders than those in low responders , whereas free fatty acid levels were similar . The fatty livers of high responders showed extensive lobular disarray by histology . Inflammatory cells and ballooned hepatocytes were also present , as were perisinusoidal fibrosis and ductular proliferation . In contrast , liver histology was normal in low responders . Hepatic gene expression revealed differences associated with the development of steatohepatitis in high responders . The accumulation of hepatic cholesterol was concomitant with upregulation of the P04035 gene and downregulation of the Q02318 , Q9H221 , and P21439 genes . Genes involved in inflammation ( P01375 , P19838 , and P35354 ) and in oxidative stress ( P13498 and P14598 ) were upregulated . Upregulation of the growth factor genes ( PDGF and P01137 ) and collagen genes ( Col1A1 , Col3A1 , and Col4A1 ) was consistent with fibrosis . Some of the histological characteristics of the fatty livers of high-responding opossums imitate those in the livers of humans with nonalcoholic steatohepatitis . Design of novel potent antihyperlipidemic agents with antioxidant/anti-inflammatory properties : exploiting phenothiazine 's strong antioxidant activity . Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia , oxidative stress , and blood clotting mechanisms , we hereby report the synthesis and evaluation of novel compounds in which antioxidant , anti-inflammatory , and squalene synthase ( P37268 ) inhibitory/hypolipidemic activities are combined in simple molecules through design . The coupling of two different pharmacophores afforded compounds 1-12 , whose biological profile was markedly improved compared to those of parent lead structures ( i.e. , the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa ( or thia ) zine and the antioxidant phenothiazine ) . Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation , exhibiting potent free-radical scavenging activity . They further significantly inhibited P37268 activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia . Finally , several compounds showed anti-inflammatory activity in vitro , inhibiting cycloxygenase ( P23219 /2 ) activity . The multimodal properties of the new compounds and especially their combined antioxidant/ P37268 / P36551 inhibitory activity render them interesting lead compounds for further evaluation against atherosclerosis . Where is the evidence that cyclooxygenase inhibition is the primary cause of nonsteroidal anti-inflammatory drug ( NSAID ) -induced gastrointestinal injury ? Topical injury revisited . In this commentary , we take a critical look at the concept that the gastrointestinal ( GI ) side-effects of nonsteroidal anti-inflammatory drugs ( NSAIDs ) are due to the ability of these drugs to inhibit cyclooxygenase-1 ( P23219 ) that is constitutively expressed in the GI mucosa . Indeed , development of the new " super aspirins , " such as DB00482 and Vioxx , that selectively inhibit the inducible P35354 , expressed in areas of inflammation , is a direct outgrowth of this concept . We discuss evidence from both the laboratory and the clinic that appears to be inconsistent with the above concept , and cite a number of examples where the depletion of mucosal prostaglandin levels and the development of GI injury can be dissociated . Instead , we revisit the possibility that NSAID-induced GI side-effects are mostly due to the ability of these drugs to topically injure the GI mucosa . We devote the remainder of the commentary to presenting evidence from our and other laboratories that NSAIDs can directly attenuate the surface hydrophobic barrier of the GI mucosa due to their ability to bind to zwitterionic phospholipids , and that even systemically administered NSAIDs that are secreted into the bile may induce GI ulceration and/or bleeding due to phospholipid interactions and the development of topical mucosal injury . P35354 inhibitors : a story of greed , deception and death . In 1999 , drug manufacturers introduced a class of NSAIDs called P35354 inhibitors or coxibs . The drugs were avidly promoted directly to the consumers and became bestsellers from the start . Arthritis sufferers were eager to take medications that eased joint pain with less risk of causing gastrointestinal pain , bleeding and other side-effects . In the year after their introduction , doctors wrote over 100 million prescriptions for celecoxib ( DB00482 ) and rofecoxib ( Vioxx ) . DB00482 is the sixth best-selling drug , with sales of more than US $ 4 billion since its debut in 1999 . Vioxx had sales of US $ 2.6 billion in 2001 . However , the coxibs increase the risk of heart attacks and strokes , and their price , in the USA , is obscene . The manufacturers faced a possibly complicit , toothless and bloodless FDA , and used every maneuvering to fleece the patients . We must now reflect on attitudes that we thought only belong to the tobacco industry . Fortunately , safe and active alternatives exist . P35354 inhibition in clinical cancer prevention . Colorectal cancer is an excellent model for studying cancer prevention by means of secondary ( e.g. , polypectomy to remove a precursor adenoma ) and primary ( chemoprevention ) strategies . Evidence has shown that regular users of aspirin and other nonsteroidal anti-inflammatory drugs ( NSAIDs ) have a reduction in risk of colorectal cancer . A possible mechanism of this benefit is decreased prostaglandin production , which is achieved through inhibition of cyclooxygenase ( P36551 ) activity , and possibly other pathways . Two isoforms of P36551 -- P23219 and P35354 -- have been identified . P35354 is expressed in colorectal adenomas and carcinomas , both in humans and rodents . Inhibition of P35354 has been shown to decrease the incidence of carcinogen-induced neoplasia in rats and to lower the incidence of adenomas in murine models . Several P35354 inhibitors , with the potential for less toxicity than that associated with traditional NSAIDs , are under development . This paper reviews potential chemoprevention of colorectal cancer using P35354 inhibitors in patients at increased risk , e.g. , patients with familial adenomatous polyposis , hereditary nonpolyposis colorectal cancer , and sporadic adenomas . Included are the rationale for use of such agents , results of a study showing a significant reduction in adenoma burden in familial adenomatous polyposis patients who received the selective P35354 inhibitor celecoxib ( DB00482 ) , and the design of other ongoing or planned clinical trials . Activation of c-Jun-N-terminal-kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor DB00712 and its-in terms of P36551 -inhibition- " inactive " enantiomer R-flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R- and DB00712 reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT-15 , no P35354 ; Caco-2 , inducible P35354 ; and HT-29 , constitutive P35354 ) . The IC50 for S- and R-flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA- and PARP-cleavage . In addition , R- and DB00712 caused a P55008 -cell cycle block . The latter was associated with an activation of c-Jun N-terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP-1 and down-regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP-1 activation was associated with a change of AP-1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R- and DB00712 -induced AP-1 DNA binding , suppression of cyclin D1 expression , and the P55008 -cell cycle block . However , JNK inhibition had no effect on flurbiprofen-induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK-activation , whereas R- and DB00712 -induced apoptosis is largely independent of JNK . Although in vitro effects of R- and DB00712 were indistinguishable , only R-flurbiprofen inhibited HCT-15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R- and DB00712 . P11511 inhibitors and cyclooxygenase-2 ( P35354 ) inhibitors in endometriosis : new questions -- old answers ? The medical treatment of endometriosis needs to be optimized . Therapeutic management strategies for endometriosis-associated pain or recurrent disease are primarily aimed at downregulating ovarian function or antagonizing the effect of estrogen in ectopic endometrial implants . In this context , basic research is providing important results for the development of new , specific treatment modalities . P11511 overexpression has recently been detected in endometriotic tissue . P11511 ( p450arom ) is responsible for converting C19 androgens into estrogen in several types of human tissue . P11511 activity causes local estrogen biosynthesis , which , in turn , stimulates prostaglandin E2 production by upregulating cyclooxygenase-2 ( P35354 ) . Thus , a positive feedback cycle develops between the two systems . Another abnormality in endometriosis , the deficient 17beta-hydroxysteroiddehydrogenase type II ( 17beta-HSD-Type-II ) expression , impairs the inactivation of estradiol to estrone . In contrast to the eutopic endometrium , these molecular aberrations increase the amount of local estradiol and prostaglandin E2 in endometriosis . In several human cell lines , prostaglandin and estrogen concentrations are associated with proliferation , migration , angiogenesis , apoptosis resistance and even invasiveness . Consequently , aromatase and P35354 are thought to be promising new therapeutic targets . Thus , specific aromatase inhibitors ( e.g. DB01006 / DB01006 , DB01217 /Arimidex or Exemestan/Aromasin ) or selective P35354 inhibitors ( e.g. Celecoxib/ DB00482 , DB00533 /Vioxx , DB00580 /Bextra ) are of great interest and should be studied in clinical trials in premenopausal woman with endometriosis to expand the spectrum of currently available treatment options . Celecoxib and radiation therapy in non-small-cell lung cancer . Overexpression of cyclooxygenase-2 ( P35354 ) is frequently present in lung cancer and may play a significant role in carcinogenesis , invasion , and metastasis . It has been associated with shortened survival in patients with resected early-stage adenocarcinoma of the lung . P35354 inhibition decreases tumor cell proliferation in vivo and has been shown to enhance tumor radiosensitivity . Additionally , P35354 inhibition may protect normal pulmonary tissue from radiation fibrosis . Clinical studies are under way to assess the potential benefits and risks of P35354 inhibition in the treatment of lung cancer . The rationale for P35354 inhibitors in the treatment of lung cancer will be reviewed . The results of a phase II study assessing the acute toxicity of concurrent celecoxib ( DB00482 ) and thoracic irradiation in patients with non-small-cell lung cancer ( NSCLC ) are reported , and an ongoing Radiation Therapy Oncology Group study using celecoxib and concurrent radiation therapy for NSCLC in patients with intermediate prognostic factors is reviewed . [ The effects of DB00482 on mammary tumorigenesis and aging in P04626 /neu transgenic mice ] . It is well known that cyclooxygenase-2 ( P35354 ) plays an important role in the development of many tumors including breast cancer . Our study was concerned with evaluating the effects of the selective P35354 inhibitor , celecoxib , on mammary tumorigenesis and aging in P04626 /neu transgenic mice ( 24 ) . Celecoxib ( celebrex ) 25 mg/kg was administered 5 times a week from the age of 2 months . Twenty-four intact females were in control . Monitoring kept track of tumor detection time , size , presence of lung metastases , food and water consumption , estral function , body weight and temperature . No significant differences between the two groups were reported as far as life-span , tumor growth rate , size and number of metastases to the lung is concerned . To sum up , celecoxib treatment failed to produce any significant effect on carcinogenesis in P04626 /neu transgenic mice . DB00917 produced by lung cancer suppresses immune function through T-regulatory cells and can be blocked by the P35354 inhibitor DB00482 . DB01095 enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type-1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high-cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg/kg per day of valsartan nor 3 mg/kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0.1 mg/kg per day and 1 mg/kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein-1 , and intercellular adhesion molecule-1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol-related effects . P00734 kringle-2 induces death of mesencephalic dopaminergic neurons in vivo and in vitro via microglial activation . We have shown that prothrombin kringle-2 ( pKr-2 ) , a domain of human prothrombin distinct from thrombin could activate cultured rat brain microglia in vitro . However , little is known whether pKr-2-induced microglial activation could cause neurotoxicity on dopaminergic ( DA ) neurons in vivo . To address this question , pKr-2 was injected into the rat substantia nigra ( SN ) . Tyrosine hydroxylase ( TH ) immunohistochemistry experiments demonstrate significant loss of DA neurons seven days after injection of pKr-2 . In parallel , pKr-2-activated microglia were detected in the SN with OX-42 and OX-6 immunohistochemistry . Reverse transcription PCR and double-label immunohistochemistry revealed that activated microglia in vivo exhibit early and transient expression of inducible nitric oxide synthase ( P35228 ) , cyclooxygenase-2 ( P35354 ) and several proinflammatory cytokines . The pKr-2-induced loss of SN DA neurons was partially inhibited by the NOS inhibitor N(G)-nitro-L-arginine methyl ester hydrochloride , and the P35354 inhibitor DuP-697 . P27361 /2 , c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were activated in the SN as early as 1 hr after pKr-2 injection , and localized within microglia . Inhibition of these kinases led to attenuation of mRNA expression of P35228 , P35354 and several proinflammatory cytokines , and rescue of DA neurons in the SN . Intriguingly , following treatment with pKr-2 in vitro , neurotoxicity was detected exclusively in co-cultures of mesencephalic neurons and microglia , but not microglia-free neuron-enriched mesencephalic cultures , indicating that microglia are required for pKr-2 neurotoxicity . Our results strongly suggest that microglia activated by endogenous compound(s) , such as pKr-2 , are implicated in the DA neuronal cell death in the SN . Molecular dynamics simulations of arachidonic acid-derived pentadienyl radical intermediate complexes with P23219 and P35354 : insights into oxygenation regio- and stereoselectivity . The two cyclooxygenase enzymes , P23219 and P35354 , are responsible for the committed step in prostaglandin biosynthesis and are the targets of the nonsteroidal antiinflammatory drugs aspirin and ibuprofen and the P35354 selective inhibitors , DB00482 , Vioxx , and Bextra . The enzymes are remarkable in that they catalyze two dioxygenations and two cyclizations of the native substrate , arachidonic acid , with near absolute regio- and stereoselectivity . Several theories have been advanced to explain the nature of enzymatic control over this series of reactions , including suggestions of steric shielding and oxygen channeling . As proposed here , selective radical trapping and spin localization in the substrate-derived pentadienyl radical intermediate can also be envisioned . Herein we describe the results of explicit , 10 ns molecular dynamics simulations of both P23219 and P35354 with the substrate-derived pentadienyl radical intermediate bound in the active site . The enzymes ' influence on the conformation of the pentadienyl radical was investigated , along with the accessible space above and below the radical plane and the width of several channels to the active site that could function as access routes for molecular oxygen . Additional simulations demonstrated the extent of molecular oxygen mobility within the active site . The results suggest that spin localization is unlikely to play a role in enzymatic control of this reaction . Instead , a combination of oxygen channeling , steric shielding , and selective radical trapping appears to be responsible . This work adds a dynamic perspective to the strong foundation of static structural data available for these enzymes . A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re-vascularization . RATIONALE : Rescuing adverse myocardial remodeling is an unmet clinical goal and , correspondingly , pharmacological means for its intended reversal are urgently needed . OBJECTIVES : To harness a newly-developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling . METHODS AND RESULTS : A P15692 -based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure . Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy , enlarged LV size and improve cardiac function was monitored . Arguing for clinical relevance of the experimental system , clinically-used drugs operating on the P00797 -Angiotensin- DB04630 -System ( RAAS ) , namely , the P12821 inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling . Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point-of-no-return . Similarly , the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature . Extending the arsenal of remodeling-reversing drugs to pathways other than RAAS , a specific inhibitor of 11β-hydroxy-steroid dehydrogenase type 1 ( 11β HSD1 ) , a key enzyme required for generating active glucocorticoids , fully rescued myocardial hypertrophy . This was associated with mitigating the hypertrophy-associated gene signature , including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization-induced reversal . CONCLUSIONS : A system was developed suitable for identifying novel remodeling-reversing drugs operating in different pathways and for gaining insights into their mechanisms of action , exemplified here by uncoupling their vascular affects . [ Selective inhibitors of type 2 cyclooxygenase : less renal effects than the classical non-steroidal anti-inflammatory agents ] . Prostaglandins play an important role in the regulation of renal hemodynamics and sodium excretion . Thus , the administration of non-steroidal anti-inflammatory drugs ( NSAIDs ) induces a renal vasoconstriction and sodium and potassium retention . In some high risk patients , this may lead to acute renal failure . The anti-inflammatory and renal effects of conventional NSAIDs are mediated by the non-selective inhibition of two cyclo-oxygenases , P23219 and P35354 . Recently , highly selective P35354 inhibitors have been developed such as celecoxib ( DB00482 ) and rofecoxib ( Vioxx ) . These drugs were designed to preserve the analgesic and anti-inflammatory properties of NSAIDs while reducing their gastro-intestinal and renal side effects . Selective P35354 inhibitors have indeed less gastro-intestinal side-effects . However , their renal profile is comparable to that of non-selective inhibitors as they induce a decrease in glomerular filtration rate and a sodium and potassium retention . Thus , despite the good gastro-intestinal safety profile of selective P35354 , one should be careful with the use of these agents in high risk patients as they may induce similar renal complications as non-selective NSAIDs . Anti-angiogenic effects of Hypericin-photodynamic therapy in combination with DB00482 in the treatment of human nasopharyngeal carcinoma . Photodynamic therapy ( PDT ) is being investigated as an alternative treatment modality in cancer treatment . It has been shown to induce tumor hypoxia and upregulation of cyclooxygenase-2 ( P35354 ) and vascular endothelial growth factor ( P15692 ) . The objective of this study was to improve in vivo tumor growth control of nasopharyngeal carcinoma ( NPC ) , treated at a subcurative dosage by using a combination of Hypericin-PDT and P35354 inhibitor , DB00482 ( CX ) . The effect of an initial CX dose at 6- and 24-h post-PDT was investigated simultaneously . It was observed that hypoxic NPC/CNE2 cells upregulate both P35354 and P15692 A genes in vitro . In vivo studies , down-regulation of P35354 and hypoxia inducible factor-1alpha ( HIF-1alpha ) genes at 24-h post-PDT and bulk tumor ablation at 48-h post-PDT was observed . However , 24-28 days later regrowth was observed . In a combination treatment , 1st CX dose at 6-h post-PDT had the highest tumor control in which tumors were < or=0.52 cm(3) ( 64.29 % , P < 0.05 ) . However , the tumors administered with a initial dose of CX at 24-h post-PDT had no tumor control . Co-suppression of P35354 , HIF-1alpha and P15692 A genes were observed in tumors with tumor control . Mice without tumor control that were subjected to therapy had increased human P15692 in serum compared to Hypericin-PDT mice . Thus , suggesting that the time of initial administration of CX post-PDT is an important factor for effective tumor control . A triple combination of atorvastatin , celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors . Because K-Ras mutation and cyclooxygenase-2 ( P35354 ) overexpression are hallmarks of majority of pancreatic cancer patients , an approach to inhibit the progression and growth of pancreatic cancer using the simultaneous administration of agents that inhibit the function of both targets , should be considered . In the present study , we assessed the effects of atorvastatin ( Lipitor ) , celecoxib ( DB00482 ) and tipifarnib ( DB04960 ) on the growth of human pancreatic cancer . In the in vitro studies , we found that treatment of human pancreatic tumor cells with a combination of atorvastatin , celecoxib and tipifarnib had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs . We also found that treatment of Panc-1 cells with a combination of all three drugs strongly decreased the levels of phosphorylated Erk1/2 and Akt . In an animal model of xenograft tumors in severe combined immunodeficient ( SCID ) mice , we found that daily i.p. injections of a combination of atorvastatin , celecoxib and tipifarnib had a stronger inhibitory effect on the growth of the tumors in mice than each drug alone or for any combination of two drugs . The results of our study indicate that a combination of atorvastatin , celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer . Selective P35354 inhibitors and the surgical patient . The identification of P35354 less than a decade ago has been followed by an unprecedented period of discovery and drug development ( Golden & Abramson , 1999 ) . Clinical studies thus far have established that the selective P35354 inhibitors , celecoxib ( DB00482 ) and rofecoxib ( Vioxx ) are effective in the treatment of OA and RA , as are conventional NSAIDs . However , they do not cause the same adverse effects on the GI mucosa nor do they increase bleeding time as do conventional NSAIDs . Therefore , their use is not contraindicated in pre or postsurgical patients . Further investigation is underway to fully elucidate the role of P35354 and to determine any additional benefits of selective P35354 inhibition . Synergism between bosutinib ( DB06616 ) and the Chk1 inhibitor ( PF-00477736 ) in highly imatinib-resistant P11274 /ABL⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib-resistant cells , including those with the T315I mutation . Bosutinib blocked PF-00477736-induced P27361 /2 activation and sharply increased apoptosis in association with Mcl-1 inhibition , p34(cdc2) dephosphorylation , BimEL up-regulation , and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF-0047736 lethality . Bosutinib/PF-00477736 co-treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph(+) ALL . Anti-inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n-butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1,1-diphenyl-2-picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti-angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan-induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid-induced vascular permeability and caused a dose-dependent inhibition on acetic acid-induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase-2 ( P35354 ) in lipopolysaccharide ( LPS ) -stimulated macrophages were also assessed . Among the fractions , the n-butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti-angiogenic , anti-inflammatory and anti-nociceptive activities through its inhibition of NO production and P35354 expression and/or its antioxidative activity . Drug insight : cyclo-oxygenase 2 inhibitors and cardiovascular risk -- where are we now ? Cyclo-oxygenase ( P36551 ) 1 mediates the production of thromboxane A2 in platelets , leading to platelet aggregation and vasoconstriction . Conversely , P35354 catalyzes endothelial prostacyclin synthesis , which effectively counteracts thromboxane A2 , triggering vasodilation and platelet inhibition . Selective P35354 inhibitors decrease prostacyclin production , potentially disrupting homeostasis and creating a prothrombotic state . The VIGOR study findings of increased cardiovascular risk with rofecoxib were subsequently confirmed by large meta-analyses , observational studies and recent APPROVe trial publication . The P25054 trial findings of increased cardiovascular risk with DB00482 ( celecoxib ) conflict with those in the ADAPT trial , the upcoming PreSAP publication , a case-control study by Graham et al. and prior large clinical trials , meta-analyses and observational studies of this drug . Therefore , while an adverse class effect is a possibility for P35354 inhibitors , the published data are inconsistent . Baseline cardiovascular risk in patients might contribute significantly to these findings . In light of the negative Vioxx ( rofecoxib ) publicity , however , P35354 inhibitors might forever remain underinvestigated . The relative selectivity of these compounds for P35354 is extremely variable , casting significant doubt on the class-effect hypothesis . Improved endothelial function has also been reported with celecoxib , leading to endothelium-dependent vasodilation , and associated decreases in P02741 and LDL cholesterol . The addition of meloxicam to low-dose aspirin and heparin has improved clinical outcomes after acute coronary syndromes . These are the first studies suggesting improvement in endothelial function and reduction of inflammation with P35354 inhibition . Thus , more randomized controlled trials are needed to study the relative cardiovascular effects of different P35354 inhibitors , alone and in combination with aspirin . Are rofecoxib and celecoxib safer NSAIDS ? NSAIDs work by inhibiting the enzyme cyclo-oxygenase ( P36551 ) , responsible for prostaglandin synthesis . This enzyme exists in two isoforms , P23219 and P35354 . Inhibition of P23219 is thought to be the main cause of the gastrointestinal unwanted effects of NSAIDs , whilst inhibition of P35354 results in anti-inflammatory effects . [ symbol : see text ] DB00533 ( Vioxx -- MSD ) and [ symbol : see text ] celecoxib ( DB00482 -- Searle ) have been developed as selective inhibitors of P35354 . DB00533 is licensed for the symptomatic treatment of osteoarthritis , but not for rheumatoid arthritis . The manufacturer claims that " in clinical studies rofecoxib inhibits P35354 but not P23219 " , has " the power of high-dose NSAIDs -- diclofenac and ibuprofen " and " superior GI safety profile compared to conventional NSAIDs " . Celecoxib is licensed for symptom relief in osteoarthritis and rheumatoid arthritis . The manufacturer claims that celecoxib has " comparable efficacy and superior GI tolerability when compared to diclofenac or naproxen " . Here , we review rofecoxib and celecoxib and consider whether they are safer than conventional NSAIDs . Inhibition of delayed rectifier potassium channels and induction of arrhythmia : a novel effect of celecoxib and the mechanism underlying it . Selective inhibitors of cyclooxygenase-2 ( P35354 ) , such as rofecoxib ( Vioxx ) , celecoxib ( DB00482 ) , and valdecoxib ( Bextra ) , have been developed for treating arthritis and other musculoskeletal complaints . Selective inhibition of P35354 over P23219 results in preferential decrease in prostacyclin production over thromboxane A2 production , thus leading to less gastric effects than those seen with nonselective P36551 inhibitors such as acetylsalicylic acid ( aspirin ) . Here we show a novel effect of celecoxib via a mechanism that is independent of P35354 inhibition . The drug inhibited the delayed rectifier ( Kv2 ) potassium channels from Drosophila , rats , and humans and led to pronounced arrhythmia in Drosophila heart and arrhythmic beating of rat heart cells in culture . These effects occurred despite the genomic absence of cyclooxygenases in Drosophila and the failure of acetylsalicylic acid , a potent inhibitor of both P23219 and P35354 , to inhibit rat Kv2.1 channels . A genetically null mutant of Drosophila Shab ( Kv2 ) channels reproduced the cardiac effect of celecoxib , and the drug was unable to further enhance the effect of the mutation . These observations reveal an unanticipated effect of celecoxib on Drosophila hearts and on heart cells from rats , implicating the inhibition of Kv2 channels as the mechanism underlying this effect . [ A pop-up menu linked to a computerized drug prescribing system. Prescribing pattern 's feedback via a simple and quick method ] . It takes time for a GP to acquire sufficient experience of a new drug to be able to prescribe competently . This article describes a project studying the use of computerized records to afford a group of GP 's swift feedback on recently introduced drugs of special interest . In the south-east of Sweden a network of primary health care centers has been created in two neighboring counties . The pharmacies of the region are also taking part . When new drugs of particular interest are introduced , each participating GP will automatically see a pop-up menu , asking questions pertaining to each computer-assisted prescription . In the pharmacies , patients are given a questionnaire regarding their expectations with respect to the drug . In this way it will be possible to provide the individual GP swift feedback from a large number of colleagues and patients concerning the drug 's effectiveness in clinical practice . We have now been studying the P35354 inhibitors rofecoxib ( Vioxx ) and celecoxib ( DB00482 ) . Results show that a pop-up menu used in this way provides the general practitioner quick feed-back on prescribing behavior as well as drug effectiveness in clinical practice . P35354 inhibitors : better than traditional NSAIDs ? Vioxx and DB00482 may be no less risky than NSAIDs . Plasma levels of vascular endothelial growth factor during and after radiotherapy in combination with celecoxib in patients with advanced head and neck cancer . DB00482 and radiotherapy in advanced head and neck cancer . This phase I dose-escalation study seeks to determine the phase II recommended dose of cyclooxygenase type 2 ( P35354 ) inhibitor in patients with locally advanced squamous cell head and neck ( H & N ) cancer , treated with accelerated radiotherapy . Anti-vasculogenic effect of this treatment on serum vascular endothelial growth factor ( P15692 ) is examined . Patients were irradiated with curative intent ( 72Gy in 6weeks ) . Celecoxib was administered throughout the radiotherapy course . Serum P15692 level were tested during radiotherapy and in follow-up . Tumor specimens were stained to quantify the P35354 expression . Thirty-two patients completed the treatment . The dose of celecoxib was escalated ( 200 , 400 and 800mg bid , then de-escalated to 600mg bid ) . The acute toxicity related to the treatment in the first and second cohort did not reach grade III ; in the third cohort three patients had grade III radiation toxicity and one had celecoxib-related toxicity . In the last fourth cohort the toxicity was acceptable . Significant P15692 level drop ( p=0.011 ) was found between radiation day 1 and post-treatment visit . Significant decrease ( p=0.022 ) of the P15692 level was shown in patients with high P35354 expression in the tumor . Phase II recommended dose of celecoxib combined with accelerated radiotherapy in advanced H & N cancer was 600mg bid . A significant decrease of the post-treatment serum P15692 level compared to the initial level was noticed only in patients with high P35354 expression in tumors . P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin-angiotensin system and toll-like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E-deficient ( ApoE(-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four-wk-old ApoE(-/-) mice were fed a high-fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . DB09026 reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . DB09026 also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein-1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren-mediated vasculoprotective effect in the ApoE(-/-) mice , but aliskiren showed no further benefits in ApoE(-/-) CatS(-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or/and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE(-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R/ O60603 -mediated CatS activation and activity , thus regressing advanced atherosclerosis . Combination of Lipitor and DB00482 inhibits prostate cancer VCaP cells in vitro and in vivo . BACKGROUND/AIM : Lipitor is a cholesterol-lowering drug and DB00482 is a P35354 inhibitor . We investigated the effects of Lipitor and DB00482 on human prostate cancer VCaP cells cultured in vitro and grown as orthotopic xenograft tumors in SCID mice . MATERIALS AND METHODS : Apoptosis was measured by morphological assessment and caspase-3 assay . Nuclear factor-kappa B ( NF-κB ) activation was determined by luciferase reporter assay . B-cell lymphoma-2 ( Bcl2 ) was measured by western blotting and immunohistochemistry . Orthotopic prostate tumors were monitored by the IVIS imaging system . RESULTS : the combination of Lipitor and DB00482 had stronger effects on the growth and apoptosis of VCaP cells than did either drug alone . The combination more potently inhibited activation of NFκB and expression of Bcl2 than either drug alone . The growth of orthotopic VCaP prostate tumors was strongly inhibited by treatment with the drug combination . CONCLUSION : Administration of Lipitor and DB00482 in combination may be an effective strategy for inhibiting the growth of prostate cancer . Initial experience combining cyclooxygenase-2 inhibition with chemoradiation for locally advanced pancreatic cancer . Pancreatic cancer is a lethal disease that is resistant to chemotherapy and radiotherapy . Gemcitabine has recently been shown to be an improvement over 5-fluorouracil in patients with advanced disease . It is also a potent radiosensitizer , which has led to the investigation of gemcitabine with concurrent radiotherapy . However , preliminary results indicate that there are significant limitations to this approach in this challenging disease . Pancreatic cancer cells have alterations in many molecular signaling pathways that may be responsible for their resistance to cytotoxic therapy and aggressive behavior . P35354 ( P35354 ) is commonly overexpressed in pancreatic tumors , and preclinical evidence indicates that selective P35354 inhibition enhances both chemotherapy and radiotherapy response , without affecting normal tissue damage . We have initiated preclinical studies as well as a phase I clinical protocol evaluating the combination of gemcitabine and celecoxib ( DB00482 ) with radiotherapy . In preclinical studies , celecelecoxib strongly enhanced the antitumor efficacy of chemoradiation . However , preliminary observations from both the preclinical experiments as well as the clinical protocol have revealed more toxicity with this combination than with gemcitabine and radiotherapy alone . These observations require further study , but are cause for concern when combining gemcitabine , radiotherapy , and celecoxib . Celecoxib and melatonin in prevention of female rat mammary carcinogenesis . The present experiment aims to evaluate tumor suppressive effects of a selective inhibitor of cyclooxygenase-2 ( P35354 ) celecoxib ( DB00482 , Pfizer ) administered alone and in combination with melatonin in the prevention of N-methyl-N-nitrosourea ( P48645 ) -induced mammary carcinogenesis in Sprague-Dawley female rats . Celecoxib was administered daily at a concentration of 1.666 g/kg diet to two groups during 20 weeks ( starting a week before first P48645 application ) . A combination of celecoxib and melatonin applied in drinking water ( 20 microg/ml drinking water ) , daily from 15:00 to 08:00 hours was administered to the second group . The anticarcinogenic effects of chemopreventive drugs were compared with control ( P48645 ) animals . Celecoxib administration decreased mammary tumor incidence ( by 24 % ) , while combination of celecoxib and melatonin decreased tumor incidence even more significantly ( -30 % ) . Significant decrease in tumor frequency per group was recorded in both groups with chemoprevention : celecoxib alone ( -54 % ) and combination of celecoxib and melatonin ( -64 % ) . Celecoxib significantly influenced tumor frequency per animal in the group with combination of both protective substances ( -52 % ) . Celecoxib administration resulted in prolonged latency by 3 % , and by 13 % in the group with combination of both protective substances . These results confirm preventive effects of celecoxib in induced rat mammary carcinogenesis . The administration of isolated P61006 had only lesser effect , but in the combination with CELE revealed some potentiating influence in mammary carcinogenesis inhibition . The present study is the first to prove efficacy of the above-mentioned celecoxib and melatonin intake . Our results point to the need for a deeper analysis of coxib efficacy in human carcinogenesis . Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 -vector . Transfection was performed by electroporation with an pCMX-GFP and pCMX-VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7(th) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer-assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs. control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 . Transgenic Panax ginseng inhibits the production of P01375 , P05231 , and P10145 as well as P35354 expression in human mast cells . The most well-known medicinal plant , Panax ginseng ( P. ginseng ) , contains various phytosterols and bioactive triterpene saponins ( ginsenosides ) . P37268 is a key regulatory enzyme for triterpene biosynthesis and overexpression of the squalene synthase confers the hyper-production of triterpene saponins to form transgenic ginseng . In this study , we have investigated whether and how transgenic P. ginseng modulates an inflammatory reaction in a stimulated human mast cell line , HMC-1 . It was found that transgenic P. ginseng inhibited the production of tumor necrosis factor ( P01375 ) -alpha , interleukin ( IL ) -6 , P10145 , and the expression of cyclooxygenase-2 in phorbol 12-myristate 13-acetate ( PMA ) plus calcium ionophore A23187 ( PMACI ) -stimulated HMC-1 . Additionally , we have shown that transgenic P. ginseng suppressed the intracellular calcium level induced by PMACI . These results provide new insights into the pharmacological actions of transgenic P. ginseng as a potential molecule for use in therapy in mast cell-mediated inflammatory diseases . Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA-approved nitrogen-containing bisphosphonate ( N-BP ) drug , at the molecular level . DB00630 not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell-induced osteoclasts and the preosteoblast MC3T3-E1 cell line were used to assess effects of anti-FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum-based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast-mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways . A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro . Statins and nitrogenous bisphosphonates ( NBP ) inhibit 3-hydroxy-3-methylglutaryl-coenzyme-A reductase ( P04035 ) and farnesyl diphosphate synthase ( P14324 ) , respectively , leading to depletion of farnesyl diphosphate ( FPP ) and disruption of protein prenylation . P37268 ( P37268 ) utilizes FPP in the first committed step from the mevalonate pathway toward cholesterol biosynthesis . Herein , we have identified novel bisphosphonates as potent and specific inhibitors of P37268 , including the tetrasodium salt of 9-biphenyl-4,8-dimethyl-nona-3,7-dienyl-1,1-bisphosphonic acid ( compound 5 ) . Compound 5 reduced cholesterol biosynthesis and lead to a substantial intracellular accumulation of FPP without reducing cell viability in HepG2 cells . At high concentrations , lovastatin and zoledronate impaired protein prenylation and decreased cell viability , which limits their potential use for cholesterol depletion . When combined with lovastatin , compound 5 prevented lovastatin-induced FPP depletion and impairment of protein farnesylation . Compound 5 in combination with the NBP zoledronate completely prevented zoledronate-induced impairment of both protein farnesylation and geranylgeranylation . Cotreatment of cells with compound 5 and either lovastatin or zoledronate was able to significantly prevent the reduction of cell viability caused by lovastatin or zoledronate alone . The combination of an P37268 inhibitor with an P04035 or P14324 inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletion . DB06643 for joints and bones . DB06643 is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . DB06643 suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . DB06643 reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo . Toll-like receptor expression in human keratinocytes : nuclear factor kappaB controlled gene activation by Staphylococcus aureus is toll-like receptor 2 but not toll-like receptor 4 or platelet activating factor receptor dependent . Cultured primary human keratinocytes were screened for their expression of various members of the toll-like receptor ( TLR ) family . Keratinocytes were found to constitutively express Q15399 , O60603 , O15455 , O60602 , and Q9NR96 but not O00206 , Q9Y2C9 , Q9NYK1 , Q9NR97 , or Q9BXR5 as shown by polymerase chain reaction analysis . The expression of the crucial receptor for signaling of staphylococcal compounds O60603 was also confirmed by immunohistochemistry , in contrast to O00206 , which showed a negative staining pattern . Next , we analyzed the activation of the proinflammatory nuclear transcription factor kappaB by Staphylococcus aureus strain 8325-4 . Using nuclear extract gel shifts , RelA staining , and luciferase reporter transfection plasmids we found a clear induction of nuclear factor kappaB translocation by the bacteria . This translocation induced the transcription of nuclear factor kappaB controlled genes such as inducible nitric oxide synthetase , P35354 , and interleukin-8 . Transcription of these genes was followed by production of increased amounts of interleukin-8 protein and NO . Inhibition experiments using monoclonal antibodies and the specific platelet activating factor receptor inhibitor CV3988 showed that nuclear factor kappaB activation by S. aureus was O60603 but not O00206 or platelet activating factor receptor dependent . In line , the purified staphylococcal cell wall components lipoteichoic acid and peptidoglycan , known to signal through O60603 , also showed nuclear factor kappaB translocation in human keratinocytes , indicating a crucial role of the staphylococcal cell wall in the innate immune stimulation of human keratinocytes . These results help to explain the complex activation of human keratinocytes by S. aureus and its cell wall components in various inflammatory disorders of the skin . Regional expression and role of cyclooxygenase-2 following experimental traumatic brain injury . Prostaglandins , potent mediators of inflammation , are generated from arachidonic acid ( AA ) via the action of cyclooxygenase-1 and -2 ( P23219 and P35354 ) . In this study , we report that lateral cortical impact injury in rats significantly increases P35354 protein levels both in the cortex surrounding the injury site and the ipsilateral hippocampus . P35354 protein level was elevated as early as 3 h postinjury and persisted for up to 3 days . Increases in immunoreactivity were detected not only in the adjacent cortex and hippocampus , but were also observed in the contralateral cortex and hippocampus , the ipsilateral piriform cortex and the ipsilateral amygdaloid complex . P35354 immunoreactive cells appear morphologically normal and do not present any of the characteristic features of apoptosis . Double immunostaining experiments using either a neuron-specific or an astroglial-specific marker show that the expression of P35354 is localized almost exclusively in neuronal cells . Administration of the P35354 inhibitor 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfona mide ( celecoxib , marketed as DB00482 ) worsens motor , but not cognitive , performance , suggesting that P35354 induction following traumatic brain injury may play a protective role .