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Nonaspirin NSAIDs, Cyclooxygenase 2 Inhibitors, and the Risk for Stroke.
Stroke. 2008 Apr 24;
Roumie CL, Mitchel EF, Kaltenbach L, Arbogast PG, Gideon P, Griffin MR
BACKGROUND AND PURPOSE: There is limited information regarding the cerebrovascular safety of cyclooxygenase 2 inhibitors (coxibs) and noncoxib nonsteroidal antiinflammatory drugs (NSAIDs). We determined whether specific NSAIDs, including coxibs, are associated with risk of stroke. METHODS: Retrospective cohort study among Tennessee Medicaid enrollees aged 50 to 84 years between January 1, 1999 and December 31, 2004. Noninstitutionalized persons with continuous enrollment in Medicaid and no stroke or other serious medical illness in the year before cohort entry were included. The 7 most common NSAIDs were examined: celecoxib, rofecoxib, valdecoxib, ibuprofen, naproxen, diclofenac, and indomethacin. Nonuse of NSAIDs was the reference group. Because new use is less susceptible to bias, we conducted a similar analysis confined to new users. The outcome was hospitalization for an incident cerebrovascular event: ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. RESULTS: The cohort included 336 906 persons, with 989 826 person-years of follow-up, and 4354 stroke hospitalizations. There were 4.51 strokes per 1000 person years in the nonuse group, 5.15 strokes per 1000 person years (adjusted HR 1.28, 95% CI 1.06, 1.53) with rofecoxib use, and 5.95 strokes per 1000 person years (adjusted HR 1.41, 95% CI 1.04, 1.91) with valdecoxib use. New use of rofecoxib and valdecoxib led to 6.06 (adjusted HR 1.46 95% CI 1.08, 1.98) and 6.19 (adjusted HR 1.39, 95% CI 0.74, 2.59) strokes per 1000 person years respectively. No other NSAID significantly increased the risk of incident stroke. CONCLUSIONS: Our results indicate an increased risk of stroke with current use of two highly selective coxibs, rofecoxib and valdecoxib, also shown to increase cardiovascular risk. These results also provide some reassurance about other specific NSAIDs regarding stroke risk.
Pancreatic cancer: From molecular signature to target therapy.
Crit Rev Oncol Hematol. 2008 Apr 22;
Longo R, Cacciamani F, Naso G, Gasparini G
Pancreatic adenocarcinoma is a leading cause of cancer death in western countries. The treatment of advanced disease with gemcitabine has only a modest activity on survival with a favourable impact on quality of life. However, recent data support the evidence that the combination of gemcitabine with erlotinib, capecitabine or platinum compounds could be more active than gemcitabine alone in advanced pancreatic cancer. New therapeutic strategies, particularly using molecular target agents, are under evaluation. A number of molecular mechanisms responsible of transformation and progression of pancreatic cancer have been identified, opening the possibility to identify also possible pharmacological targets. A promising approach is the pharmacological inhibition of tumor angiogenesis with anti-vascular endothelial growth factor (VEGF) agents, such as bevacizumab, cyclooxygenase-2 inhibitors (celecoxib), thalidomide and others. Also epidermal growth factor receptor (EGFR) plays an important role in progression of pancreatic cancer. Erlotinib, an oral available anti-EGFR compound, was the first agent capable to significantly improve overall survival in a phase III trial, leading to its approval by Food and Drug Administration (FDA) in combination with gemcitabine as first-line therapy. Ongoing studies are exploring the role of targeted therapy in the adjuvant setting. However, despite these promising results, several questions remain to be resolved, including the rational selection of the patients who are more likely to obtain benefit of target therapy, the choice of the optimal therapeutic schedule of therapy, the clinical setting of choice, and the management of the toxicity.
The anti-inflammatory effect of celecoxib does not prevent liver fibrosis in bile duct-ligated rats.
Liver Int. 2008 Apr 23;
Yu J, Hui AY, Chu ES, Go MY, Cheung KF, Wu CW, Chan HL, Sung JJ
Background/Aims: Celecoxib was used in the treatment of inflammation in patients with cirrhosis. However, data on the progression of liver fibrosis after treatment by celecoxib are not available. This study aims to elucidate the effects of celecoxib on cholestatic liver fibrosis in rats. Methods: Rats underwent bile duct ligation (BDL) for 1 or 2 weeks to induce hepatic fibrosis. Celecoxib was introduced on day 1 after operation. The effects of celecoxib were assessed by comparison of the severity of hepatic fibrosis. Results: Infiltration of inflammatory cells and proliferation of bile ducts was seen after 1 week of BDL and fibrosis was induced after 2 weeks. Reduced alanine aminotransferase (ALT) levels and blunted expression of inflammatory factors [tumour necrosis factor-alpha, interleukin (IL)-1beta and IL-6] were seen in the liver of BDL-treated rats that received celecoxib at week 1. Although celecoxib was sufficient in suppressing the cyclo-oxygenase (COX)-2 expression in the control organ (kidney), it failed to suppress the enhanced hepatic COX-2 expression. At week 2, celecoxib did not alter the ALT level, the severity of fibrosis and hepatic collagen contents. This was associated with unchanged alpha-smooth muscle actin protein expression and tissue inhibitor of metalloproteinase-2 (TIMP-2), matrix metalloproteinase (MMP)-2 and MMP-9 mRNA expressions in the liver. Celecoxib had no effect on the BDL-dependent increase in bilirubin levels at any time point. Conclusions: The present study provides morphological and molecular biological evidences for the role of celecoxib in cholestatic liver fibrosis. Celecoxib protects against hepatic inflammation in the early stage of BDL rats, but does not have an effect on liver fibrosis.
J Clin Pharmacol. 2008 Apr 23;
Schwartz JI, Dallob AL, Larson PJ, Laterza OF, Miller J, Royalty J, Snyder KM, Chappell DL, Hilliard DA, Flynn ME, Cavanaugh PF, Wagner JA
We determined cyclo-oxygenase-1 and cyclo-oxygenase-2 inhibition in healthy middle-aged subjects (41-65 years) randomly assigned to four 7-day treatment sequences of etoricoxib 90 mg every day, celecoxib 200 mg twice a day, diclofenac 75 mg twice a day, or placebo in a double-blind, randomized, 4-period crossover study. Maximum inhibition of thromboxane B2 (cyclo-oxygenase-1 activity) in clotting whole blood on day 7 (0-24 hours postdose) was the primary endpoint. Inhibition of lipopolysaccharide-induced prostaglandin E2 in whole blood (cyclo-oxygenase-2 activity) was assessed on day 7 (0-24 hours postdose) as a secondary endpoint. Diclofenac had significantly greater maximum inhibition of thromboxane B2 versus each comparator (P < .001); placebo 2.4% (95% confidence interval: -8.7% to 12.3%), diclofenac 92.2% (91.4% to 92.9%), etoricoxib 15.5% (6.6% to 23.5%), and celecoxib 20.2% (11.5% to 28.1%). Prostaglandin E2 synthesis was inhibited with a rank order of potency of diclofenac > etoricoxib > celecoxib. In summary, at doses commonly used in rheumatoid arthritis, diclofenac significantly inhibits both cyclo-oxygenase-1 and cyclo-oxygenase-2, whereas etoricoxib and celecoxib significantly inhibit cyclo-oxygenase-2 and do not substantially inhibit cyclo-oxygenase-1.
[What is new about nonsteroidal antiinflamatory drugs?]
Pol Merkur Lekarski. 2007 Dec; 23(138): 454-8
Dzielska-Olczak M
NSAIDs contain nonselective cyclooksygenase inhibitors (for COX-1 and COX-2), inhibitors to the preferential COX-2, the coxibs (sulphonamides, methylsulphones, phenylacethic acid derivatives) with 1000 fold selectivities for COX-2. COX-2 enzyme isoform are constitutively expressed in normal gastric tissue in animals and humans, in the cardiovascular system, renal, central nervous system and other. COX-2 is involved in the ischemic preconditioning mechanism and sulphones have a prooxidant activity. COX-2 inhibitors increased risk for thrombotic cardiovascular events. Long-term study VIGOR, CLASS, TARGET MEDAL revealed that celecoxib, rofecoxib, lumiracoxib, etoricoxib significantly reduced the risk of major gastrointestinal effects (ulcers, perforations, bleeding) than nonselective NSAIDs, but the rates of complicated upper gastrointestinal events were similar for etoricoxib and diclofenac. Only in VIGOR trial incidence of cardiovascular events was greater. No evidence that concomitant ASA reduced risk for cardivascular events. Potential differences in cardiovascular outcomes with the selective COX-2 inhibitors may be due to differences in the drugs molecular structures, pharmacokinetics and pharmacodynamics. In the "prothrombotic environment" contribution disorders in the balance between thromboxan A2 and prostacyclin, increased aggregation plaque, hypertension, endothelial cell dysfunction, impaired angiogenesis. Moreover COX-2 may plays a crucial role in atherosclerotic plaque stability or instability. The cardiovascular risk may be dose related and depends on duration therapy, variable selectivity for COX-2.
Bioorg Med Chem. 2008 Apr 9;
Abouzid K, Bekhit SA
Herein, we report the design, synthesis, and pharmacological properties of a series of arylethenylpyridazinones 3a-h and arylethylpyridazinone derivatives 3k-i from the corresponding aryloxohexenoic 1a-e and aryloxohexanoic acids 2a,d, respectively. The synthesized compounds were tested for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Compound 3j demonstrated the greatest in vivo activity with ED(50) equal to 17mumol compared with celecoxib with no ulceration on the gastric mucosa. Docking study of the synthesized compounds into the active site of COX-2 revealed a similar binding mode to RS-57067, a COX-2 inhibitor.
Basic evidence of molecular targeted therapy for oral cancer and salivary gland cancer.
Head Neck. 2008 Apr 21;
Hamakawa H, Nakashiro KI, Sumida T, Shintani S, Myers JN, Takes RP, Rinaldo A, Ferlito A
BACKGROUND: Recently, attention has been focused on molecular targeted cancer therapy in various tumors. Although there is no single consistent molecular target specific for oral squamous cell carcinoma (OSCC) and salivary gland cancer (SGC), there are a number of promising candidate proteins. The aim of this review is to introduce the basic evidences to support the molecular targeting for OSCC and SGC. METHODS: We focused on the 4 molecules, epidermal growth factor receptor (EGFR), cyclooxygenase-2 (COX-2), peroxisome proliferator-activated receptor gamma (PPARgamma), and progesterone receptor, that are, respectively, associated with the proliferation and the differentiation of OSCC and SGC. RESULTS: Gefitinib ("Iressa," ZD1839), a small molecule EGFR tyrosine kinase inhibitor, can inhibit the proliferation of OSCC cell lines in a dose- and time-dependent manner and lead to cell cycle arrest with accumulation of cells in the G1 phase, and a decrease of cells in S phase. The agent suppressed tumor metastasis in the animal model. Furthermore, a cooperative antiproliferative effect was obtained when cancer cells were treated with radiation followed by gefitinib. While radiation alone did not significantly affect p38 mitogen-activated protein kinase and MAP kinase kinase (MEK)1/2 autophosphorylation, the combination of gefitinib and radiation completely inhibited the downstream signaling of EGFR. Gefitinib enhanced tumor radioresponsiveness by multiple mechanisms, including the growth inhibition and effects on DNA repair after exposure to radiation. Next, the level of COX-2 expression correlated inversely with increased tumor radiation sensitivity. Treatment with celecoxib, a COX-2 selective inhibitor, enhanced the radioresponsiveness of HSC-2 cells, which constitutively expressed COX-2. Another promising molecular target is the PPARgamma, which is a member of the nuclear receptor superfamily of ligand-activated transcription factors. Recent studies have demonstrated that PPARgamma ligands induce cellular differentiation and inhibit cell growth in carcinomas of various types. These data suggest that synthetic PPARgamma ligands may be useful for molecular targeting of oral cancer. Finally, the possibility of using molecular targeted therapy directed at hormone receptors in the treatment of advanced SGCs was described. CONCLUSION: The basic data strongly suggested the possibility of tumor suppression by targeting these molecules. Studies of different targeted agents alone or with more conventional treatment modalities are needed to fully determine what role the targeted therapy will play in the management of patients with OSCC and SGC. (c) 2008 Wiley Periodicals, Inc. Head Neck, 2008.
Thermodynamic behavior of glassy state of structurally related compounds.
Eur J Pharm Biopharm. 2008 Feb 14;
Kaushal AM, Bansal AK
Thermodynamic properties of amorphous pharmaceutical forms are responsible for enhanced solubility as well as poor physical stability. The present study was designed to investigate the differences in thermodynamic parameters arising out of disparate molecular structures and associations for four structurally related pharmaceutical compounds - celecoxib, valdecoxib, rofecoxib, and etoricoxib. Conventional and modulated temperature differential scanning calorimetry were employed to study glass forming ability and thermodynamic behavior of the glassy state of model compounds. Glass transition temperature of four glassy compounds was in a close range of 327.6-331.8K, however, other thermodynamic parameters varied considerably. Kauzmann temperature, strength parameter and fragility parameter showed rofecoxib glass to be most fragile of the four compounds. Glass forming ability of the compounds fared similar in the critical cooling rate experiments, suggesting that different factors were determining the glass forming ability and subsequent behavior of the compounds in glassy state. A comprehensive understanding of such thermodynamic facets of amorphous form would help in rationalizing the approaches towards development of stable glassy pharmaceuticals.
Central ghrelin gastroprotection involves nitric oxide/prostaglandin cross-talk.
Br J Pharmacol. 2008 Apr 14;
Sibilia V, Pagani F, Rindi G, Lattuada N, Rapetti D, De Luca V, Campanini N, Bulgarelli I, Locatelli V, Guidobono F, Netti C
Background and purpose:Ghrelin, a gut-brain peptide, is considered a gastroprotective factor in gastric mucosa. We investigated the role of prostaglandins (PG) and the possible interplay between PGs and nitric oxide (NO) in ghrelin gastroprotection against ethanol (EtOH)-induced gastric lesions.Experimental approach:We examined the effects of (1) central ghrelin (4 mug per rat) injection on PGE(2) accumulation in normal or EtOH-lesioned gastric mucosa, (2) pretreatment with indomethacin (10 mg kg(-1), p.o.), a non-selective cyclooxygenase (COX) inhibitor, and with a selective COX-1, SC560 (5 mg kg(-1), p.o.) or COX-2 inhibitor, celecoxib (3.5 mg kg(-1), p.o.) on ghrelin gastroprotection against 50% EtOH (1 mL per rat)-induced gastric lesions, (3) the NO synthase inhibitor, L-NAME (70 mg kg(-1), s.c), on gastric PGE(2) content in ghrelin-treated rats and (4) central ghrelin on the expression of constitutive and inducible NOS and COX mRNA and on the localization of the immunoreactivity for COX-2 in the gastric mucosa exposed to EtOH.Key results:Ghrelin increased PGE(2) in normal mucosa, whereas, it reversed the EtOH-induced PGE(2) surge. Ghrelin had no effect on mucosal COX-1 expression but reduced the EtOH-induced increase in COX-2 expression and immunoreactivity. Indomethacin and SC560, but not celecoxib, removed ghrelin gastroprotection. L-NAME prevented the PGE(2) surge induced by ghrelin and, like indomethacin, reduced EtOH-induced PGE(2) increase. Ghrelin enhanced eNOS expression and reduced iNOS mRNA.Conclusions and implications:This study shows that COX-1-derived PGs are mainly involved in ghrelin gastroprotection and that the constitutive-derived NO together with PGE(2) are involved in ghrelin gastroprotective activity.British Journal of Pharmacology advance online publication, 14 April 2008; doi:10.1038/bjp.2008.120.
Mol Cancer Ther. 2008 Apr; 7(4): 897-904
Dhawan D, Jeffreys AB, Zheng R, Stewart JC, Knapp DW
Transitional cell carcinoma of the urinary bladder is the second most common genitourinary malignancy in people in the United States. Cyclooxygenase-2 (COX-2) is overexpressed in bladder cancer. COX-2 inhibitors have had antitumor activity against bladder cancer, but the mechanisms of action are unclear. Clinically relevant concentrations of COX-2 inhibitors fail to inhibit proliferation in standard in vitro assays. In pilot experiments, different culture conditions [standard monolayer, modified monolayer, soft agar, collagen, and poly(2-hydroxyethyl methacrylate)-coated plates] were assessed to determine conditions suitable for the study of COX inhibitor growth-inhibitory effects. This was followed by studies of the effects of clinically relevant concentrations of a selective COX-2 inhibitor (celecoxib) on urinary bladder cancer cell lines (HT1376, TCCSUP, and UMUC3). Celecoxib (