Doses Of Celecoxib Research Articles

(258) Reversal of Mechanical Hyperalgesia by a Dual-Acting, Peripherally-Restricted Kappa/Delta Opioid Agonist (CA1001) in a Rat Model of Inflammatory Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory pain condition. In RA and other inflammatory states, normally sequestersed peripheral delta-opioid receptors may become active, allowing delta-opioid agonists to participate in the pain pathway directly and through allosteric modulation of peripheral kappa-opioid receptors. This study evaluated the efficacy of a single intraperitoneal injection of CA1001 (a novel dual-acting, peripherally restricted kappa/delta opioid agonist) on hyperalgesic nociceptive behaviors in the CFA (Complete Freund's Adjuvant) Model of Inflammatory Arthritis Pain in Rats. Following IACUC approval, inflammatory arthritis pain was induced with injection of 50 μL CFA into the tibio-tarsal joint. Mechanical hyperalgesia was assessed via joint compression thresholds (JCTs). 50 animals were randomly assigned to 5 groups (Power: 80%). Ipsilateral and contralateral joint compression thresholds (JCTs) were assessed prior to CFA injection, pre-dosing on Day 0, and 1, 2, and 4 hours post-dosing. Animals were administered a single dose of vehicle, CA1001 (1, 5, or 10 mg/kg IP), or celecoxib (30 mg/kg PO: active control; internal validity) on day 0 (14 days after CFA). All behavioral evaluations were performed by a blinded observer. Mechanical hyperalgesia was measured using a digital Randall-Selitto device. CA1001 (10 mg/kg) significantly increased paw compression thresholds compared to vehicle at all time points, (p

Impact of a selective cyclooxygenase-2 inhibitor, celecoxib, on cortical excitability and electrophysiological properties of the brain in healthy volunteers: A randomized, double-blind, placebo-controlled study.

The inflammatory response is considered a defence mechanism against physical or infectious insults and is prevalent within the central nervous system. Seizures also result in a robust inflammatory cascade, leading to enhanced activation of excitatory synaptic networks. Ample evidence based on animal models of epilepsy has demonstrated that celecoxib, a highly selective inhibitor of cyclooxygenase-2, has anticonvulsant effects. We aimed to evaluate the impact of celecoxib on the cortical excitability and electrophysiological properties of the brain in healthy humans. Electroencephalography (EEG) or transmagnetic stimulation (TMS) was used to measure neurophysiological activity. Forty healthy volunteers were randomized to 4 groups (n = 10 in each group): 1) celecoxib and EEG, 2) placebo and EEG, 3) celecoxib and TMS, and 4) placebo and TMS. For the EEG study, resting EEG was performed at baseline just before administering 400 mg of celecoxib or placebo and repeated 4 hours after administration. The subjects took 200 mg of celecoxib or placebo twice a day for 7 subsequent days, and a third EEG was conducted 4 hours after the final dose. Power spectra were compared at each time point. For the TMS study, the resting motor threshold (RMT), motor evoked potential (MEP) peak-to-peak amplitude, and cortical silent period (CSP) were measured at baseline and after taking 200 mg of celecoxib or placebo twice a day for 7 days. Celecoxib did not significantly change brain activity in the EEG study. However, the sum of power recorded from all electrodes tended to increase in the celecoxib group only at 4 hours after administration (p = 0.06). In detail, one dose of celecoxib (400 mg) transiently and significantly increased the alpha band power recorded in the frontal and parietal areas as well as in the whole brain (p = 0.049, 0.017, and 0.014, respectively) and the beta frequency in the central and parietal regions (p = 0.013 and 0.005, respectively), whereas the placebo did not. This effect was abolished after 7 days of treatment. In the TMS study, we found no statistically significant change in the RMT, MEP peak-to-peak amplitude or CSP. This evidence suggests that celecoxib transiently alters the electrophysiological properties of the brain but does not suppress neuronal excitability in healthy humans.

Preoperative chemoradiotherapy using S-1 combined with celecoxib for advanced lower rectal cancer: Phase I/II study.

Objectives: To clarify the safety and efficacy of celecoxib combined with chemoradiotherapy using S-1 for lower rectal cancer. Methods: Twenty-one patients with pathologically proven lower rectal adenocarcinoma (cT3-T4, Tx N+, M0) were included in this study. A total dose of 45 Gy was administered in daily fractions of 1.8 Gy. Celecoxib was given orally twice daily with S-1 on the day of irradiation. The dose of celecoxib was set at 400 mg/day. In Phase I, the S-1 dose was started at 80 mg/m2/day; in Phase II, S-1 was administered in the same dose as Phase I. Patients underwent surgery six to eight weeks after completing chemoradiotherapy, followed by six months of postoperative adjuvant chemotherapy. Results: The S-1 recommended dose was 80 mg/m2/day. The pathological complete remission rate was 15.8%, the rate of protocol completion was 14.3%, and the rate of adverse events exceeding Grade 3 was 19.0%. Surgery was performed in 19 cases, with a sphincter-sparing rate of 31.6%. Postoperative complications exceeding Grade 3 occurred in 52.4% of cases. The three year overall survival and relapse-free survival rates were 89.3% and 67.0%, respectively. Conclusions: We failed to show a synergistic or additive therapeutic effect of preoperative CRT using S-1, combined with celecoxib, for lower advanced rectal cancer beyond CRT using 5 FU or capecitabine alone. The incidence of complications, evidently involving intestinal ischemia, was relatively high. This treatment strategy is not recommended at present.

Effects of Therapeutic Doses of Celecoxib on Several Physiological Parameters of Cultured Human Osteoblasts.

Non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2)-selective NSAIDs, are associated with adverse effects on bone tissue. These drugs are frequently the treatment of choice but are the least studied with respect to their repercussion on bone. The objective of this study was to determine the effects of celecoxib on cultured human osteoblasts. Human osteoblasts obtained by primary culture from bone samples were treated with celecoxib at doses of 0.75, 2, or 5μM for 24 h. The MTT technique was used to determine the effect on proliferation; flow cytometry to establish the effect on cell cycle, cell viability, and antigenic profile; and real-time polymerase chain reaction to measure the effect on gene expressions of the differentiation markers RUNX2, alkaline phosphatase (ALP), osteocalcin (OSC), and osterix (OSX). Therapeutic doses of celecoxib had no effect on osteoblast cell growth or antigen expression but had a negative impact on the gene expression of RUNX2 and OSC, although there was no significant change in the expression of ALP and OSX. Celecoxib at therapeutic doses has no apparent adverse effects on cultured human osteoblasts and only inhibits the expression of some differentiation markers. These characteristics may place this drug in a preferential position among NSAIDs used for analgesic and anti-inflammatory therapy during bone tissue repair.

Safety of celecoxib versus traditional nonsteroidal anti-inflammatory drugs in older patients with arthritis

BackgroundA 2011 systematic review found an increased cardiovascular (CV) risk at both ≤200 mg/day and >200 mg/day doses of celecoxib. This study aimed to evaluate adverse drug events with celecoxib relative to traditional nonsteroidal anti-inflammatory drugs (NSAIDs) in real-world practice settings, focusing on gastrointestinal (GI), CV, and renal toxicity, in older patients with osteoarthritis or rheumatoid arthritis.MethodsIn this population-based retrospective cohort study using national health insurance claims data in Korea, patients aged 65 years and older with arthritis who were treated with celecoxib or traditional NSAIDs for ≥30 days in 2016, were included for study analyses. The primary outcome was hospital encounter for GI bleeding associated with celecoxib vs traditional NSAIDs use. The secondary outcomes included a composite of CV diseases, coronary revascularization, and incident renal events.ResultsAfter 1:1 propensity score matching, 73,748 patients in each cohort were identified for study entry. Celecoxib treatment which lasted for ≥120 days was associated with a lower risk of GI bleeding than traditional NSAIDs (OR=0.84, P=0.03). Such a relationship was not observed in shorter treatment strata and overall in all strata combined. When patients with gastroprotective prophylaxis were excluded from subgroup analysis, no evidence of improved GI tolerability was observed with celecoxib. CV and renal risks appeared higher with celecoxib than with traditional NSAIDs (OR=1.08, P<0.001 and OR=1.22, P<0.001, respectively). About 4.7 % of celecoxib users received a higher than maximum dose (400 mg/day); a dose-dependent increase in CV and renal risks was assessed with celecoxib.ConclusionCelecoxib was associated with decreased risk of GI bleeding compared with traditional NSAIDs when treatment lasted for ≥120 days, but such a relationship was not found among subgroup patients with no concomitant use of gastroprotective prophylaxis. Celecoxib users were more likely to experience CV and renal events than traditional NSAIDs users, and a dose-dependent risk relationship was observed with celecoxib.

The effect of celecoxib on blood pressure and plasma oxidant/antioxidant status in co-administration with glucocorticoid in rat.

There is limited information about the concomitant uses of selective COX-2 inhibitors with corticosteroids or with antihypertensive medications. The aim of this study was to investigate the effect of celecoxib on blood pressure and plasma oxidant/antioxidant status in glucocorticoid-induced hypertension and in co-administration with captopril. Male Wistar rats received dexamethasone (30 μg/kg/day, s.c.) for 14 days. The tested groups received dexamethasone and orally treated with celecoxib (10, 25 or 50 mg/kg) or captopril (10, 20 or 40 mg/kg) or celecoxib (50 mg/kg) + captopril from day 8 to 14. Heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) were measured using tail-cuff method. Hydroperoxides concentration and ferric reducing antioxidant power (FRAP) value were determined in plasma samples. Dexamethasone significantly increased BP and plasma hydroperoxides level and decreased body weights. High dose of celecoxib resulted in a small but significant increase in SBP, DBP and MAP in normotensive rats however it did not alter BP markers in dexamethasone-induced hypertensive rats. Celecoxib reduced the hypotensive effect of all doses of captopril in dexamethasone-induced hypertensive rats however the SBP and MAP was preserved near to normal at low and middle doses of captopril but DBP was more than normal at low dose of captopril. Heart rate was not significantly altered by different treatments. High dose of celecoxib also increased plasma hydroperoxides concentration without effect on FRAP level. In conclusion, celecoxib did not change blood pressure in glucocorticoid-induced hypertensive rats but may blunt the hypotensive effect of low dose of captopril. Further studies are needed for detailed information addressing the effects of COX-2 inhibitors on blood pressure in concomitant uses with corticosteroids.

Adjunctive use of celecoxib with anti-tuberculosis drugs: evaluation in a whole-blood bactericidal activity model

COX-2 inhibition may be of benefit in the treatment of tuberculosis (TB) through a number of pathways including efflux pump inhibition (increasing intracellular TB drug levels) and diverse effects on inflammation and the immune response. We investigated celecoxib (a COX-2 inhibitor) alone and with standard anti-tuberculosis drugs in the whole-blood bactericidal activity (WBA) model. Healthy volunteers took a single dose of celecoxib (400 mg), followed (after 1 week) by a single dose of either rifampicin (10 mg/kg) or pyrazinamide (25 mg/kg), followed (after 2 or 7 days respectively) by the same anti-tuberculosis drug with celecoxib. WBA was measured at intervals until 8 hours post-dose (by inoculating blood samples with Mycobacterium tuberculosis and estimating the change in bacterial colony forming units after 72 hours incubation). Celecoxib had no activity alone in the WBA assay (cumulative WBA over 8 hours post-dose: 0.03 ± 0.01ΔlogCFU, p = 1.00 versus zero). Celecoxib did not increase cumulative WBA of standard TB drugs (mean cumulative WBA −0.10 ± 0.13ΔlogCFU versus −0.10 ± 0.12ΔlogCFU for TB drugs alone versus TB drugs and celecoxib; mean difference −0.01, 95% CI −0.02 to 0.00; p = 0.16). The lack of benefit of celecoxib suggests that efflux pump inhibition or eicosanoid pathway-related responses are of limited importance in mycobacterial killing in the WBA assay.

Efficacy and safety of combined low doses of either diclofenac or celecoxib with gabapentin versus their single high dose in treatment of neuropathic pain in rats

Neuropathic pain is a worldwide health problem with no consensus regarding its optimal therapy. This study compared the analgesic effect and gastric, hepatic, and renal safety of combined low doses of diclofenac and celecoxib with gabapentin versus their individual high doses in the treatment of neuropathic pain in rats. Left sciatic nerve ligation was used as neuropathic pain model. Rats were allocated into 7 groups (7 rats for each): sham control; model group (received vehicle); Gaba-group (received gabapentin (100 mg/kg /day); Diclo 10-group (received diclofenac (10 mg/kg); Cele 10-group (received celecoxib (10 mg/kg/day); Gaba + Diclo 5 (receivedgabapentin(100 mg/kg /day) plus diclofenac (5 mg/kg); Gaba + Cele 5 (received gabapentin (100 mg/kg/day) plus celecoxib (5 mg/kg)). The analgesic effect was assessed using both hot plate and acetone tests. The impact of the used drugs on peptic ulcer index, liver enzymes, and serum urea and creatinine was evaluated, along with histopathological examination and oxidative stress parameters. Combination therapy of low dose of either diclofenac or celecoxib, with gabapentin showed higher analgesic effect compared with their individual high doses as indicated by prolonged response time in hot plate test and decreased frequency of paw withdrawal in acetone test. Their effect was associated with gentle effect on gastric mucosa, renal and hepatic integrity and oxidative stress parameters. In conclusion, the use of combined low doses of either diclofenac or celecoxib with gabapentin is better than high dose monotherapy regarding both the efficacy and safety.

Increase of reactive oxygen species in different tissues during lipopolysaccharide-induced fever and antipyresis: an electron paramagnetic resonance study

Fever is a regulated increase in body temperature and a component of the acute-phase response, triggered mainly after the invasion of pathogens in the body. Reactive oxygen species (ROS) are generated during the physiological and pathological processes, and can act as both signalling molecules as well as promoters of oxidative stress. Male Wistar rats, pretreated with oral doses of acetaminophen, celecoxib, dipyrone, or ibuprofen 30 min before an intravenous lipopolysaccharide (LPS) or sterile saline injection, showed a reduced febrile response in all animals tested. The formation of ROS in the fresh blood, liver, brown adipose tissue (BAT), and hypothalamus of febrile and antipyretic-treated animals was assessed by electron paramagnetic resonance using the spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (CMH). While the CM• concentrations remained unaltered in the blood samples examined 5 h after the induction of fever, we found increased CM• levels in the liver (in µM, saline: 290 ± 42; LPS: 512 ± 34), BAT (in µM, saline: 509 ± 79, LPS: 855 ± 79), and hypothalamus (in µM, saline: 292 ± 35; LPS: 467 ± 8) at the same time point. Importantly, none of the antipyretics were seen to alter the CM• accumulation profile. Data from this study suggest that there is an increased formation of ROS in the different tissues during fever, which may cause oxidative stress, and that the antipyretics tested do not interfere with ROS production.

Comparing the Safety and Efficacy of Celecoxib for the Treatment of Osteoarthritis in Asian and non-Asian Populations: An Analysis of Data from Two Randomized, Double-blind, Placebo-controlled, Active-comparator Trials.

IntroductionCelecoxib is an effective treatment for pain associated with osteoarthritis. There are differences in patient demographics among ethnic groups, with Asian populations typically smaller in body size. As a consequence, there may be a perception that celecoxib is less effective, or has poorer tolerability in Asian patients.MethodsThis analysis compares data from two multicenter, randomized, double-blind, placebo-controlled, active-comparator trials of celecoxib for the treatment of osteoarthritis of the knee: one study in Asian patients and the other in a mixed population comprised mostly of non-Asian patients (from which Asian patients were excluded for this analysis). Each trial was of similar design, with patients randomized 2:2:1 to 6 weeks treatment with celecoxib 200 mg once daily, active comparator (naproxen 500 mg twice daily or ibuprofen 800 mg three times daily), or placebo. The primary efficacy endpoint in each trial was the change from baseline to week 6 in the Patient’s Assessment of Arthritis Pain, as measured on a visual analog scale.ResultsIn total, 329 patients were included in the efficacy analysis, 179 in the Asian study and 150 in the non-Asian study. The Asian population was significantly older and smaller in body size (P < 0.0001). There was no significant difference between the Asian and non-Asian populations in change in pain score (95% confidence interval) at study endpoint with celecoxib [−1.1 (−7.7, 5.5); P = 0.7400] or placebo [−5.2 (−14.8, 4.4); P = 0.2870]. There were also no notable differences in safety outcomes between populations.ConclusionsDue to the smaller size of some Asian patients with OA, physicians may be tempted to decrease the dose of celecoxib below the therapeutic range recognized by regulatory authorities; these data suggest that dose changes are not necessary.FundingPfizer Inc.

Abstract 5047: Celecoxib fixed dose combination - therapeutic drug monitoring

Abstract Background: The anticancer properties of Celecoxib (CEL) have been demonstrated in different cancer indications, including colorectal, breast and non-small cell lung cancers. However, its use is associated with dose related cardiovascular adverse events including edema and hypertension. We have shown that combination of CEL and OLM (Olmesartan) would negate drug induced edema caused by CEL. To further improve on the safety of this combination, we are now exploring therapeutic drug monitoring (TDM) guided dosing on CEL. This study demonstrated that TDM via lateral flow platform would be able to quantify plasma drug concentration and guide the optimal dosing for CEL. Methods: Pharmacokinetic (PK) data (Cmax and AUC) to oral formulations of CEL as single dose to healthy adults were collected from published clinical trials. PK data were analyzed against dose and demographic factors to evaluate the variability. To develop the lateral flow methods for quantification, mAbs against CEL were generated by synthesizing BSA-CEL immunogen and hybridoma technology. The best clones demonstrating a dose response to CEL were selected and tested. The assay requires the configuration of immobilizing BSA-CEL onto the membrane followed by flowing the colloidal-gold labeled mAb against CEL through in presence of test analyte. This resulted in a competitive assay where the signal decreased as the concentration of CEL in blood increased. Results: For CEL, the AUC and Cmax across multiple doses were significantly overlapped. With 200 mg CEL, we used meta-analysis to show that older subjects have a significantly higher AUC than young subjects (p&amp;lt;0.001). These results indicated that different individuals may have very different drug exposure with same dose of CEL, depending on their age and other factors, resulting in over exposure and toxicity. Using a cutoff of 6,741 ng*hr/mL, we were able to separate out almost all of the elderly subjects from the young subjects. Therefore, to avoid toxicity, we will use TDM guided dosing to maintain AUC at the target AUC of 6,741 ng*hr/mL. To make possible TDM guided dosing, we developed a quantitative point of care lateral flow assay for CEL. mAb against CEL were selected based on good sensitivity and binding ability to CEL. Coupled with the lateral flow reader by Qiagen, the assay exhibited a dynamic range of 7.5ng/ml to 30mg/ml of CEL, from a drop of blood with read time of less than 20 min. Conclusion: A quantitative lateral flow platform coupled to a reader was developed to easily detect the CEL concentrations in finger-prick blood samples, allowing for in-home personal PK testing. The individual PK profiles built from the concentration data will be used to guide the optimal dosing of CEL, to maximize treatment efficacy and minimize toxicity. This should allow for higher dosing of CEL without hitting the toxic exposure limit. This additional enhancement on top of combination with OLM in the fixed dose combination should insure the safety of our patients on these drugs. Citation Format: Cynthia Lee, Dongwon Lee, Sam Khateri, Wen Wang, Vuong Trieu. Celecoxib fixed dose combination - therapeutic drug monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5047. doi:10.1158/1538-7445.AM2017-5047

Abstract 2597: Celecoxib fixed dose combinations - patient level data analyses

Abstract Background: Celecoxib is a highly effective anti-inflammatory drug. However, its use is associated with adverse events including edema and hypertension (HTN). High dose celecoxib has been shown to be effective against familial adenomatous polyposis (FAP). However, it was discontinued because of safety concerns. Here we examined the impact of celecoxib intake on HTN and edema. The concomitant intake of celecoxib and one of the antihypertensives (AH) was also evaluated as means to suppress the side effects of celecoxib. Methods: This is a retrospective study that uses two patient level data (PLD) sources: (1) anonymous PLD from Symphony from Jan 2012 to Dec 2014 (3 years), and (2) Pinnacle registry data from American College of Cardiology (ACC) over the same time period with detailed clinical data such as blood pressure (BP) readings, peripheral edema flags, etc. In Symphony dataset there are 162 million (M) unique patients, 4.3M patients on celecoxib, 16.3M patients with osteoarthritis (OA)(15.4M only OA) ,and 2.3M patients with rheumatoid arthritis (RA) (1.4M only RA). In ACC dataset, there are 1.58M unique patients with BP readings, 870K patients with edema flag. Results: There was no impact of celecoxib consumed on the change in BP readings. There were as many increases as decreases, regardless of the amount of celecoxib consumed between BP readings. A breakdown by baseline BP readings did not reveal any trends. Concomitant use of AH with celecoxib did not impact BP. Onset of edema was not correlated with total dose of celecoxib. Less than 10% of the observations indicated a change in edema status. However, unlike BP, increasing % of edema was observed for increment in doses and days of treatment with celecoxib plus any other drug combination, suggesting drug induced edema. Edema was baselined with concomitant consumption of angiotensin receptor blocker (ARB) or angiotensin converting enzyme (ACE) or hydrochlorothiazide. It was further aggravated by non-thiazide diuretics and minimally impacted by calcium channel blocker. Conclusion: Previous analysis has shown that dose increment of celecoxib to more than 200mg/day did not improve treatment efficacy, but significantly increased the edema rate but not BP in OA patients. Here we confirmed our meta-analysis using PLD data. Celecoxib with ARB exhibited the lowest incidence of edema and with non-thiazide diuretics the highest incidence (Odds ratio = 3.34 (95% CI = 2.85-3.94), p&amp;lt;0.0001). ARB with celecoxib displayed a significant reduction in edema incidence compared to celecoxib alone (Odds ratio = 0.626 (95% CI = 0.539-0.724), p&amp;lt;0.0001). The celecoxib-ARB and celecoxib-ACE FDCs are being investigated further as therapy for FAP and more broadly for colorectal cancers. Citation Format: Sanjive Qazi, Lynne Murphy, Anshuma Mehta, Wen Wang, Mihir Munsif, Zachary Yim, Vuong Trieu. Celecoxib fixed dose combinations - patient level data analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2597. doi:10.1158/1538-7445.AM2017-2597

Anti-cancer effect of low dose of celecoxib may be associated with lnc-SCD-1:13 and lnc-PTMS-1:3 but not COX-2 in NCI-N87 cells.

In order to investigate the mechanism of celecoxib and whether long non-coding RNAs (lncRNAs) were involved in the effects of celecoxib treatment in NCI-N87 cells, NCI-N87 cells were treated with 15, 30 and 60 µM celecoxib and an MTT assay was performed to assess cell viability. Following treatment with 15 µM celecoxib, the cell cycle and apoptosis were analyzed by flow cytometry, and the mRNA levels of lnc-SCD-1:13, lnc-PTMS-1:3, cyclooxygenase-2 (COX-2), integrin α3 (ITGA3) and DSH homolog 1 (DVL1) were detected by reverse transcription quantitative PCR (RT-qPCR) in NCI-N87 cells. MTT analysis demonstrated that celecoxib significantly inhibited cell viability in treated cells compared with untreated cells. Flow cytometry analysis revealed that, compared with untreated cells, the percentage of cells in the G0/G1 phase was significantly increased, and the percentage of cells in the S and G2 phase was decreased. In addition, the percentage of early and late apoptotic cells was increased in cells treated with 15 µM celecoxib compared with the control. RT-qPCR analysis also demonstrated that the mRNA levels of lnc-SCD-1:13, lnc-PTMS-1:3, ITGA3 and DVL1 were increased following treatment with celecoxib (15 µM; P<0.05). However, there were no significant differences in the expression of COX-2 mRNA between cells treated with celecoxib (15 µM) and untreated cells. The present study demonstrated that a low dose of celecoxib may be involved in regulating cell growth independent of COX-2 in NCI-N87 cells. Furthermore, ITGA3 and/or DVL1 co-expressed with lnc-SCD-1:13 and lnc-PTMS-1:3 may be associated with the effects of treatment with a low dose of celecoxib in NCI-N87 cells.

Evaluating the Cardiovascular Safety of Nonsteroidal Anti-Inflammatory Drugs.

Some drugs used to treat noncardiovascular conditions may adversely impact the cardiovascular status of individuals both with and without known cardiovascular disease. When the US Food and Drug Administration judges the potential cardiovascular safety signal to be of sufficient concern, it may require the pharmaceutical manufacturer of the drug in question to conduct a postmarketing (phase 4) randomized controlled trial (RCT). Although historically many phase 4 RCTs focused on efficacy (using a superiority design), contemporary phase 4 RCTs often are focused on safety and use a noninferiority design. The choices made by investigators during the planning stage of a postmarketing phase 4 RCT dedicated to the evaluation of cardiovascular safety can influence the ability to compare the standard and test agents. Multiple factors reflecting the conduct of a phase 4 RCT for a general medical condition may influence interpretation of a cardiovascular safety signal. The higher the rates of failure to adhere to the protocol and dropout from the study, the greater the risk of bias. Trials evaluating the cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs) when used for arthritis are difficult to conduct and even more challenging to interpret. Concerns include the comparison of drug regimens that do not provide comparable analgesic efficacy and problems with adherence to the protocol and retention in the study. On the basis of phase 4 RCTs of NSAIDs to date, it appears that a comparatively low dose of celecoxib administered to low-risk subjects is associated with approximately the same cardiovascular risk as NSAIDs with less cyclooxygenase-2 inhibitory activity, but at the cost of not controlling arthritic pain as effectively.

Inhibition of A&#946;(1-42)Oligomerization, Fibrillization and Acetylcholinesterase Activity by Some Anti-Inflammatory Drugs: An in vitro Study.

Number of contradictory reports are available on the effects of antiinflammatory drugs on Alzheimer's disease (AD) including beneficial, adverse and stage dependent effects. We provide insights of the effects exerted by some anti-inflammatory drugs on the chemistry of AD. Three different doses of dexamethasone (0.015, 0.030, 0.060 μM), piroxicam (5, 7.5, 10 μM), indomethacin (1, 1.25, 1.50 μM), diclofenac (0.6, 0.8, 1.0 μM), aspirin (90, 120, 150 μM) and celecoxib (30, 45, 60 μM) were used. Rivastigmine, methylene blue and butylated hydroxyanisole were used as standard drug, oligomerization inhibitor and antioxidant, respectively. Oligomerization and fibrillization reactions were performed using Aβ1-42 peptides. Results-Indomethacin and aspirin mainly inhibited oligomerization, while rivastigmine and piroxicam inhibited fibrillization. Diclofenac and celecoxib inhibited both oligomerization and fibrillization almost equally. Dexamethasone showed poor efficiency on both the processes, but exert comparably more inhibition of oligomerization than fibrillization. Inhibition of acetylcholinesterase activity was also potent and was in the following order: celecoxib> piroxicam> diclofenac> aspirin> indomethacin> dexamethasone. Strong radical scavenging (More than 50%) activity was showed by indomethacin and aspirin for NO radicals. Present study consistently revealed that anti-inflammatory drugs have potential to Modulate chemistry of AD progression. Inclusion of anti-inflammatory drugs in low doses along with routine therapies may provide therapeutically and economically more efficient therapies for AD. However, further studies are warranted, because the overall therapeutic effect seems to be the function of stage of disease, dose of drug, main underlying mechanism of action(s).

Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of celecoxib and its carboxylic acid metabolite.

Celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, is used for the treatment of rheumatoid arthritis and osteoarthritis. The predominant hepatic metabolism of celecoxib to celecoxib carboxylic acid (CCA) is mediated mainly by CYP2C9. We investigated the effects of the major CYP2C9 genetic variants in Asian populations, CYP2C9*3 and CYP2C9*13, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in healthy Korean subjects. A single 200-mg oral dose of celecoxib was given to 52 Korean subjects with different CYP2C9 genotypes: CYP2C9EM (n=26; CYP2C9*1/*1), CYP2C9IM (n=24; CYP2C9*1/*3 and *1/*13), and CYP2C9PM (n=2; CYP2C9*3/*3). Celecoxib and CCA concentrations in plasma samples collected up to 48 or 96h after drug intake were determined by HPLC-MS/MS. The mean area under the plasma concentration-time curve (AUC0-∞) of celecoxib was increased 1.63-fold (P<0.001), and the apparent oral clearance (CL/F) of celecoxib was decreased by 39.6% in the CYP2C9IM genotype group compared with that of CYP2C9EM (P<0.001). The overall pharmacokinetic parameters for celecoxib in CYP2C9*1/*13 subjects were similar to those in CYP2C9*1/*3 subjects. Two subjects with CYP2C9PM genotype both showed markedly higher AUC0-∞, prolonged half-life, and lower CL/F for celecoxib than did subjects with CYP2C9EM and IM genotypes. CYP2C9*3 and CYP2C9*13 variant alleles significantly affected the plasma concentration of celecoxib.

Intradiscal Injection of a Slow Release Formulation of Celecoxib for the Treatment of Dogs with Low Back Pain

Introduction Intervertebral disc (IVD) disease characterized by low back pain is common in both humans and large breed dogs. Inflammatory mediators such as prostaglandin E2 (PGE2) play a key role in IVD degeneration, causing structural changes of the IVD and low back pain. The current conservative and surgical treatment modalities do not reverse IVD degeneration and have certain drawbacks. Long term systemic administration of non-steroidal anti-inflammatory drugs can cause gastro-intestinal side effects. Decompressive surgery is effective in over 80% of the patients, but is rather costly and has a long recovery period. Injectable formulations that enable local sustained release of anti-inflammatory drugs aim at decreasing inflammation and thereby inhibiting degeneration and pain. In vitro , controlled release of celecoxib, a COX-2 inhibitor, from a thermoreversible acetyl-capped PCLA-PEG-PCLA hydrogel inhibited PGE2 production and enhanced matrix production for 28 days in 3D culture of canine nucleus pulposus cells that were subjected to the catabolic effects of TNF-α. In vivo, sustained release of celecoxib by the hydrogel for up to 60 days was shown and safely applied intradiscally in laboratory dogs with naturally occurring IVD degeneration. The aim of the present study is to report the safety and feasibility of intradiscal application in client-owned dogs with low back pain related to IVD degeneration. Material and Methods Client-owned dogs with low back pain were diagnosed by MRI with degenerative lumbosacral stenosis marked by mild to moderate IVD degeneration and protrusion. The dogs were surgical candidates but were offered intradiscal injection. The PCLA-PEG-PCLA thermogel, loaded with 0.013mg/ml celecoxib, was percutaneously injected into the nucleus pulposus of L7-S1 under fluoroscopy guidance. Follow-up consisted of clinical examination, owner questionnaires, and objective gait analysis by measurement of ground reaction forces (GRFs) using force plate analysis (FPA) at 6 weeks, and 3 and 6 months after injection. MRI was repeated after 3 months and included T2- and T1-weighted images and T2-mapping. Results Ten dogs with DLLS were injected with the celecoxib-loaded hydrogel. None of the dogs showed adverse reactions after intradiscal injection. Follow up MRI showed no worsening of the IVD degeneration. Clinical improvement was achieved by reduction of low back pain in 9/10 dogs, as was shown by clinical examination, force plate analysis and owner questionnaires. In 3/10 dogs low back pain recurred at 3 months and they subsequently underwent standard-of-care surgical treatment. Conclusion This study showed the safety and feasibility of intradiscal injections with a thermoresponsive hydrogel loaded with celecoxib. Ongoing studies concentrate on the long term clinical follow up of these patients. Future studies will determine the optimal loading dose of celecoxib for clinical efficacy. In this setup, the dog can be used as a model for the development of novel treatment modalities in both canine and human patients with chronic low back pain.

Involvement of Spinal CB1 Cannabinoid Receptors on the Antinociceptive Effect of Celecoxib in Rat Formalin Test

Background: The pivotal role of cyclooxygenase-2 (COX-2) inhibitors in inflammatory pain is well documented, but its mechanism is not entirely clear. Nonsteroidal anti-inflammatory drugs (NSAIDs) as inhibitors of COX could inhibit fatty acid amide hydrolase, the enzyme responsible for the metabolism of endocannabinoids. Therefore, it is expected that celecoxib administration (selective COX-2 inhibitor) preserve the increased level of endocannabinoids after noxious stimuli, which leads to more pain suppression. Objectives: This study was designed to evaluate the interaction between the intrathecally administered celecoxib in combination with rimonabant, a selective cannabinoid CB1 receptor antagonist/reverse agonist on the pain behavior induced by formalin test in rat. Materials and Methods: Male Wistar rats with inserted lumbar intrathecal catheters were randomly grouped and tested in blinded manner by the same experimenter. Antinociceptive effects of different intrathecally doses of celecoxib (0.5, 5 and 10 µg/rat) in absence and with pretreatment of rimonabant at doses of 100 and 200 µg/rat were examined on the formalin test. Results: Celecoxib reduced the pain behavior in both phases of the formalin test, but this antinociceptive effect was a dose-dependent manner in the late phase. Rimonabant alone induced hyperalgesia as compared with the control group and pretreatment of rats with rimonabant reversed the analgesic activity of celecoxib. Conclusions: Antinociceptive effect of celecoxib may be mediated partly through the cannabinoid system. These effects are possibly attributed to inhibition of endocannabinoid degradation and consequently enhancement of endocannabinoids concentration at the spinal cord level. However, the hyperalgesic effects of rimonabant are not fully responsible for the reversal of celecoxib analgesia. Accordingly, NSAIDs intensify their effects through maintenance of the endocannabinoid tone. Therefore, combination of NSAIDs and cannabinoid agents could be used for synergistic effects.

Increased bioavailability of celecoxib under fed versus fasted conditions is determined by postprandial bile secretion as demonstrated in a dynamic gastrointestinal model

The objective of this study was to utilize physiologically relevant dynamic dissolution testing with the TNO intestinal model (TIM-1) in vitro gastrointestinal model to investigate the bioaccessibility of celecoxib. A single 200-mg dose of celecoxib was evaluated under average adult human physiological conditions simulated in the TIM-1 system. The in vitro data were compared with the clinically established pharmacokinetic data. When expressed as a percent of drug that progresses from the duodenum to the jejunum and ileum compartments (bioaccessible sites), the study demonstrated a 2-fold increase in the total bioaccessibility for celecoxib when co-administered with a high-fat meal as opposed to co-administration with a glass of water (fasted conditions). That increase in bioaccessibility was similar to a 1.2 to 1.6-fold increase in systemic exposure in adults and children following co-administration with a high-fat meal when compared to the exposure measured when celecoxib was co-administered with only water. Following that comparison, the flexibility of the TIM-1 system was used to more specifically investigate individual parameters of gastrointestinal conditions, such as the rate of bile secretion (emptying of the bile bladder) that accompanies high-fat meal consumption. We demonstrated that increased bile secretion after co-administration of a high-fat meal played a more important role in the increased celecoxib bioaccessibility than did the food matrix. This indicates that in humans without a bile bladder the exposure of celecoxib administered with food might be as low as under fasted state.

Fish oil augments celecoxib mediated alteration in apoptotic pathway in the initiation phase of 7,12-dimethylbenz(α)anthracene-induced mammary carcinogenesis.

Resistance in apoptosis by disruption in signaling pathways is a common trait in malignancy. Celecoxib, a specific COX-2 inhibitor, has been reported to exert chemopreventive effect by inducing apoptosis. However, high doses or chronic usage of celecoxib for longer periods have various side effects. n-3 PUFA rich fish oil also abrogates COX-2 expression in tumors and thereby, has chemopreventive action. Combinatorial strategy using these two has been reported to be beneficial in mammary carcinoma. The present study was designed to understand the role of intrinsic and extrinsic apoptotic pathways in chemopreventive effect of celecoxib and fish oil in the initial phases of mammary carcinogenesis. Female Wistar rats were distributed into control and DMBA treated groups and further subdivided based on pretreatment with celecoxib and/or fish oil. The animals were subsequently maintained for 90 days and then sacrificed. The proteins involved in intrinsic and extrinsic pathways were assessed in isolated mammary epithelial cells using flowcytometry. An increase in Bax, Bcl-2, Fas, FasL and caspase 8 levels was observed in DMBA treated animals. Celecoxib and/or fish oil further upregulate Bax, Fas, Fas L and caspase-8 while Bcl-2 levels were decreased. However maximal effect was observed with combinatorial dose of celecoxib and fish oil regimen. Administration of a combinatorial therapy of fish oil and celecoxib in mammary carcinoma exert better chemopreventive effect by modulation of both intrinsic and extrinsic apoptotic pathways.