Celecoxib,but not rofecoxib or naproxen,attenuates cardiac hypertrophy and fibrosis induced in vitro by angiotensin and aldosterone

1. Cyclo‐oxygenase (COX)‐2 inhibitors and other non‐steroidal anti‐inflammatory drugs (NSAIDs) have been implicated in increased cardiovascular events. However, the direct effects of these drugs on cardiac function have not been explored extensively. Given the important role of the renin–angiotensin–aldosterone system (RAAS) in cardiac remodelling, we sought to determine the effect of COX‐2 inhibitors and non‐specific (NS‐) NSAIDs on RAAS‐induced cardiac hypertrophy and fibrosis in neonatal rat cardiac myocytes (NCM) and fibroblasts (NCF) isolated from 1–2‐day‐old Sprague‐Dawley rat pups. 2. The NCM were pretreated for 2 h with COX‐2 inhibitors (celecoxib or rofecoxib) or NS‐NSAIDs (naproxen; all at 0.1–10 μmol/L) before being stimulated with 10 μmol/L aldosterone for 72 h or with 0.1 μmol/L angiotensin (Ang) II for 60 h. Hypertrophy of NCM was assessed by [³H]‐leucine incorporation. 3. The NCF were pretreated with COX‐2 inhibitors or naproxen as described for NCM before being stimulated with 0.1 μmol/L AngII for 48 h. Collagen synthesis was subsequently assayed by [³H]‐proline incorporation. 4. Pooled cryopreserved male and female rat hepatocytes were treated with or without COX‐2 inhibitors for 1 h before 1 nmol/L aldosterone (～540 pg/mL) was added to all wells. Cells were incubated for a further 60 min and culture media harvested by centrifugation. Human hepatic HepG2 cells were treated with compounds with or without serum starvation for 48 h. All cells were pretreated with COX‐2 inhibitors for 2 h before the addition of aldosterone. Cell culture media were harvested after a further 3, 18, 24 or 48 h incubation. Aldosterone concentrations in the culture media were determined by enzyme immunoassay. 5. Aldosterone‐ and AngII‐stimulated NCM hypertrophy was inhibited by celecoxib, but not by rofecoxib or naproxen. In NCF, AngII‐stimulated collagen synthesis was inhibited by celecoxib and, to a lesser extent, by rofecoxib, whereas naproxen had no effect. The COX‐2 inhibitors inhibited aldosterone uptake and/or metabolism by rat hepatocytes, but had no effect in human hepatic HepG2 cells. 6. These results demonstrate a potential antiremodelling effect of selective COX‐2 inhibitors in the setting of RAAS stimulation in cardiac cells, whereas naproxen has no effect.     

Inhibition of cyclooxygenase-2 causes regression of gastric adenomas in trefoil factor 1 deficient mice

Cyclooxygenase-2 (Cox-2) expression is a marker of reduced survival in gastric cancer patients, and inhibition of Cox-2 suppresses gastrointestinal carcinogenesis in experimental animal models. To investigate the role of Cox-2 in gastric carcinogenesis in vivo, we utilized trefoil factor 1 (Tff1) deficient mice, which model the neoplastic process of the stomach by developing gastric adenomas with full penetrance. These tumors express Cox-2 protein and mRNA, and we have now investigated the effects of genetic deletion of the mouse Cox-2 gene [also known as prostaglandin-endoperoxide synthase 2 (Ptgs2)] and a Cox-2 selective drug celecoxib. Our results show that genetic deletion of Cox-2 in the Tff1 deleted background resulted in reduced adenoma size and ulceration with a chronic inflammatory reaction at the site of the adenoma. To characterize the effect of Cox-2 inhibition in more detail, mice that had already developed an adenoma were fed with celecoxib for 8-14 weeks, which resulted in disruption of the adenoma that ranged from superficial erosion to deep ulcerated destruction accompanied with chronic inflammation. Importantly, mice fed with celecoxib for 16 weeks, followed by control food for 9 weeks, redeveloped a complete adenoma with no detectable inflammatory process. Finally, we determined the identity of the Cox-2 expressing cells and found them to be fibroblasts. Our results show that inhibition of Cox-2 is sufficient to reversibly disrupt gastric adenomas in mice.     

Response to dual blockade of epidermal growth factor receptor (EGFR) and cycloxygenase-2 in nonsmall cell lung cancer may be dependent on the EGFR mutational status of the tumor

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated clinical benefit in patients with nonsmall cell lung cancer (NSCLC), particularly those with tumors that have EGFR-TK domain mutations. Moreover, the EGFR and cyclooxygenase (COX)-2 pathways are known to enhance the procarcinogenic effects of each other in different tumor types. Therefore, it was hypothesized that tumor EGFR mutation status may influence the effectiveness of simultaneous EGFR and COX-2 inhibition in patients with NSCLC. METHODS: Three NSCLC cell lines with varying EGFR mutation status and sensitivities to EGFR-TKIs were selected: H3255 (L858R), H1650 (del E746-A750), and H1781 (wild-type EGFR). Cells were treated with erlotinib, gefitinib, or celecoxib alone, and the combination of both EGFR-TKI inhibitors with celecoxib. Cell survival and apoptosis was assessed and correlated with the expression of COX-2, EGFR, pEGFR, Akt, pAkt, expression, and derived prostaglandin E2 (PGE(2)). RESULTS: Celecoxib by itself was found to have no effects on cell growth or apoptosis in any of the cell lines. Erlotinib and gefitinib inhibited cell growth and induced apoptosis in both mutant cell lines and did so in H1781 cells at 10-fold higher concentrations. Celecoxib when added to erlotinib or gefitinib significantly enhanced the antiproliferative and proapoptotic effects in both mutant cell lines but had no additional effects in H1781 cells. Greater down-regulation of COX-2, EGFR, pEGFR, Akt, pAkt, and PGE(2) was found when H3255 cells were treated with the combination compared with any of the single agents alone. CONCLUSIONS: The results of the current study demonstrate that the effectiveness of the addition of celecoxib to an EGFR-TKI is significantly greater in NSCLC cells with EGFR mutations, which is likely due to more complete inhibition of both pathways.     

Risk and risk reduction involving arginine intake and meat consumption in colorectal tumorigenesis and survival

Elevated polyamine and nitric oxide levels (both derived from arginine) promote tumorigenesis, whereas non-steroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal cancer (CRC) incidence in experimental and epidemiologic studies. We investigated dietary arginine-induced intestinal tumorigenesis and NSAID-inhibitory effects in Apc(Min/+) mice differentially expressing nitric oxide synthase-2 (Nos2). We also studied effects of estimated arginine exposures through meat consumption on tumor characteristics and survival in human CRC cases. Dietary arginine increased high-grade colon adenoma incidence in Apc(Min/+)Nos2(+/+) mice, but not in Nos2 knockout mice. Additionally, celecoxib suppressed intestinal steady state ornithine decarboxylase RNA levels (p < 0.001), induced steady state spermidine/spermine N(1)-acetyltransferase RNA levels (p = 0.002), decreased putrescine levels (p = 0.04) and decreased tumor number in the small intestines of Apc(Min/+)Nos2(+/+) mice (p = 0.0003). Five hundred and eleven cases from our NCI-supported CRC gene-environment study were analyzed based on self-reported meat (as a surrogate for arginine) consumption. Familial CRC cases (n = 144) in the highest meat consumption quartile (Q4) had no statistically significant differences in tumor grade compared to cases in Q1-Q3 (p = 0.32); however, they were observed to have decreased overall survival (OS) (10-year OS = 42% vs. 65%; p = 0.017), and increased risk of death in an adjusted analysis (hazards ratio [HR] = 2.24; p = 0.007). No differences in tumor grade, OS or adjusted HR were observed for sporadic CRC cases (n = 367) based on meat consumption. Our results suggest important roles for arginine and meat consumption in CRC pathogenesis, and have implications for CRC prevention.     

Spray Drying for Generation of a Ternary Amorphous System of Celecoxib,PVP, and Meglumine

Generation of amorphous forms of a poorly soluble drug by solid dispersion techniques has been a subject of intensive research for decades. Apart from the stability of the dispersions, development of a suitable production technology is a major challenge to the successful commercialization of these products. Coprocessing of celecoxib (CEL), poly(vinyl pyrrolidone), and meglumine by spray drying resulted in an amorphous drug product that provided enhanced solubility and stability to an otherwise poorly soluble crystalline form of CEL. The spray-drying process parameters were optimized to provide an amorphous product with required characteristics. The product was stable for 3 months under the accelerated stability storage conditions. This technique can serve as a suitable means for generating a ready-to-formulate amorphous drug-additive(s) composite that can be directly filled into hard gelatin capsules.     

Intradiscal application of a PCLA–PEG–PCLA hydrogel loaded with celecoxib for the treatment of back pain in canines: What's in it for humans?

Chronic low back pain is a common clinical problem in both the human and canine population. Current pharmaceutical treatment often consists of oral anti‐inflammatory drugs to alleviate pain. Novel treatments for degenerative disc disease focus on local application of sustained released drug formulations. The aim of this study was to determine safety and feasibility of intradiscal application of a poly(ε‐caprolactone‐co‐lactide)‐b‐poly(ethylene glycol)‐bpoly(ε‐caprolactone‐co‐lactide) PCLA–PEG–PCLA hydrogel releasing celecoxib, a COX‐2 inhibitor. Biocompatibility was evaluated after subcutaneous injection in mice, and safety of intradiscal injection of the hydrogel was evaluated in experimental dogs with early spontaneous intervertebral disc (IVD) degeneration. COX‐2 expression was increased in IVD samples surgically obtained from canine patients, indicating a role of COX‐2 in clinical IVD disease. Ten client‐owned dogs with chronic low back pain related to IVD degeneration received an intradiscal injection with the celecoxib‐loaded hydrogel. None of the dogs showed adverse reactions after intradiscal injection. The hydrogel did not influence magnetic resonance imaging signal at long‐term follow‐up. Clinical improvement was achieved by reduction of back pain in 9 of 10 dogs, as was shown by clinical examination and owner questionnaires. In 3 of 10 dogs, back pain recurred after 3 months. This study showed the safety and effectiveness of intradiscal injections in vivo with a thermoresponsive PCLA–PEG–PCLA hydrogel loaded with celecoxib. In this set‐up, 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.     

Delivery of celecoxib for treating diseases of the eye: influence of pigment and diabetes

Importance of the field: Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are two major causes of blindness. In these disorders, growth factors such as vascular endothelial growth factor (VEGF) are upregulated, leading to either enhanced vascular permeability or proliferation of endothelium. While corticosteroid therapies available at present suffer from side effects including cataracts and elevated intraocular pressure, anti-VEGF antibody therapies require frequent intravitreal injections, a procedure that can potentially lead to retinal detachment or endophthalmitis. Thus, there is a need to develop safe, sustained release therapeutic approaches for treating AMD and DR.

Areas covered in this review: This review discusses the pharmacological basis for using celecoxib, an anti-inflammatory drug capable of selectively inhibiting cycloxygenase 2, in treating AMD and DR. In addition, this article discusses the safety, delivery advantage and efficacy of celecoxib by transscleral retinal delivery, a periocular delivery approach that is less invasive to the globe compared with intravitreal injections.

What the reader will gain: The reader will gain insights into the development of a pharmacological agent and a sustained release delivery system for treating DR and AMD. Further, the reader will gain insights into the influence of eye physiology including pigmentation and disease states such as DR on retinal drug delivery.

Take home message: Transscleral sustained delivery of anti-inflammatory agents is a viable option for treating retinal disorders.     

Renal effects of cyclooxygenase inhibitors in volume-depleted dogs

Objective: The objective of this study was to investigate the renal effects of celecoxib, a cyclooxygenase-2 (COX-2) specific nonsteroidal anti-inflammatory drug (NSAID). Subjects and treatment: Six volume-depleted, conscious, chronically instrumented dogs received four treatments using a cross-over design, with at least 13 days between treatments. An i.v. bolus dose (3, 10, and 30 mol/kg) of vehicle, indomethacin, celecoxib, or 6-MNA, the active metabolite of nabumetone, were administered with an hour between doses. Methods: Renal function was assessed at baseline and 30 min after each dose. Results: Treatment with indomethacin or celecoxib resulted in a dose-dependent reduction in renal plasma flow (RPF), glomerular filtration rate (GFR), urine flow, sodium excretion, and fractional sodium excretion. GFR was reduced by 27% with 30 mol/kg indomethacin (p < 0.05) and by 58% with 30 mol/kg celecoxib (p < 0.5). Similarly, RPF was significantly (p < 0.05) reduced by 33% and 65% with 30 mol/kg indomethacin and celecoxib, respectively. Reductions in renal function with celecoxib occurred at a therapeutic index (determined by comparison anti-edemic activities of the drugs in rat paw carrageenan assays) equal to or lower than indomethacin. In contrast, treatment with vehicle or 6-MNA resulted in no reductions in renal function. Conclusion: Administration of either celecoxib (specific COX-2 inhibitor) or indomethacin (selective COX-1 inhibitor) resulted in significant reductions in renal function. COX-2 specific inhibitors do not appear to lack the renal effects of NSAIDs.     

COX‐2 inhibitors and the heart: are all coxibs the same?

The selective COX-2 inhibitors (coxibs) were originally developed to minimise the adverse effects of conventional non-steroidal anti-inflammatory drugs (NSAIDs) while maintaining the same analgesic and anti-inflammatory properties. Many large studies confirmed the improved gastric side effect profile of coxibs compared with non-selective NSAIDs; however, reports of increased cardiovascular morbidity and mortality followed, and the manufacturer Merck was forced to withdraw rofecoxib (Vioxx) from the market. Other coxibs have also either perished or had restrictions placed on their use. However, there seem to be significant differences between coxibs regarding their cardiovascular profiles, and the evidence for a class effect is dubious. In this paper, the current body of knowledge regarding the cardiovascular toxicities of coxibs is reviewed. The take home message for prescribing NSAIDs and those coxibs still on the market seems to be one of caution rather than contraindication, except in patients with significant cardiovascular risk factors.