Cyclooxygenase-2 (COX-2) and its metabolic product prostaglandin E2 (PGE2 ) are induced in response to growth factors, inflammatory cytokines, tumour promoters, activated oncogenes and, in the skin, ultraviolet (UV) radiation. Accumulating evidence suggests a role for the COX-2/PGE2 pathway in tumourigenesis in various tissue types including cutaneous squamous cell carcinoma. There is also strong evidence for a role in the development of actinic keratoses (AKs) - common dysplastic lesions of the skin associated with UV radiation overexposure - considered as part of a continuum with skin cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) exert their anti-inflammatory, analgesic and antipyretic effects by reversibly or irreversibly acetylating COX isoforms, inhibiting downstream prostaglandins, and may have a chemo-preventive role in malignancies, including skin cancer. Topical treatment of AK lesions with the NSAID diclofenac sodium 3% in combination with hyaluronic acid 2.5% has been shown to be effective and well tolerated, although the mechanism of action remains to be elucidated. This article is protected by copyright. All rights reserved.

Osteoarthritis constitutes one of the leading causes of pain and disability worldwide with a significant impact on health-care costs. Patients with osteoarthritis are often affected by a number of cardiovascular comorbidities, including hypertension, which is present in about 40% of cases. Just recently, a single tablet combination of amlodipine besylate, a calcium channel blocker, and celecoxib, a nonsteroidal anti-inflammatory drug, indicated for patients for whom treatment with amlodipine for hypertension and celecoxib for osteoarthritis are appropriate, has been recently approved. Areas covered: We reviewed data from clinical studies that investigated safety and efficacy of the combination of amlodipine and celecoxib in hypertensive patients with osteoarthritis published before 31 August 2018. The literature search was conducted using research Methodology Filters. Expert commentary: The advantages of this single formulation over sequential administration include increased compliance, possibly reduced cost, and less likelihood of dosage-related issues. Moreover, this single tablet formulation combines the anti-inflammatory activity of the celecoxib with the systemic vasodilatation induced by the amlodipine. It is a promising treatment for patients with osteoarthritis and hypertension. Nevertheless, celecoxib may cause a variable degree of blood pressure increase and only a small clinical trial has been conducted before approval to assess interactions related to blood pressure effect between these two molecules.

A series of novel derivatives exhibiting high affinity and selectivity towards the COX-2 enzyme in the (aza) indazole series was developed. A short synthetic route involving a bromination/arylation sequence under microwave irradiation and direct C-H activation were established in the indazole and azaindazole series respectively. In vitro assays were conducted and structural modifications were carried out on these scaffolds to furnish compound 16 which exhibited effective COX-2 inhibitory activity, with IC50 values of 0.409 µM and an excellent selectivity versus COX-1. Radiolabeling of this most potent derivative [18F]16 was achieved after boron ester release and the tracer was evaluated in vivo in a rat model of neuroinflammation. All chemistry, radiochemistry and biological experimental data are discussed.

Both breast cancer and autoimmune diseases (ADs) are predominant in women. NSAIDs are common medications for AD. Evidence on the association between NSAIDs use and breast cancer risk is controversial. We investigated the association between NSAIDs exposure and breast cancer risk in female patients with AD. AD patients older than 18 years of age were enrolled from Taiwan Longitudinal Health Insurance Database 2005. The NSAID users were defined as AD patients who had ever taken NSAIDs for at least 3 months between 2000 and 2009. All individuals were followed from the date of first diagnosis of AD to the end of 2013 to evaluate the risk of breast cancer. We estimated the adjusted hazard ratio (HR) using Cox proportional hazard regression after adjusting for age, comorbidities and medications. A total of 12 331 NSAID users and 12 331 non-NSAID users were included in this study after 1 : 1 individual matching. The NSAID users were less likely to develop breast cancer than the non-NSAID users (adjusted HR: 0.37; 95% confidence interval: 0.27-0.50; P<0.001), even if they used NSAIDs with low cumulative defined daily doses (adjusted HR: 0.42; 95% confidence interval: 0.34-0.53; P<0.001). The incidence of new-onset breast cancer in NSAID users was significantly decreased in users taking selective cyclooxygenase 2 inhibitors, diclofenac, ibuprofen and piroxicam. Lower cumulative hazard rates were found in the AD patients who used NSAIDs (P<0.001). NSAID exposure is associated with a decreased risk of breast cancer in female AD patients.

From ancient times, natural products have been continuously used as therapeutic agents in the treatment of various ailments. Many drugs from the natural origin are available in the market as potent medicines. Over expression of cyclooxygenase-2 (COX-2) enzyme is associated with various physical disorders like various types of inflammations associated with cardiovascular diseases or malignancies. The COX-2 inhibitory activity of many active constituents derived from plants is well established in the literature. These include coumarins, alkaloids, flavonoids, cinnamates, stilbenes and xanthines. In the present review, an attempt has been made to summarize applications of compounds since 2000 obtained from natural sources as COX-2 inhibitors. A brief synthetic methodology to access these natural product derivatives has been highlighted along with the Structure Activity Relationship (SAR).

Non-steroidal anti-inflammatories (NSAIDs) are among the most commonly used drugs in clinical practice. They block cyclooxygenases (COX) enzymes, but the degree of inhibition of COX-1 and COX-2 varies between them. In general, NSAIDs are classified in selective COX-2 or coxibs and non-selective or traditional NSAIDs. Both the analgesic and antiinflammatory effects, as well as the cardiovascular adverse effects, depend on the COX-2 inhibition. This paper reviews the available evidence of the increased risk of thrombotic events for both coxibs and traditional NSAID. The prothrombotic effect could be due to the inhibition of endothelial COX-2, with a decrease in production of prostacyclin and a relative increase in platelet thromboxane levels. Coxibs and diclofenac 150 mg/day seem to increase the risk of major vascular events by more than a third. Ibuprofen 2400 mg/day could slightly increase the risk of coronary events. Naproxen 1000 mg/day apparently does not increase the risk of vascular events. Besides ibuprofen and naproxen have the potential to decrease the cardioprotective effect of low doses of aspirin. Naproxen (= 1000 mg/day) and low doses of ibuprofen (= 1200 mg/day) are considered to have the most favorable thrombotic cardiovascular safety profiles of all NSAIDs. Therapeutic decisions should be based on an assessment of a person's individual risk factors, using the safest NSAIDs, at the lowest effective doses, for the shortest duration necessary to control symptoms, restricting their use in patients with increased cardiovascular risk.

Nowadays, diabetes and its associated inflammatory complications are important public health problems worldwide. Market limitations of drugs with dual actions as anti-inflammatory (AI) and anti-diabetic have been led to a temptation for focusing on the discovery and development of new compounds with potential AI and anti-diabetic activities. Herein, we synthesized two new series containing pyrazole ring with vicinal diaryl rings as selective COX-2 moiety and thiazolidindione (series 12a-f) or thiazolidinone (series 13a-f) as anti-diabetic moiety and the two moieties were linked together with methylene or methylenehydrazone functionality. The two series were evaluated for their COX inhibition, AI activity and ulcerogenic liability and for the anti-diabetic activity; 12a-f and 13a-f were assessed in vitro against α-glucosidase, β- glucosidase, in vivo hypoglycemic activity (one day and 15 days studies) in addition to PPARγ activation study. Four compounds (12c, 12f, 13b and 13f) had higher COX-2 S.I. (8.69-9.26) than the COX-2 selective drug celecoxib (COX-2 S.I. = 8.60) and showed the highest AI activities and the lowest ulcerogenicity than other derivatives. Also, two thiazolidindione derivatives 12e and 12f and two thiazolidinone derivatives 13b and 13c showed higher inhibitory activities against α- and β-glucosidase (% inhibitory activity = 62.15, 55.30, 65.37, 59.08 for α-glucosidase and 57.42, 60.07, 58.19, 66.90 for β-glucosidase respectively) than reference compounds (acarbose with % inhibitory activity = 49.50 for α-glucosidase and d-saccharic acid 1,4-lactone monohydrate with % inhibitory activity = 53.42 for β-glucosidase) and also showed good PPAR-γ activation and good hypoglycemic effect in comparison to pioglitazone and rosiglitazone. Moreover, Shape comparison and docking studies were carried out to understand their interaction and similarity with standard drugs.

Chemical degradation of drug substances remains a major drawback of extrusion. Larger-scale extrusion equipment has advantages over smaller equipment due to deeper flight elements and added flexibility in terms of screw design, unit operations, and residence time. In a previous study, we extruded a meloxicam-copovidone amorphous solid dispersion (ASD) on a Nano-16 extruder and achieved 96.7% purity. The purpose of this study is to introduce a strategy for scaling the process to an extruder with dissimilar geometry and to investigate the impact on the purity of the ASD. The formulation previously optimized on the Nano-16, 10:90 meloxicam and copovidone, was used for scale-up. Our approach to scale-up to the ZSE-18, utilized specific mechanical energy input and degree of fill from the Nano-16. Vacuum was added to prevent hydrolysis of meloxicam. Downstream feeding and micronization of meloxicam were introduced to reduce the residence time. In-line monitoring of the solubilization of meloxicam was monitored with a UV probe positioned at the die. We were able to achieve the same purity of meloxicam with the Micro-18 as we achieved with Nano-16. When process conditions alone were not sufficient, meglumine was added to further stabilize meloxicam. In addition to the chemical stability advantage that meglumine provided, we also observed solubility enhancement which allowed for an increase in drug loading to 20% while maintaining 100% purity.