Sustained delivery of celecoxib from nanoparticles embedded in hydrogel injected into the biopsy cavity to prevent biopsy-induced breast cancer metastasis.

PURPOSE: We have previously reported that protracted Cyclooxygenase-2 (COX-2) activity in bone marrow-derived cells (BMDCs) infiltrating into biopsy wounds adjacent to the biopsy cavity of breast tumors in mice promotes M2-shift of macrophages and pro-metastatic changes in cancer cells, effects which were suppressed by oral administration of COX-2 inhibitors. Thus, local control of COX-2 activity in the biopsy wound may mitigate biopsy-induced pro-metastatic changes. METHODS: A combinatorial delivery system-thermosensitive biodegradable poly(lactic acid) hydrogel (PLA-gel) incorporating celecoxib-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Cx-NP/PLA-gel)-was injected into the biopsy cavity of Py230 murine breast tumors to achieve local control of COX-2 activity in the wound stroma. RESULTS: A single intra-biopsy cavity injection of PLA-gel loaded with rhodamine-encapsulated nanoparticles (NPs) showed sustained local delivery of rhodamine preferentially to infiltrating BMDCs with minimal to no rhodamine uptake by the reticuloendothelial organs in mice. Moreover, significant reductions in M2-like macrophage density, cancer cell epithelial-to-mesenchymal transition, and blood vessel density were observed in response to a single intra-biopsy cavity injection of Cx-NP/PLA-gel compared to PLA-gel loaded with NPs containing no payload. Accordingly, intra-biopsy cavity injection of Cx-NP/PLA-gel led to significantly fewer metastatic cells in the lungs than control-treated mice. CONCLUSION: This study provides evidence for the feasibility of sustained, local delivery of payload preferential to BMDCs in the wound stroma adjacent to the biopsy cavity using a combinatorial delivery system to reduce localized inflammation and effectively mitigate breast cancer cell dissemination.

Combination Nano-Delivery Systems Remodel the Immunosuppressive Tumor Microenvironment for Metastatic Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor microenvironment (TME) and activation of the body's immune system to fight tumors with well-designed nanoparticles have emerged as pivotal breakthroughs in tumor treatment. To simultaneously remodel the immunosuppressive TME and trigger immune responses, we designed two potential therapeutic nanodelivery systems to inhibit TNBC. First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs). Then, the biomimetic nanosystem MM@P3 was prepared by coating branched polymer poly(ß-amino ester) self-assembled NPs with melittin embedded macrophage membranes (MM). Both in vitro and in vivo, the CS@JQ1/CXB and MM@P3 NPs showed excellent immune activation efficiencies. Combination treatment exhibited synergistic cytotoxicity, antimigration ability, and apoptosis-inducing and immune activation effects on TNBC cells and effectively suppressed tumor growth and metastasis in TNBC tumor-bearing mice by activating the tumor immune response and inhibiting angiogenesis. In summary, this study offers a novel combinatorial immunotherapeutic strategy for the clinical TNBC treatment.

The efficacy and safety of adding celecoxib to escitalopram for improving symptoms of major depressive disorder.

OBJECTIVE: There is growing evidence that adding non-steroidal anti-inflammatory drugs to some psychopharmacological treatments may help to improve symptoms in patients suffering from major depressive disorder. The present study examined the therapeutic efficacy of adding celecoxib to escitalopram and the safety of doing so. METHOD: In this double-blind randomized controlled trial, 60 patients with major depressive disorder were randomly assigned to either treatment with escitalopram plus celecoxib (intervention group) or escitalopram and placebo. All patients were evaluated blind to treatment group with the Hamilton Depression Rating Scale (HDRS) before the intervention as well at 4 and 8 weeks after initiating treatment. Chi-square and paired t-test were used to examine between-group differences at those assessment times. RESULTS: There was no significant difference in depressive symptoms between intervention and placebo groups at baseline. However, at 4 and 8 weeks after the beginning of treatment, there were significant between-group differences in HDRS scores, favoring the intervention group. No between-group differences were found in treatment-related side effects. CONCLUSIONS: Adding celecoxib to escitalopram may improve symptoms of depression in patients with major depressive disorder without increasing the risk of drug-related side effects.

Assessing the efficacy of celecoxib after tonsillectomy and/or adenoidectomy: A systematic review and meta-analysis of randomised control trials.

OBJECTIVES: Tonsillectomy and adenoidectomy are common surgical procedures that cause persistent pain, bleeding, and functional limitations. We aimed to investigate the efficacy of celecoxib compared with a placebo for managing post-tonsillectomy or adenoidectomy pain and other adverse events. DESIGN: Systematic review and meta-analysis. METHODS: We conducted a systematic literature search in the PubMed, Cochrane, and Google Scholar databases from inception until July 2023. Dichotomous outcomes have been reported as risk ratios (RR) while continuous outcomes were reported using mean differences (MD). A funnel plot was drawn to investigate publication bias. RESULTS: From 1394 records identified, 6 randomised double-blind trials comprising 591 participants undergoing tonsillectomy and/or adenoidectomy were eligible for inclusion. A high dose (400 mg) of celecoxib was effective in decreasing the pain score for 'worst pain' after the procedure (MD: -10.98, [95% CI: -11.53, -10.42], p < .01, I2 = 0%) while a low dose (200 mg) was not significantly effective (p = 0.31). For managing other outcomes such as vomiting (RR: 1.37 [95% CI: 0.69, 2.68], p = 0.37, I2 = 67%), diarrhoea (RR: 1.41, [95% CI: 0.75, 2.64], p = .29, I2 = 42%), dizziness/drowsiness (RR: 0.90, [95% CI: 0.71, 1.15], p = .48, I2 = 0%), functional recovery time (p = .74), and headache (p = .91), there was no significant difference between the group on celecoxib and the placebo group regardless of dosage. Finally, there was no significant difference (RR: 1.02, [95% CI: 0.91, 1.15], p = .69, I2 = 0%) in the effect of the intervention on minimum bleeding, moderate bleeding, and profuse bleeding. CONCLUSION: This meta-analysis provides robust evidence pooled from high-quality trials and raises questions about the efficacy of celecoxib for tonsillectomy and/or adenoidectomy, challenging existing perceptions.

[Current challenges for therapy of comorbid patients: a new look at celecoxib. A review].

The use of non-steroidal anti-inflammatory drugs (NSAIDs) for a wide range of diseases is increasing, in part due to an increasing elderly population. Elderly patients are more vulnerable to adverse drug reactions, including side effects and adverse effects of drug-drug interactions, often occurring in this category of patients due to multimorbidity and polypharmacy. One of the most popular NSAIDs in the world is celecoxib. It is a selective cyclooxygenase (COX)-2 inhibitor with 375 times more COX-2 inhibitory activity than COX-1. As a result, celecoxib has a better gastrointestinal tract safety profile than non-selective NSAIDs. Gastrointestinal tolerance is an essential factor that physicians should consider when selecting NSAIDs for elderly patients. Celecoxib can be used in a wide range of diseases of the musculoskeletal system and rheumatological diseases, for the treatment of acute pain in women with primary dysmenorrhea, etc. It is also increasingly used as part of a multimodal perioperative analgesia regimen. There is strong evidence that COX-2 is actively involved in the pathogenesis of ischemic brain damage, as well as in the development and progression of neurodegenerative diseases, such as Alzheimer's disease. NSAIDs are first-line therapy in the treatment of acute migraine attacks. Celecoxib is well tolerated in patients with risk factors for NSAID-associated nephropathy. It does not decrease the glomerular filtration rate in elderly patients and patients with chronic renal failure. Many meta-analyses and epidemiological studies have not confirmed the increased risk of cardiovascular events reported in previous clinical studies and have not shown an increased risk of cardiovascular events with celecoxib, irrespective of dose. COX-2 activation is one of the key factors contributing to obesity-related inflammation. Specific inhibition of COX-2 by celecoxib increases insulin sensitivity in overweight or obese patients. Combination therapies may be a promising new area of treatment for obesity and diabetes.

The hyperthermic effect of central cholecystokinin is mediated by the cyclooxygenase-2 pathway.

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam, or etoricoxib (10 mg/kg for both) and, 30 min later, treated with intracerebroventricular CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ∼0.4°C from 10 min postinfusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ∼70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ∼50% in both); all these changes were completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways and that the activation of COX-2 is required for the development of this response.NEW & NOTEWORTHY An association between central cholecystokinin signaling and the cyclooxygenase-prostaglandin E pathway has been proposed but remained poorly understood. We show that the hyperthermic response to the central administration of cholecystokinin alters the neuronal activity within efferent thermoeffector pathways and that these effects are fully blocked by the inhibition of cyclooxygenase. We also show that the activation of cyclooxygenase-2 is required for the hyperthermic effect of cholecystokinin and that cholecystokinin is a modulator of endotoxin-induced fever.

NSAIDs, gastrointestinal toxicity and inflammatory bowel disease. / AINE, toxicidad gastrointestinal y enfermedad inflamatoria intestinal.

Non-steroidal antiinflammatory drugs (NSAIDs) are currently one of the most widely used drugs. The use of NSAIDs is associated with gastrointestinal toxicity, affecting both upper gastrointestinal tract (peptic ulcer disease) and lower gastrointestinal tract (NSAID-induced enteropathy). NSAIDs use has been associated with an increased risk of clinical relapse in inflammatory bowel disease patients. In this article, we review the upper and lower gastrointestinal toxicity of NSAIDs, with a focus on the risks and specific data of these drugs in inflammatory bowel disease patients, giving recommendations for its appropriate use in the clinical practice. Although evidence is scarce, short-term use of NSAIDs appears to be safe, and the data available suggest that selective COX-2 inhibitors are the safer option. NSAIDs should be avoided as long-term treatment or with high doses, especially in patients with active inflammation.

Meloxicam and/or Etoricoxib Could Be Administered Safely in Two Equal Doses during an Open Oral Challenge in Patients with Nonsteroidal Anti-Inflammatory Drug Hypersensitivity.

BACKGROUND: Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are common. These patients require an effective and safe analgesic alternative. OBJECTIVE: The aim of the study was to demonstrate the safety of meloxicam and etoricoxib administered by open oral challenge in 2 equal steps in patients with NSAID hypersensitivity. METHODS: A cross-sectional, descriptive study of patients with a diagnosis of NSAID hypersensitivity who underwent an oral drug provocation test (DPT) with meloxicam or etoricoxib between January 2011 and August 2017 was conducted. The analysis was performed from a database in BD Clinic. RESULTS: Two hundred and twenty-eight oral provocations were performed with an alternative NSAID (203 with meloxicam and 25 with etoricoxib) in 217 patients with hypersensitivity to NSAIDs. The median age was 38 years. Ninety-eight percent of meloxicam and 100% of etoricoxib DPTs were performed in 2 steps (without previous placebo), and 52% and 64% of meloxicam and etoricoxib DPTs, respectively, were performed with 50% of the therapeutic dose in each step. Tolerance to meloxicam was demonstrated in 192 patients (94.5%) and in 100% of patients receiving etoricoxib. CONCLUSIONS: Open oral provocation with meloxicam and etoricoxib carried out in 2 steps without placebo seems to be safe and implies less costs and less time expenditure. Also, it could be performed with 2 equal doses.

Long-term safety evaluation of Daxocox® tablets (enflicoxib) in dogs after weekly oral administrations for seven months.

BACKGROUND: Daxocox® [Ecuphar/Animalcare Group] contains the selective COX-2 inhibitor enflicoxib, approved in the EU for the treatment of pain and inflammation associated with osteoarthritis in dogs. The safety of Daxocox® was evaluated in a target animal safety study: Groups of 4 dogs per sex each were treated once weekly with placebo or Daxocox tablets at 1-, 3- and 5-times (1X, 3X and 5X) the maximum recommended therapeutic dose of enflicoxib (0, 4, 12 or 20 mg/kg, respectively). After an initial loading dose, dogs in the placebo control, 1X and 3X groups were administered for 32 weeks, and those in the 5X group were administered for 13 weeks. Dogs were subjected to daily food consumption measurements and clinical and dose observations. Body weight measurements, physical examinations, clinical pathology, urinalysis, faecal occult blood (FOB) and electrocardiographic (ECG) and blood pressure measurements, buccal mucosal bleeding time (BMBT), ophthalmology and gastroduodenal endoscopy examinations were conducted throughout the study. At study completion, all dogs were subjected to gross necropsy. Histopathology was performed on selected tissues from all animals in all groups. RESULTS: No clinical signs were noted, and no toxicologically relevant dose-associated effects were observed. CONCLUSIONS: Results show that Daxocox® is well-tolerated and has a broad safety margin when administered as directed in dogs.

Effects of bilateral Pecto-intercostal Fascial Block for perioperative pain management in patients undergoing open cardiac surgery: a prospective randomized study.

BACKGROUND: Open cardiac surgical patients may experience severe acute poststernotomy pain. The ultrasound-guided Pecto-intercostal Fascial Block (PIFB) can cover anterior branches of intercostal nerves from T2 to T6. The aim of this study was to investigate the effect of bilateral PIFB in patients undergoing open cardiac surgery. METHODS: A group of 108 patients were randomly allocated to either receive bilateral PIFB (PIFB group) or no nerve block (SALI group). The primary endpoint was postoperative pain. The secondary outcome measures included intraoperative and postoperative sufentanil and parecoxib consumption, time to extubation, time to first feces, length of stay in the ICU and the length of hospital stay. Insulin, glucose, insulin resistance and interleukin (IL)-6 at 1, 2, 3 days after surgery were mearsured. The homeostasis model assessment (HOMA-IR) was used to measure perioperative insulin resistance. RESULTS: The PIFB group reported significantly less sufentanil and parecoxib consumption than the SALI group. Compared to the PIFB group, the SALI group had higher Numerical Rating Scale (NRS) pain scores at 24 h after operation both at rest and during coughing. The time to extubation, length of stay in the ICU and length of hospital stay were significantly decreased in the PIFB group compared with the SALI group. The PIFB group had a lower insulin, glucose, IL-6, HOMA-IR level than the SALI group 3 days after surgery. CONCLUSION: Bilateral PIFB provides effective analgesia and accelerates recovery in patients undergoing open cardiac surgery. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry ( ChiCTR 2000030609 ) on 08/03/2020.

"Azole" as privileged heterocycle for targeting the inducible cyclooxygenase enzyme.

An over-expression of COX-2 isoenzyme belonging to the Cyclooxygenase Enzyme Family triggers the overproduction of pro-inflammatory prostaglandins that instigate the development of chronic inflammation and related disorders. Hence, the rationally designed drugs for mitigating over-activity of COX-2 isoenzyme play a regulatory role toward the alleviation of the progression of these disorders. However, a selective COX-2 inhibition chemotherapy prompts several side effects that necessitate the identification of novel molecular scaffolds for deliberating state-of-the-art drug designing strategies. The heterocyclic "azole" scaffold, being polar and hydrophilic, possesses remarkable physicochemical advantages for designing physiologically active molecules capable of interacting with a wide range of biological components, including enzymes, peptides, and metabolites. The substituted derivatives of azole nuclei enable a comprehensive SAR analysis for the appraisal of bioactive profile of the deliberated molecules for obtaining the rationally designed compounds with prominent activities. The comprehensive SAR analysis readily prompted the identification of Y-shaped molecules and the eminence of bulkier group for COX-2 selective inhibition. This review presents an epigrammatic collation of the pharmacophore-profile of the chemotherapeutics based on azole motif for a selective targeting of the COX-2 isoenzyme.

Evaluation of the oral administration of α-l-guluronic acid on COX-1 and COX-2 gene expression profile in ankylosing spondylitis patients.

Ankylosing spondylitis (AS) is a chronic autoimmune arthritis disease with a genetic background, affecting the skeletal axis, sacroiliac, and peripheral joints. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment for AS to alleviate the inflammation and pain. Despite the beneficial effect, their use is accompanied by a wide variety of possible side effects in the gastrointestinal and kidneys. The α-l-guluronic acid (G2013) is a new nonsteroidal anti-inflammatory patented (PCT/EP2017/067920) drug, which has shown its anti-inflammatory properties in the previous investigations. The present study revealed the oral administration effect of G2013 on COX-1 and COX-2 gene expression in AS patients. The blood samples of twelve 18-45 years old patients suffering AS and BASDAI >4, and BASFI >4, before and after 12 weeks of treatment with G2013 and 12 blood samples of healthy volunteers were collected and the effect of G2013 on the gene expression of COX-1 and COX-2 enzymes were assessed by Real-Time PCR. The results indicate that G2013 is able to reduce the gene expression level of COX-1 and COX-2 enzymes in treated AS patients compared to healthy control. Statistically significant differences were not observed between the treatment and the healthy control groups. According to the findings, G2013 might be categorized and introduced as a novel NSAID for the treatment of AS.

Formulation, optimization, and characterization of whey protein isolate nanocrystals for celecoxib delivery.

AIM: Current study aimed to improve the solubility and release profile of the celecoxib for cancer application. However, the low water solubility of celecoxib limited its application for cancer chemotherapy. Hence, new drug delivery-based approaches are compulsory for the efficient delivery of hydrophobic celecoxib for chemotherapy. METHODS: The celecoxib-loaded nanocrystals were prepared by anti-solvent precipitation-ultrasonication technique, and the formulation was optimised through various process parameters. RESULTS: The optimised formulation had an average particle diameter of 171.09 ± 6.23 nm, with a PDI of 0.123 ± 0.009 and high ZP -27.3 ± 0.2 mV. The optimised formulation was stable, had higher entrapment efficiency 97.26 ± 1.12%. The conformational changes in the denatured protein solution were detected through fluorescence spectroscopy. The transmission electron microscopy investigation showed rod-shaped nanocrystals morphology, and no chemical interactions were observed in optimised formulation through FTIR. The DSC and PXRD analysis exhibited an amorphous state of the freeze-dried formulation drug. Also, optimised nanocrystals enhance drug solubility around 26.01-fold, 15.51-fold and 19.08-fold in purified water, pH 6.8 and pH 7.4, and accomplish sustained drug delivery, respectively. CONCLUSION: It can be concluded that biopolymer-coated celecoxib nanocrystals might be potential drug delivery of hydrophobic molecules for cancer therapy.

Efficacy and safety between early use and late use of celecoxib in hip osteoarthritis patients who receive total hip arthroplasty: a randomized, controlled study.

Celecoxib is commonly used for pain management after total hip arthroplasty (THA), while the optimal timing of analgesic celecoxib remains unclear. This randomized, controlled study aimed to investigate the pain control efficacy and safety of preoperative celecoxib versus postoperative celecoxib in osteoarthritis (OA) patients undergoing THA. Totally, 192 hip OA patients about to undergo THA were randomized into pre-treatment group (N = 96) and post-treatment group (N = 96). The former was given 400 mg celecoxib at 4 h before THA, 200 mg at 4 h after THA, and then 200 mg every 12 h until 72 h post-operation. The latter was given 400 mg celecoxib at 4 h after THA, and then 200 mg every 12 h until 72 h post-operation. Pain at rest visual analog scale (VAS) score at 6 h, and pain at flexion VAS scores at 6 h, 12 h, and on D1, D2 were decreased in pre-treatment group compared to post-treatment group (all P < 0.05). Furthermore, additional consumption of patient-controlled analgesia (PCA) (P = 0.006) and total consumption of PCA (P = 0.006) were both reduced in pre-treatment group compared to post-treatment group. Meanwhile, compared to post-treatment group, patient satisfaction in pre-treatment group was higher on D1 (P = 0.010) and D2 (P = 0.039). While, Harris hip score showed no difference between pre-treatment group and post-treatment group on M1 or M3 (both P > 0.05). In conclusion, preoperative celecoxib exhibits better analgesic efficacy and patients' satisfaction management with similar tolerance compared to postoperative celecoxib in hip OA patients undergoing THA.

Perioperative COX2 and ß-adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: A randomized controlled trial.

BACKGROUND: Preclinical studies have implicated excess release of catecholamines and prostaglandins in the mediation of prometastatic processes during surgical treatment of cancer. In this study, we tested the combined perioperative blockade of these pathways in patients with colorectal cancer (CRC). METHODS: In a randomized, double-blind, placebo-controlled biomarker trial involving 34 patients, the ß-blocker propranolol and the COX2-inhibitor etodolac were administered for 20 perioperative days, starting 5 days before surgery. Excised tumors were subjected to whole genome messenger RNA profiling and transcriptional control pathway analyses. RESULTS: Drugs were well-tolerated, with minor complications in both the treatment group and the placebo group. Treatment resulted in a significant improvement (P < .05) of tumor molecular markers of malignant and metastatic potential, including 1) reduced epithelial-to-mesenchymal transition, 2) reduced tumor infiltrating CD14+ monocytes and CD19+ B cells, and 3) increased tumor infiltrating CD56+ natural killer cells. Transcriptional activity analyses indicated a favorable drug impact on 12 of 19 a priori hypothesized CRC-related transcription factors, including the GATA, STAT, and EGR families as well as the CREB family that mediates the gene regulatory impact of ß-adrenergic- and prostaglandin-signaling. Alterations observed in these transcriptional activities were previously associated with improved long-term clinical outcomes. Three-year recurrence rates were assessed for long-term safety analyses. An intent-to-treat analysis revealed that recurrence rates were 12.5% (2/16) in the treatment group and 33.3% (6/18) in the placebo group (P = .239), and in protocol-compliant patients, recurrence rates were 0% (0/11) in the treatment group and 29.4% (5/17) in the placebo group (P = .054). CONCLUSIONS: The favorable biomarker impacts and clinical outcomes provide a rationale for future randomized placebo-controlled trials in larger samples to assess the effects of perioperative propranolol/etodolac treatment on oncological clinical outcomes.

Statin and cyclooxygenase-2 inhibitors improve survival in newly diagnosed diffuse large B-cell lymphoma: a large population-based study of 4913 subjects.

Preclinical data suggests anti-lymphoma potential for statins, metformin and cyclooxygenase-2 (COX-2) inhibitors. We performed a retrospective population-based study of all adults aged ≥66 years diagnosed with diffuse large B-cell lymphoma (DLBCL) or transformed lymphoma treated with a rituximab containing regimen, between 2005 and 2015 in Ontario, Canada. Using administrative databases, we assessed the impact of medication exposures, prior to chemo-immunotherapy, on lymphoma survival. Cox regression analyses, controlling for sociodemographic factors and comorbidities, examined the relationship between medication exposure and survival. In total, 4913 patients were treated with curative intent (median age 75 years, 51% male) and 52·2% died at a median of 1 year from treatment initiation (67% due to DLBCL). In the year prior to commencing treatment, 45·7% received statins, 16·3% metformin, and 25·0% a COX-2 inhibitor. Adjusting for confounders, exposure to statin and COX-2 inhibitors prior to chemo-immunotherapy independently conferred a survival advantage: statin exposure for 30 days (hazard ratio [HR] 0·97, 95% confidence interval [CI] 0·96-0·98), 180 days (HR 0·84, 95% CI 0·80-0·89) and 365 days (HR 0·71, 95% CI 0·63-0·79) and COX-2 inhibitor exposure for 30 days (HR 0·95, 95% CI 0·95-0·98), 180 days (HR 0·76, 95% CI 0·66-0·86) and 365 days (HR 0·57, 95% CI 0·43-0·74). Metformin had no significant impact. This population-based study found a dose-related survival benefit of exposure to statins and COX-2 inhibitors prior to chemo-immunotherapy for newly diagnosed DLBCL.

Incidence of venous thromboembolism following initiation of non-steroidal anti-inflammatory drugs in U.S. women.

OBJECTIVE: To evaluate the risk of venous thromboembolism (VTE, i.e. deep vein thrombosis or pulmonary embolism, or both) following new use of NSAIDs in a long-term cohort of U.S. women. METHODS: We investigated initiation of coxibs and traditional NSAIDs (excluding aspirin) and incident VTE in 39 876 women enrolled in the Women's Health Study from 1993-95 and followed with yearly questionnaires until 2012. We defined initiation as the first reported use of NSAIDs for ≥4 days per month. Incident VTE was confirmed by an end point committee. We estimated hazard ratios (HRs) and risk differences (RDs, expressed as percentages) comparing NSAID initiation with non-initiation and acetaminophen initiation (active comparator) via standardization using a propensity score that incorporated age, BMI, calendar time, and relevant medical, behavioural, and socioeconomic variables updated over time. RESULTS: The HR (95% CI) for risk of VTE in the as treated analyses comparing initiation with non-initiation, was 1.5 (1.2, 1.8) for any NSAID, 1.3 (1.1, 1.7) for traditional NSAIDs, and 2.0 (1.3, 3.1) for coxibs, with 2-year RDs 0.11, 0.08 and 0.32, respectively. When comparing the risk of VTE after initiation of any NSAID with that after acetaminophen initiation, the HRs were 0.9 (0.6, 1.5), 0.9 (0.5, 1.5) and 1.4 (0.6, 3.4), with 2-year RDs 0.03, -0.01, and 0.13, respectively. CONCLUSION: New use of NSAIDs was associated with increased VTE risk compared with non-use, but the association was null or diminished when compared with acetaminophen initiation. Elevated VTE risks associated with NSAID use in observational studies may in part reflect different baseline risks among individuals who need analgesics and may overstate the risk patients incur compared with pharmacologic alternatives.

Efficacy, Tolerability, and Safety of DFN-15 (Celecoxib Oral Solution, 25 mg/mL) in the Acute Treatment of Episodic Migraine: A Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: The objective of this study was to evaluate the efficacy, tolerability, and safety of 120 mg DFN-15 vs placebo for the acute treatment of migraine. BACKGROUND: Certain nonsteroidal anti-inflammatory drugs (NSAIDs) are guideline-recommended therapies for the acute treatment of migraine, but patients who use them may have issues with gastrointestinal tolerability. Celecoxib, a selective inhibitor of cyclooxygenase-2, produces analgesia similar to nonselective NSAIDs. DFN-15 is an oral, ready-made liquid solution of celecoxib being investigated for the acute treatment of migraine. METHODS: A randomized, double-blind, placebo-controlled, efficacy, tolerability, and safety study in adults with migraine was conducted. Subjects treated a single migraine attack with 120 mg DFN-15 or placebo as soon as possible after the onset of pain of moderate to severe intensity. The 2 independent coprimary efficacy endpoints were the proportion of subjects with freedom from pain and the absence of the most bothersome symptom (MBS) at 2 hours postdose. A second double-blind treatment period followed the first, but did not contribute to the primary outcomes and will be reported elsewhere. RESULTS: There were 622 subjects randomized (1:1) to double-blind treatment with either 120 mg DFN-15 or placebo, and 567 (91.2%) treated a migraine with study drug (n = 285 DFN-15; n = 282 placebo). Groups were balanced in demographic characteristics; the mean age was 40, and most subjects were female (87% [494/567]). At 2 hours postdose, DFN-15 was significantly superior to placebo for pain freedom (35.6% [98/275] vs 21.7% [57/263], P < .001), with an odds ratio (95% CI) of 2.00 (1.36, 2.94) and for freedom from the MBS (57.8% [134/232] vs 44.8% [104/232], P = .007), with an odds ratio (95% CI) of 1.68 (1.17, 2.43). A total of 13.3% (38/285) of DFN-15-treated subjects and 8.9% (25/282) of placebo-treated subjects reported a treatment-emergent adverse event (TEAE). Study drug-related TEAEs were reported by 9.1% (26/285) of DFN-15 subjects and 6.0% (17/282) of placebo subjects, the most common of which were dysgeusia (4.2% [12/285] vs 1.4% [4/282]) and nausea (3.2% [9/285] vs 1.8% [5/282]). No subjects treated with DFN-15 reported TEAEs that were severe or led to withdrawal, and no serious TEAEs or deaths were reported in the study. CONCLUSIONS: DFN-15 was significantly more effective than placebo for the acute treatment of migraine, with a generally favorable tolerability and safety profile.

The Headache Pipeline: Excitement and Uncertainty.

There are many new treatment options available for migraine and more are coming. Three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. Small molecule CGRP receptor-blocking oral compounds, both for acute care and prevention, are also coming. Four neurostimulators are available, with others on the way. New acute treatments coming soon include the 5HT1F agonist lasmiditan, a zolmitriptan intradermal micro-needle patch, and a nasal mist sumatriptan with a permeability enhancer. Farther out, three novel dihydroergotamine delivery systems, and a liquid-filled capsule of celecoxib show early promise. A new, safer form of methysergide is in the works, as is a longer-duration onabotulinumtoxinA. As always with new products, questions regarding safety, tolerability, cost, and insurance coverage will need to be addressed. Despite these concerns and uncertainties, a robust headache treatment pipeline is good for patients who are not satisfied with the results of their treatment and/or cannot tolerate existing treatments.

Conjugation of 4-aminosalicylate with thiazolinones afforded non-cytotoxic potent in vitro and in vivo anti-inflammatory hybrids.

Eicosanoids like leukotrienes and prostaglandins that produced within the arachidonic acid cascade are involved in the pathogenesis of pain, acute and chronic inflammatory diseases. A promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Aiming to develop balanced COX/LOX inhibitors; 4-aminosalicylate based thiazolinones having different substituents at the 5th position of the 4-thiazolinone ring (2-22) were designed, synthesized, characterized and evaluated in vitro and in vivo for their anti-inflammatory activity. Most of the investigated compounds showed high COX-2 inhibitory potencies (IC50 39-200 nM) with selectivity indexes (30-84). Two compounds, 19 and 21, (IC50 = 41 and 44 nM), are equipotent to celecoxib (IC50 = 49 nM), while compound 22 (IC50 = 39 nM) was the most potent. For 15-LOX, compounds 5, 11, 19, 21 and 22 revealed higher potency (IC50 1.5-2.2 µM) than zileuton (IC50 15 µM). Thus, compounds 5, 11, 19, 21 and 22 are potent dual inhibitors of COX-2 and 15-LOX. In vivo anti-inflammatory testing of these compounds revealed that, compounds 5 and 21 had an anti-inflammatory activity similar to indomethacin and celecoxib (% inhibition of oedema = 60 ±â€¯9) and higher than diclofenac potassium (% inhibition = 52 ±â€¯29), while compound 22 (% inhibition = 63 ±â€¯5) was more active than the reference drugs. The results showed that the activity is controlled by the bulkiness and lipophilicity of the substituent at the 5th position. The cytotoxicity results revealed that all compounds are not cytotoxic, additionally, in an experimental model of ulcerogenic effect, the most active compounds 21 and 22 showed better safety profile than indomethacin. Further, at the active sites of the COX-1, COX-2 and 15-LOX co-crystal, 19, 21, and 22 showed high binding forces in free binding energy study, which is consistent with in vitro and in vivo results. In conclusion, these compounds are good candidates for further biological investigation as potential anti-inflammatory drugs with dual balanced inhibition of COX and 15-LOX and good safety profile.