The Combination of Auranofin and Celecoxib Suppresses Local Synovial Sarcoma Progression In Vivo.

BACKGROUND/AIM: Synovial sarcoma (SS) is a rare malignant tumor with a poor survival rate. We previously reported that a combination of auranofin (AUR), a thioredoxin reductase inhibitor, and celecoxib (CE), an anti-inflammatory drug, significantly impedes the local progression of osteosarcoma (OS). However, the role of redox regulation in SS remains to be elucidated. This study aimed to investigate the efficacy of combined treatment of AUR and CE on the local progression of SS in vivo. MATERIALS AND METHODS: Nu/nu mice were implanted with the human SS cell line, Aska-SS, and treated with vehicle control, AUR, or a combination of AUR and CE (AUR-CE). Primary tumor size and weight were evaluated for the study duration and upon resection, respectively. Hematoxylin and eosin (H&E) and Ki-67 staining were performed to assess the local progression of SS. RESULTS: A statistically significant reduction in tumor size and weight was observed in the AUR- and AUR-CE-treated groups upon excision compared to that in the vehicle-treated group. The AUR-CE-treated group showed synergistic inhibition of local tumor growth. H&E staining of local SS tumors revealed decreased cell density and nuclear deformation in the AUR- and AUR-CE-treated groups compared to those in the vehicle-treated group. Immunohistochemical staining revealed a statistically significant decrease in Ki-67-positive cells in the AUR-CE-treated group compared to the vehicle-treated group. CONCLUSION: The combination of AUR and CE showed significant potential for delaying the local progression of SS. These findings support the repurposing of AUR and CE as early treatment options for SS.

First derivative synchronous spectrofluorimetric method for the simultaneous determination of tramadol and celecoxib in their dosage forms and human plasma.

One of the most common features of many different clinical conditions is pain; hence, there is a crucial need for eliminating or reducing it to a tolerable level to retrieve physical, psychological and social functioning. A first derivative synchronous spectrofluorimetry technique is proposed for the simultaneous determination of celecoxib and tramadol HCl, a recent coformulation authorized for treating acute pain in adults. The method includes using synchronous spectrofluorimetry at ∆λ = 80 nm where tramadol HCl was determined using first derivative technique at λ = 230.2 nm, while celecoxib was determined at λ = 288.24 nm. The proposed method was successfully applied to their co-formulated dosage forms in addition to spiked human plasma and validated in agreement with the guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). The linear ranges were found to be 0.50-5.0 and 0.15-0.50, the limits of detection to be 0.088 and 0.011 and the limits of quantification to be 0.266 and 0.032 µg/ml for celecoxib and tramadol, respectively. Statistical analysis revealed no significant difference when compared with previously reported methods as evidenced by the values of the variance ratio F-test and Student t-test. The proposed method was successfully applied to commercial dosage forms and spiked human samples. Moreover, the greenness of the proposed method was investigated based on the analytical eco-scale approach, with the results showing an excellent green scale with a score of 95.

Pharmacokinetic interactions between fexuprazan, a potassium-competitive acid blocker, and nonsteroidal anti-inflammatory drugs in healthy males.

Fexuprazan, a novel potassium-competitive acid blocker, is expected to be used for the prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) induced ulcer. This study aimed to evaluate pharmacokinetic (PK) interactions between fexuprazan and NSAIDs in healthy subjects. A randomized, open-label, multicenter, six-sequence, one-way crossover study was conducted in healthy male subjects. Subjects randomly received one of the study drugs (fexuprazan 40 mg BID, celecoxib 200 mg BID, naproxen 500 mg BID, or meloxicam 15 mg QD) for 5 or 7 days in the first period followed by the combination of fexuprazan and one of NSAIDs for the same days and the perpetrator additionally administered for 1-2 days in the second period. Serial blood samples for PK analysis were collected until 48- or 72-h post-dose at steady state. PK parameters including maximum plasma concentration at steady state (Cmax,ss) and area under plasma concentration-time curve over dosing interval at steady state (AUCτ,ss) were compared between monotherapy and combination therapy. The PKs of NSAIDs were not significantly altered by fexuprazan. For fexuprazan, differences in PK parameters (22% in Cmax, 19% in AUCτ,ss) were observed when co-administered with naproxen, but not clinically significant. The geometric mean ratio (90% confidence interval) of combination therapy to monotherapy for Cmax,ss and AUCτ,ss was 1.22 (1.02-1.46) and 1.19 (1.00-1.43), respectively. There were no significant changes in the systemic exposure of fexuprazan by celecoxib and meloxicam. Fexuprazan and NSAIDs did not show clinically meaningful PK interactions.

Exploring the effect of protein secondary structure on the solid state and physical stability of protein-based amorphous solid dispersions.

Amorphous solid dispersions (ASDs) using proteins as carriers have emerged as a promising strategy for stabilizing amorphous drug molecules. Proteins possess diverse three-dimensional structures that significantly influence their own properties and may also impact the properties of ASDs. We prepared ß-lactoglobulin (BLG) with different contents of ß-sheet and α-helical secondary structures by initially dissolving BLG in different mixed solvents, containing different ratios of water, methanol/ethanol, and acetic acid, followed by spray drying of the solutions. Our findings revealed that an increase in α-helical content resulted in a decrease in the glass transition temperature (Tg) of the protein. Subsequently, we utilized the corresponding mixed solvents to dissolve both BLG and the model drug celecoxib (CEL), allowing the preparation of ASDs containing either ß-sheet-rich or α-helix/random coil-rich BLG. Using spray drying, we successfully developed BLG-based ASDs with drug loadings ranging from 10 wt% to 90 wt%. At drug loadings below 40 wt%, samples prepared using both methods exhibited single-phase ASDs. However, heterogeneous systems formed when the drug loading exceeded 40 wt%. At higher drug loadings, physical stability assessments demonstrated that the α-helix/random coil-rich BLG structure exerted a more pronounced stabilizing effect on the drug-rich phase compared to the ß-sheet-rich BLG. Overall, our results highlight the importance of considering protein secondary structure in the design of ASDs.

A series of indole-derived γ-hydroxy propiolate esters as potent anti-inflammatory agents: Design, synthesis, in-vitro and in-vivo biological studies.

A variety of novel indole-derived γ-hydroxy propiolate esters were designed, synthesized, and evaluated for their anti-inflammatory activity in-vitro and in-vivo. According to the nitric oxide (NO) inhibitory analysis, all compounds showed potent NO inhibitory ability in a dose-dependent manner, with no apparent cytotoxicity. The model compound, L-37, also exhibited significant potency in PGE2 inhibition. In addition, compounds L-37 and L-39 can downregulate the expression of COX-2 enzyme at 5 µM via ELISA experiment. Compound L-37 (1 µM) also inhibited the PGF1 production as well as the expression of COX-1, but displayed weak inhibition activity towards the Leukotrienes (LT) and Thromboxane-B2 (TXB-2) production. However, the expression of 5-LOX was significantly inhibited by compound L-39 at 5 µM. Xylene-induced ear edema model was explored for in-vivo anti-inflammatory evaluation, compound L-37 showed similar inhibitory activity compared with celecoxib, approximately 80% at 50 mg/kg dosage. Every outcome showed that the newly synthesized compounds can effectively inhibit inflammation.

A Low Transition Temperature Mixture-based viscosupplementation complemented with celecoxib for osteoarthritis treatment.

Viscosupplementation consists of hyaluronic acid (HA) intra-articular injections, commonly applied for osteoarthritis treatment while non-steroidal anti-inflammatory drugs (NSAIDs) are widely administered for pain relief. Here, HA and a NSAID (celecoxib) were combined in a formulation based on a low transition temperature mixture (LTTM) of glycerol:sorbitol, reported to increase celecoxib's solubility, thus rendering a potential alternative viscosupplement envisioning enhanced therapeutic efficiency. The inclusion of glucosamine, a cartilage precursor, was also studied. The developed formulations were assessed in terms of rheological properties, crucial for viscosupplementation: the parameters of crossover frequency, storage (G') and loss (G'') moduli, zero-shear-rate viscosity, stable viscosity across temperatures, and shear thinning behaviour, support viscoelastic properties suitable for viscosupplementation. Additionally, the gels biocompatibility was confirmed in chondrogenic cells (ATDC5). Regarding drug release studies, high and low clearance scenarios demonstrated an increased celecoxib (CEX) release from the gel (6 to 73-fold), compared to dissolution in PBS. The low clearance setup presented the highest and most sustained CEX release, highlighting the importance of the gel structure in CEX delivery. NMR stability studies over time demonstrated the LTTM+HA+CEX (GHA+CEX) gel as viable candidate for further in vivo evaluation. In sum, the features of GHA+CEX support its potential use as alternative viscosupplement.

Design and Evaluation of NSAID Derivatives as AKR1C3 Inhibitors for Breast Cancer Treatment through Computer-Aided Drug Design and In Vitro Analysis.

Breast cancer is a major global health issue, causing high incidence and mortality rates as well as psychological stress for patients. Chemotherapy resistance is a common challenge, and the Aldo-keto reductase family one-member C3 enzyme is associated with resistance to anthracyclines like doxorubicin. Recent studies have identified celecoxib as a potential treatment for breast cancer. Virtual screening was conducted using a quantitative structure-activity relationship model to develop similar drugs; this involved backpropagation of artificial neural networks and structure-based virtual screening. The screening revealed that the C-6 molecule had a higher affinity for the enzyme (-11.4 kcal/mol), a lower half-maximal inhibitory concentration value (1.7 µM), and a safer toxicological profile than celecoxib. The compound C-6 was synthesized with an 82% yield, and its biological activity was evaluated. The results showed that C-6 had a more substantial cytotoxic effect on MCF-7 cells (62%) compared to DOX (63%) and celecoxib (79.5%). Additionally, C-6 had a less harmful impact on healthy L929 cells than DOX and celecoxib. These findings suggest that C-6 has promising potential as a breast cancer treatment.

Colon impairments and inflammation driven by an altered gut microbiota leads to social behavior deficits rescued by hyaluronic acid and celecoxib.

BACKGROUND: The exact mechanisms linking the gut microbiota and social behavior are still under investigation. We aimed to explore the role of the gut microbiota in shaping social behavior deficits using selectively bred mice possessing dominant (Dom) or submissive (Sub) behavior features. Sub mice exhibit asocial, depressive- and anxiety-like behaviors, as well as systemic inflammation, all of which are shaped by their impaired gut microbiota composition. METHODS: An age-dependent comparative analysis of the gut microbiota composition of Dom and Sub mice was performed using 16S rRNA sequencing, from early infancy to adulthood. Dom and Sub gastrointestinal (GI) tract anatomy, function, and immune profiling analyses were performed using histology, RT-PCR, flow cytometry, cytokine array, and dextran-FITC permeability assays. Short chain fatty acids (SCFA) levels in the colons of Dom and Sub mice were quantified using targeted metabolomics. To support our findings, adult Sub mice were orally treated with hyaluronic acid (HA) (30 mg/kg) or with the non-steroidal anti-inflammatory agent celecoxib (16 mg/kg). RESULTS: We demonstrate that from early infancy the Sub mouse gut microbiota lacks essential bacteria for immune maturation, including Lactobacillus and Bifidobacterium genera. Furthermore, from birth, Sub mice possess a thicker colon mucin layer, and from early adulthood, they exhibit shorter colonic length, altered colon integrity with increased gut permeability, reduced SCFA levels and decreased regulatory T-cells, compared to Dom mice. Therapeutic intervention in adult Sub mice treated with HA, celecoxib, or both agents, rescued Sub mice phenotypes. HA treatment reduced Sub mouse gut permeability, increased colon length, and improved mouse social behavior deficits. Treatment with celecoxib increased sociability, reduced depressive- and anxiety-like behaviors, and increased colon length, and a combined treatment resulted in similar effects as celecoxib administered as a single agent. CONCLUSIONS: Overall, our data suggest that treating colon inflammation and decreasing gut permeability can restore gut physiology and prevent social deficits later in life. These findings provide critical insights into the importance of early life gut microbiota in shaping gut immunity, functionality, and social behavior, and may be beneficial for the development of future therapeutic strategies.

Celecoxib and sulindac sulfide elicit anticancer effects on PIK3CA-mutated head and neck cancer cells through endoplasmic reticulum stress, reactive oxygen species, and mitochondrial dysfunction.

Gain-of-function mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha gene (PIK3CA) is a significant factor in head and neck cancer (HNC). Patients with HNC harboring PIK3CA mutations receive therapeutic benefits from the use of non-steroidal anti-inflammatory drugs (NSAIDs). However, the molecular mechanisms underlying these effects remain unknown. Here, we examined the Detroit562 and FaDu cell lines as HNC models with and without a hyperactive PIK3CA mutation (H1047R), respectively, regarding their possible distinct responses to the NSAIDs celecoxib and sulindac sulfide (SUS). Detroit562 cells exhibited relatively high PI3K/Akt pathway-dependent cyclooxygenase-2 (COX-2) expression, associated with cell proliferation. Celecoxib treatment restricted cell proliferation and upregulated endoplasmic reticulum (ER) stress-related markers, including GRP78, C/EBP-homologous protein, activating transcription factor 4, death receptor 5, and reactive oxygen species (ROS). These effects were much stronger in Detroit562 cells than in FaDu cells and were largely COX-2-independent. SUS treatment yielded similar results. Salubrinal (an ER stress inhibitor) and N-acetyl-L-cysteine (a ROS scavenger) prevented NSAID-induced ROS generation and ER stress, respectively, indicating crosstalk between ER and oxidative stress. In addition, celecoxib and/or SUS elevated cleaved caspase-3 levels, Bcl-2-associated X protein/Bcl-2-interacting mediator of cell death expression, and mitochondrial damage, which was more pronounced in Detroit562 than in FaDu cells. Salubrinal and N-acetyl-L-cysteine attenuated celecoxib-induced mitochondrial dysfunction. Collectively, our results suggest that celecoxib and SUS efficiently suppress activating PIK3CA mutation-harboring HNC progression by inducing ER and oxidative stress and mitochondrial dysfunction, leading to apoptotic cell death, further supporting NSAID treatment as a useful strategy for oncogenic PIK3CA-mutated HNC therapy.

Successful Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus with Celecoxib: A Promising Therapeutic Option.

BACKGROUND Nephrogenic diabetic insipidus (NDI) poses a challenge in clinical management, particularly when associated with lithium ingestion. Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for the treatment of numerous diseases worldwide, including NDI. However, many studies have reported the diverse adverse effects of long-term use of non-selective NSAIDs. Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is a better drug to relieve pain and inflammation in terms of long-term safety and efficacy than non-selective NSAIDs. Nevertheless, there are few reports describing the effectiveness of celecoxib in treating NDI. CASE REPORT We report a case of a 46-year-old woman with schizophrenia who presented with severe hypernatremia and refractory polyuria due to lithium-induced NDI. Cessation of lithium ingestion and traditional treatments, including trichlormethiazide and desmopressin, yielded minimal improvement in her hypernatremia and polyuria. Her sodium level needed to be strictly controlled with the infusion of dextrose 5% in water. Given the safety of celecoxib, we decided to initiate celecoxib as the treatment of lithium-induced NDI instead of indomethacin. Notably, the introduction of celecoxib led to a substantial and sustained amelioration of polyuria and hypernatremia without any celecoxib-associated adverse effects. Even after transfer to another hospital, stability in serum sodium levels persisted with celecoxib. CONCLUSIONS We presented a case of lithium-induced NDI successfully treated with celecoxib, a selective COX-2 inhibitor. To the best of our knowledge, this is the first reported case of successful treatment of lithium-induced NDI with celecoxib, and suggests celecoxib is a viable therapeutic option warranting further exploration. Physicians should consider its use when faced with the challenging management of lithium-induced NDI.

Injectable, self-healing hydrogels based on gelatin, quaternized chitosan, and laponite as localized celecoxib delivery system for nucleus pulpous repair.

Utilization of injectable hydrogels stands as a paradigm of minimally invasive intervention in the context of intervertebral disc degeneration treatment. Restoration of nucleus pulposus (NP) function exerts a profound influence in alleviating back pain. This study introduces an innovative class of injectable shear-thinning hydrogels, founded on quaternized chitosan (QCS), gelatin (GEL), and laponite (LAP) with the capacity for sustained release of the anti-inflammatory drug, celecoxib (CLX). First, synthesis of Magnesium-Aluminum-Layered double hydroxide (LDH) was achieved through a co-precipitation methodology, as a carrier for celecoxib and a source of Mg ions. Intercalation of celecoxib within LDH layers (LDH-CLX) was verified through a battery of analytical techniques, including FTIR, XRD, SEM, EDAX, TGA and UV-visible spectroscopy confirmed a drug loading efficiency of 39.22 ± 0.09 % within LDH. Then, LDH-CLX was loaded in the optimal GEL-QCS-LAP hydrogel under physiological conditions. Release behavior (15 days profile), mechanical properties, swelling ratio, and degradation rate of the resulting composite were evaluated. A G* of 15-47 kPa was recorded for the hydrogel at 22-40 °C, indicating gel stability in this temperature range. Self-healing properties and injectability of the composite were proved by rheological measurements. Also, ex vivo injection into intervertebral disc of sheep, evidenced in situ forming and NP cavity filling behavior of the hydrogel. Support of GEL-QCS-LAP/LDH-CLX (containing mg2+ ions) for viability and proliferation (from ~94 % on day 1 to ~134 % on day 7) of NP cells proved using MTT assay, DAPI and Live/Dead assays. The hydrogel could significantly upregulate secretion of glycosaminoglycan (GAG, from 4.68 ± 0.1 to 27.54 ± 1.0 µg/ml), when LHD-CLX3% was loaded. We conclude that presence of mg2+ ion and celecoxib in the hydrogel can lead to creation of a suitable environment that encourages GAG secretion. In conclusion, the formulated hydrogel holds promise as a minimally invasive candidate for degenerative disc repair.

Tailored quinoline hybrids as promising COX-2/15-LOX dual inhibitors endowed with diverse safety profile: Design, synthesis, SAR, and histopathological study.

Complications of the worldwide use of non-steroidal anti-inflammatory drugs (NSAIDs) sparked scientists to design novel harmless alternatives as an urgent need. So, a unique hybridization tactic of quinoline/pyrazole/thioamide (4a-c) has been rationalized and synthesized as potential COX-2/15-LOX dual inhibitors, utilizing relevant reported studies on these pharmacophores. Moreover, we extended these preceding hybrids into more varied functionality, bearing crucial thiazole scaffolds(5a-l). All the synthesized hybrids were evaluatedin vitroas COX-2/15-LOX dual inhibitors. Initially, series4a-cexhibited significant potency towards 15-LOX inhibition (IC50 = 5.454-4.509 µM) compared to meclofenamate sodium (IC50 = 3.837 µM). Moreover, they revealed reasonable inhibitory activities against the COX-2 enzyme in comparison to celecoxib.Otherwise, conjugates 5a-ldisclosed marked inhibitory activity against 15-LOX and strong inhibitory to COX-2. In particular, hybrids5d(IC50 = 0.239 µM, SI = 8.95), 5h(IC50 = 0.234 µM, SI = 20.35) and 5l (IC50 = 0.201 µM, SI = 14.42) revealed more potency and selectivity outperforming celecoxib (IC50 = 0.512 µM, SI = 4.28). In addition, the most potentcompounds, 4a, 5d, 5h, and 5l have been elected for further in vivoevaluation and displayed potent inhibition of edema in the carrageenan-induced rat paw edema test that surpassed indomethacin. Further, compounds5d, 5h, and 5l decreased serum inflammatory markers including oxidative biomarkersiNO, and pro-inflammatory mediators cytokines like TNF-α, IL-6, and PGE. Ulcerogenic liability for tested compounds demonstrated obvious gastric mucosal safety. Furthermore, a histopathological study for compound 5l suggested a confirmatory comprehensive safety profile for stomach, kidney, and heart tissues. Docking and drug-likeness studies offered a good convention with the obtained biological investigation.

Celecoxib attenuates interleukin 33-induced expression of vascular cell adhesion molecule-1 in human ovarian endometriotic stromal cells.

OBJECTIVE: Endometriosis is an estrogen-dependent chronic inflammatory disease in women of reproductive age. A review of the literature revealed that cytokines and inflammatory factors are associated with endometriosis-associated infertility. Interleukin 33 (IL-33) is a strong inducer of other pro-inflammatory cytokines. Vascular cell adhesion molecule-1 (VCAM-1) plays a central role in recruiting inflammatory cells, whose expression facilitates leukocyte adhesion and is rapidly induced by pro-inflammatory cytokines. Many studies have indicated that VCAM-1 expression is high in endometriosis; however, whether the expression of VCAM-1 is related to IL-33 is unclear. MATERIALS AND METHODS: Human ovarian endometriotic stromal cells (hOVEN-SCs) were treated with IL-33 to enable investigation of cell characterization, gene and protein expression, and signal pathways. Proliferation potential was measured using an MTT assay. Gene expression was analyzed using reverse transcription-polymerase chain reaction. Protein expression assay was performed using western blot analysis. RESULTS: This study investigated the effects of IL-33 on VCAM-1 and COX-2 expression in hOVEN-SCs. First, the results revealed that the IL-33/ST2/mitogen-activated protein kinase (MAPK) signaling pathway could increase the expression of VCAM-1 and COX-2 in hOVEN-SCs. Second, we discovered that COX-2 expression was essential for IL-33-induced VCAM-1 expression because the effects could be negated through NS398, a selective COX-2 inhibitor. Finally, treatment of IL-33-treated hOVEN-SCs with celecoxib significantly and dose-responsively decreased VCAM-1 expression. CONCLUSION: Taken together, these results indicate that IL-33 can upregulate VCAM-1 expression in hOVEN-SCs through the IL-33/ST2/MAPK/COX-2 signaling pathway and thereby contribute to endometriosis.

Cardioprotective role of royal jelly in the prevention of celecoxib-mediated cardiotoxicity in adult male albino rats.

BACKGROUND: Celecoxib, a cyclooxygenase-2 selective inhibitor non-steroidal anti-inflammatory drugs, is used for the management of short- and long-term pain as well as in other inflammatory conditions. Unfortunately, its chronic use is highly associated with serious abnormal cardiovascular events. The current study was designed to explore the effect of long-term administration of celecoxib on the cardiac tissues of male albino rats. The study also examined the alleged cardioprotective effect of royal jelly. METHODS: Thirty, male albino rats were randomly divided into 3 equal groups; 10 each: (1) rats served as the control group and received no drug; (2) rats received celecoxib (50 mg/kg/day, orally), for 30 consecutive days; (3) rats received celecoxib (50 mg/kg/day, orally) plus royal jelly (300 mg/kg/day, orally) for 30 consecutive days. Sera were collected to assay cardiac enzymes and oxidant/antioxidant status. Rats were euthanatized and cardiac tissues were dissected for quantitative estimation of apoptotic genes (Bax) and anti-apoptotic gene (Bcl-2). RESULTS: Long-term celecoxib administration caused cardiotoxicity in male albino rats as manifested by significant elevation of serum levels of creatine phosphokinase (CPK), creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH), with ameliorative effects of royal jelly against celecoxib-induced cardiotoxicity as manifested by significantly decrease in serum CPK, CK-MB, and LDH levels. It also showed a significant decrease in the oxidative stress indicator malondialdehyde (MDA) levels and the bax gene. Additionally, it demonstrated significant increases in the bcl-2 gene and superoxide dismutase (SOD) levels, which contribute to its therapeutic effects against celecoxib-induced cardiotoxicity. CONCLUSION: Long-term celecoxib administration caused cardiotoxicity in male albino rats with protective effect of royal jelly being given together. It could be concluded that royal jelly may prove a useful adjunct in patients being prescribed celecoxib. TRIAL REGISTRATION: Not applicable.

Drug-induced liver injury (DILI) ascribed to non-steroidal anti-inflammatory drugs (NSAIDs) in the USA-Update with genetic correlations.

OBJECTIVE: To describe patients with NSAID-DILI, including genetic factors associated with idiosyncratic DILI. METHODS: In DILIN, subjects with presumed DILI are enrolled and followed for at least 6 months. Causality is adjudicated by a Delphic approach. HLA sequencing of multiethnic NSAID-DILI patients and HLA allele imputation of matching population controls were performed following overall, class and drug-based association analysis. Significant results were tested in a non-Hispanic White (NHW) case-control replication cohort. RESULTS: Between September 2004 and March 2022, causality was adjudicated in 2498, and 55 (41 [75%] women) were assessed as likely due to NSAIDs. Median age at onset was 55 y (range 22-83 y). Diclofenac was the causative drug in 29, celecoxib in 7, ibuprofen in 5, etodolac and meloxicam each in 4. Except for meloxicam and oxaprozin (n = 2), the liver injury was hepatocellular with median R 15-25. HLA-DRB1*04:03 and HLA-B*35:03 were significantly more frequent in NSAID-DILI patients than in non-NSAID DILI controls. Interestingly, 85% of the HLA-DRB1*04:03 carriers developed DILI due to the use of acetic acid derivative NSAIDs, supporting the hypothesis that HLA-DRB1*04:03 could be a drug and/or class risk factor. HLA-B*35:03 but not HLA-DRB1*04:03 association was confirmed in the independent NHW replication cohort, which was largely driven by diclofenac. CONCLUSIONS: Despite prevalent use, NSAID-DILI is infrequent in the United States. Diclofenac is the most commonly implicated, and adherence to warnings of risk and close observation are recommended. The increased frequency of HLA-B*35:03 and DRB1*04:03, driven by diclofenac, suggests the importance of immune-mediated responses.

Repurposed Drugs Celecoxib and Fmoc-L-Leucine Alone and in Combination as Temozolomide-Resistant Antiglioma Agents-Comparative Studies on Normal and Immortalized Cell Lines, and on C. elegans.

Glioblastoma multiforme therapy remains a significant challenge since there is a lack of effective treatment for this cancer. As most of the examined gliomas express or overexpress cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptors γ (PPARγ), we decided to use these proteins as therapeutic targets. Toxicity, antiproliferative, proapoptotic, and antimigratory activity of COX-2 inhibitor (celecoxib-CXB) and/or PPARγ agonist (Fmoc-L-Leucine-FL) was examined in vitro on temozolomide resistant U-118 MG glioma cell line and comparatively on BJ normal fibroblasts and immortalized HaCaT keratinocytes. The in vivo activity of both agents was studied on C. elegans nematode. Both drugs effectively destroyed U-118 MG glioma cells via antiproliferative, pro-apoptotic, and anti-migratory effects in a concentration range 50-100 µM. The mechanism of action of CXB and FL against glioma was COX-2 and PPARγ dependent and resulted in up-regulation of these factors. Unlike reports by other authors, we did not observe the expected synergistic or additive effect of both drugs. Comparative studies on normal BJ fibroblast cells and immortalized HaCaT keratinocytes showed that the tested drugs did not have a selective effect on glioma cells and their mechanism of action differs significantly from that observed in the case of glioma. HaCaTs did not react with concomitant changes in the expression of COX-2 and PPARγ and were resistant to FL. Safety tests of repurposing drugs used in cancer therapy tested on C. elegans nematode indicated that CXB, FL, or their mixture at a concentration of up to 100 µM had no significant effect on the entire nematode organism up to 4th day of incubation. After a 7-day treatment, CXB significantly shortened the lifespan of C. elegans at 25-400 µM concentration and body length at 50-400 µM concentration.

Preparation of celecoxib loaded bioactive glass chitosan composite hydrogels: a simple approach for therapeutic delivery of NSAIDs.

Arthritis causes inflammatory damage to joints and connective tissues. In the treatment of arthritis, precise and controlled drug delivery to the target site is among the frontline research approaches. In the present research work, celecoxib drug and bioactive glass incorporated chitosan hydrogels were fabricated by the freeze gelation method. Fourier transform infrared spectroscopy, scanning electron microscopy, and thermogravimetric analysis/differential scanning calorimetry techniques were used to characterize the hydrogels. Different kinetic models were applied to study the drug release kinetics. The celecoxib release was mainly controlled by a Fickian diffusion process followed by the Higuchi model. Maximum 86.2% drug entrapment was observed in 20 mg drug-loaded hydrogel and its swelling ratio was 115.5% in 28 d. Good hydrophilicity, good drug entrapment efficiency, and moderate drug release patterns of hydrogels can make them suitable for sustained drug release. The cytocompatibility of hydrogels was established by performing an MTT assay on the BHK-21 fibroblast cell line. The promising results have proved that hydrogels can be considered potential material for the slow release of anti-inflammatory drug at the target site in arthritis.

Celecoxib attenuates hindlimb unloading-induced muscle atrophy via suppressing inflammation, oxidative stress and ER stress by inhibiting STAT3.

Improving inflammation may serve as useful therapeutic interventions for the hindlimb unloading-induced disuse muscle atrophy. Celecoxib is a selective non-steroidal anti-inflammatory drug. We aimed to determine the role and mechanism of celecoxib in hindlimb unloading-induced disuse muscle atrophy. Celecoxib significantly attenuated the decrease in soleus muscle mass, hindlimb muscle function and the shift from slow- to fast-twitch muscle fibers caused by hindlimb unloading in rats. Importantly, celecoxib inhibited the increased expression of inflammatory factors, macrophage infiltration in damaged soleus muscle. Mechanistically, Celecoxib could significantly reduce oxidative stress and endoplasmic reticulum stress in soleus muscle of unloaded rats. Furthermore, celecoxib inhibited muscle proteolysis by reducing the levels of MAFbx, MuRF1, and autophagy related proteins maybe by inhibiting the activation of pro-inflammatory STAT3 pathway in vivo and in vitro. This study is the first to demonstrate that celecoxib can attenuate disuse muscle atrophy caused by hindlimb unloading via suppressing inflammation, oxidative stress and endoplasmic reticulum stress probably, improving target muscle function and reversing the shift of muscle fiber types by inhibiting STAT3 pathways-mediated inflammatory cascade. This study not only enriches the potential molecular regulatory mechanisms, but also provides new potential therapeutic targets for disuse muscle atrophy.

Reproducible Synthesis of Biocompatible Albumin Nanoparticles Designed for Intra-articular Administration of Celecoxib to Treat Osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis, with intra-articular (IA) delivery of therapeutics being the current best option to treat pain and inflammation. However, IA delivery is challenging due to the rapid clearance of therapeutics from the joint and the need for repeated injections. Thus, there is a need for long-acting delivery systems that increase the drug retention time in joints with the capacity to penetrate OA cartilage. As pharmaceutical utility also demands that this is achieved using biocompatible materials that provide colloidal stability, our aim was to develop a nanoparticle (NP) delivery system loaded with the COX-2 inhibitor celecoxib that can meet these criteria. We devised a reproducible and economical method to synthesize the colloidally stable albumin NPs loaded with celecoxib without the use of any of the following conditions: high temperatures at which albumin denaturation occurs, polymer coatings, oils, Class 1/2 solvents, and chemical protein cross-linkers. The spherical NP suspensions were biocompatible, monodisperse with average diameters of 72 nm (ideal for OA cartilage penetration), and they were stable over 6 months at 4 °C. Moreover, the NPs loaded celecoxib at higher levels than those required for the therapeutic response in arthritic joints. For these reasons, they are the first of their kind. Labeled NPs were internalized by primary human articular chondrocytes cultured from the knee joints of OA patients. The NPs reduced the concentration of inflammatory mediator prostaglandin E2 released by the primaries, an indication of retained bioactivity following NP synthesis. Similar results were observed in lipopolysaccharide-stimulated human THP-1 monocytes. The IA administration of these NPs is expected to avoid side-effects associated with oral administration of celecoxib and to maintain a high local concentration in the knee joint over a sustained period. They are now ready for evaluation by IA administration in animal models of OA.

Emotional Blunting in Depression in the PREDDICT Clinical Trial: Inflammation-Stratified Augmentation of Vortioxetine With Celecoxib.

BACKGROUND: Emotional symptoms are recognized as a key feature in individuals with major depressive disorder. Previously, emotional blunting has been described both as a side effect of antidepressant treatment and as a symptom of depression. Little is known about the change of emotional blunting during antidepressant treatment. METHODS: The PREDDICT trial is a randomized, placebo-controlled, 6-week trial on the augmentation of vortioxetine with the anti-inflammatory agent celecoxib or placebo. Presently we report on exploratory secondary outcomes of changes in emotional blunting in depression assessed with the Oxford Depression Questionnaire (ODQ) total score and subscores from baseline to 8-week, 3-month, and 6-month follow-up assessments. RESULTS: In the whole group, there was a significant improvement in the ODQ total score and all subscores after 8 weeks. After stratification of participants into the treatment groups, the ODQ total score as well as subscores related to emotional blunting as a symptom of depression (reduction in positive emotions, not caring) improved between baseline and all follow-up time points in both treatment groups. Changes in subscores considered as a side effect of antidepressants (general reduction in emotions, emotional detachment) were inconclusive in both treatment groups. Overall, the placebo-augmented group showed slightly better results in changes of emotional blunting scores than the celecoxib group as did those with elevated inflammation at screening, regardless of treatment group. CONCLUSIONS: This analysis suggests favorable effects of vortioxetine on emotional blunting in both short- and long-term course. The beneficial impact of vortioxetine on emotional blunting was weaker in celecoxib-augmented patients compared with placebo, possibly due to pharmacokinetic interactions. Clinical Trials Registration: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p.