Combination Of Celecoxib Research Articles

Abstract 5275: Celecoxib and chloroquine enhance the antitumor effect of immune checkpoint blockade therapy, in a syngeneic mouse model for pancreatic cancer

Abstract Immune checkpoint inhibitors (ICIs) have shown impressive clinical activities in some cancer types, but they have yet to demonstrate any meaningful clinical benefit in patients with pancreatic ductal adenocarcinoma (PDAC) except those with microsatellite instability high (MSI-H) tumors. Several recent studies showed that concomitant use of NSAIDs such as celecoxib by patients with certain cancers could improve the survival benefit of ICI treatment (e.g., Sebastian et al, Clin Lung Cancer, 2023;). Furthermore, autophagy inhibitors such as chloroquine were also reported to sensitize pancreatic tumors to the treatment of ICIs in mouse models for PDAC (Yamamoto, et al, Nature, 2020). We recently reported that the combination of chemotherapy (triple combination of nab-paclitaxel + gemcitabine + cisplatin) and a mouse surrogate of the IFc-enhanced anti-CTLA-4 antibody botensilimab, showed significantly improved antitumor activity in immune competent KPC syngeneic mouse model for PDAC [Tanne, et al, Cancer Res (13_Supplement), 2020]. In this study, we sought to determine whether or not the addition of celecoxib and/or chloroquine further improve the antitumor activity of triple chemotherapy and ICI in the syngeneic KPC model. We first found that celecoxib (30mg/kg P.O. QDx21) significantly enhanced the tumor growth inhibition when added to triple chemotherapy (Gemcitabine 70mg/kg I.P., Cisplatin 4mg/kg I.P., Nab-paclitaxel 25mg/kg I.V. days 1,4 and 7) plus the murine equivalents of botensilimab (100ug I.P. BIW for three weeks) and balstilimab (200ug I.P. BIW for three weeks) (p=0.004, N=10). We then performed a pilot study to assess if adding chloroquine could further improve the activity. While adding chloroquine (60mg/kg I.P. QDx21) alone did not significantly affect tumor growth the addition of both chloroquine and celecoxib greatly improve the tumor growth inhibition compared to just the triple chemotherapy and ICIs (p=0.009, N=5). Overall, our data showed that celecoxib or the combination of celecoxib and chloroquine could substantially sensitize the mouse pancreatic tumors to the treatment of chemotherapy and ICIs. (This work was supported in part by the Seena Magowitz Foundation and the Purple Pansies) Citation Format: Jaeger Moore, Dhan Chand, Daniel Levey, Daniel Von Hoff, Haiyong Han. Celecoxib and chloroquine enhance the antitumor effect of immune checkpoint blockade therapy, in a syngeneic mouse model for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5275.

Celecoxib enhances the response of tumor cells to cisplatin through upregulating PUMA in non–small cell lung cancer carrying wild-type p53

Abstract Celecoxib, a cyclooxygenase-2 inhibitor, can enhance the efficacy of chemotherapy; however, its effect seems inconsistent. In this study, we investigated whether celecoxib would increase the antiproliferative effects of cisplatin in human lung cancer cells. Our data demonstrated the synergistic effects of celecoxib with cisplatin in wild-type p53 cells and their antagonistic effects in mutated or deleted p53 cells. Combination indices of 0.82 to 0.93 reflected a synergistic effect between celecoxib and cisplatin in lung cancer cells with wild-type p53. Combination indices of 1.63 to 3.00 reflected antagonism between celecoxib and cisplatin in lung cancer cells with mutated or deleted p53. Compared with that in cells with mutated or deleted p53, apoptosis significantly increased with the addition of celecoxib and cisplatin in wild-type p53 cells (P < 0.05). Moreover, the results in vivo were similar to those in vitro: celecoxib combined with cisplatin slowed tumor growth in wild-type p53 groups and not in mutated or deleted p53 groups. In addition, celecoxib promoted p53 translocation into the nucleus and upregulated active p53 expression in wild-type p53 cells. Celecoxib combined with cisplatin upregulated PUMA (PUMA is a downstream gene of p53) after active p53 increased in wild-type p53 cells. In summary, the combination of celecoxib and cisplatin demonstrates clear synergistic effects in wild-type p53 cells and antagonistic effects in mutated or deleted p53 cells. The synergistic effect was achieved by apoptosis, induced by upregulating PUMA. Our results will provide a new treatment strategy for patients carrying wild-type p53, insensitive to cisplatin.

ADT-OH synergistically enhanced the antitumor activity of celecoxib in human colorectal cancer cells.

Colorectal cancer is one of the most prevalent cancers in the world, but the research on its prevention, early diagnosis and treatment is still a major challenge in clinical oncology. Thus, there is a pressing requirement to find effective strategies to improve the survival of colon cancer patients. Celecoxib has been accounted to be an effective antitumor drug, but may exhibit significant side effects. In recent studies, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), one of the most commonly used reagents for the synthesis of sustained-release H2 S donors, has also been reported to inhibit cancer progression by affecting processes such as cell cycle, angiogenesis, and apoptosis. Therefore, we evaluated the therapeutic effect of the combination of ADT-OH and celecoxib on colorectal cancer through in vitro and in vivo, hoping to achieve better therapeutic effect and reduce the effect of celecoxib on gastric injury through exogenous administration of H2 S. Our results demonstrated that ADT-OH combined with celecoxib synergistically inhibited the proliferation and migration ability of human colorectal cancer HCT116 cells, altered cell cycle and cytoskeleton, increased intracellular reactive oxygen species (ROS), and promoted cell apoptosis. Noteworthy, in vivo studies also indicated the excellent antitumor therapeutic effect of the combination therapy without apparent toxicity. In general, our results provide a reasonable combination strategy of low-dose ADT-OH and celecoxib in the preclinical application of colorectal cancer.

Eco-friendly simultaneous multi-spectrophotometric estimation of the newly approved drug combination of celecoxib and tramadol hydrochloride tablets in its dosage form

Food and Drug Administration (FDA) recently approved co-formulated celecoxib and tramadol for the treatment of acute pain in adults. Three spectrophotometric methods were efficiently applied to estimate the co-formulated Celecoxib and Tramadol in their tablets; second derivative 2D-spectrophotometry technique (method I), induced dual-wavelength technique (method II) and dual-wavelength resolution technique (method III). The proposed methods were successfully validated following the International Council for Harmonisation (ICH) guidelines and statistically assessed based on the correlation coefficients, relative standard deviations as well as detection and quantitation limits. The obtained results revealed non-significant differences compared to the reported results as revealed by the variance ratio F test and Student t test. Moreover, the applied techniques were further assessed concerning their greenness based on the analytical eco-scale method revealing an excellent green scale with a final score of 95. The proposed spectrophotometric techniques could be applied for the routine analysis and quality control of the studied drugs in their dosage form.

Codelivery of afuresertib and celecoxib by IL4RPep-1-targeting nanoparticles for effective treatment against melanoma

Melanoma is one of the most aggressive and deadly forms of skin cancer, and effective treatments need to be developed. The combination of chemoimmunotherapy has emerged as a promising strategy for treating cancer. However, this strategy still has several limitations, including the inability of more than two drugs to reach tumor tissue simultaneously and the risk of serious adverse effects. The use of nanodrug delivery systems is an effective method to successfully combine these therapies, as they reduce side effects and improve bioavailability. In this study, we developed IL4RPep-1-targeting peptide nanoparticles (IPP NPs) for the codelivery of afuresertib and celecoxib for melanoma treatment by taking advantage of the high drug loading capacity and favorable pharmacokinetic profile of the poly(lactide-co-glycolide) nanoparticle platform. IPP NPs efficiently target three different types of melanoma cells in vitro and significantly accumulate at the tumor site in vivo. ​In both ectopic and pulmonary metastatic melanoma models, targeted codelivery of afuresertib and celecoxib not only promotes melanoma cell apoptosis but also reprograms M2-type macrophages into M1-type macrophages, reconstructing the tumor immune microenvironment and activating the immune response against cancer cells. In addition, this highly coordinated precise delivery of the drug to tumor cells significantly reduces adverse reactions associated with the combination of afuresertib and celecoxib. In summary, IPP NPs exhibit an accurate pH response and ideal targeted drug delivery capabilities for combination chemotherapy and immunotherapy, offering therapeutic potential for this combination in melanoma.

Thermoresponsive mucoadhesive hydrogel based on Pluronic F127/thiolated glycol chitosan for intravesical administration of celecoxib/gemcitabine

In recent years, mucoadhesivein situ gelling formulations for intravesical application have been studied to improve the therapeutic outcomes of bladder cancer patients. Here, we carefully tuned a Pluronic F127-based thermoresponsive gel using two mucoadhesive thiolated derivatives of glycol chitosan, S-preactivated N-acetylcysteine (NAC)- and glutathione (GSH)-glycol chitosan (GC). The gel was loaded with a combination of Gemcitabine (GEM) and Celecoxib (CEX), and the aqueous solubility of the latter was increased for a synergic influence between Pluronic and the inclusion complex of 2-Hydroxypropyl-β-cyclodextrin/CEX. The effect of the inclusion complex of two mucoadhesive polymers on rheological features of Pluronic based gels was highlighted to select the best performance. Finally, ex-vivo retention studies, mucosal penetration and in-vitro drug release of the selected systems were monitored for 24 h, providing enhanced retention properties (50% after 6 h) and continued drug release.

Phase I Study of a Combination of Fluvastatin and Celecoxib in Children with Relapsing/Refractory Low-Grade or High-Grade Glioma (FLUVABREX)

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.

Investigating the effect of vandetanib and celecoxib combination on angiogenesis

ObjectiveAngiogenesis plays an important role in various physiological and pathological conditions and is essential for tumor growth and metastasis. The aim of this study was to evaluate the effect of a combination of vandetanib and celecoxib on angiogenic tube formation and its effect on angiogenic genes (MMP-2 and MMP-9) using an in vitro model of human umbilical vein endothelial cells (HUVECs). MethodsHUVECs were cultured and verified by flow cytometry. HUVECs were then treated with vandetanib, celecoxib, and the combination of both drugs. Then, we investigated cell viability and cell apoptosis by MTT assays and flow cytometry. The process of angiogenesis was analyzed by tube formation assays, and the effect on angiogenic genes was determined by RT-qPCR. ResultsHUVECs were positive for CD144 and negative for CD14. Vandetanib, celecoxib, and their combination inhibited HUVEC viability in a dose-dependent manner (p < 0.001). The rate of apoptosis was 13.1%, 9%, and 23.7% (p < 0.001) when treated with vandetanib, celecoxib, or the combination of both drugs, respectively. Vandetanib inhibited tube formation by 43.7%, celecoxib by 21%, and their combination by 77.3% (p < 0.001), respectively. RT-qPCR revealed that both vandetanib and celecoxib reduced the expression levels of MMP-2 and MMP-9, and their combination resulted in an even greater extent of reduction in expression levels (p < 0.001). ConclusionCelecoxib enhanced the effect of vandetanib in inhibiting in vitro angiogenesis and the combination of these two drugs led to even greater extents of inhibition than vandetanib alone.

Effect of a Cyclooxygenase-2 Inhibitor in Combination with (-)-Epigallocatechin Gallate or Polyphenon E on Cisplatin-Induced Lung Tumorigenesis in A/J Mice.

We investigated the effects of celecoxib combined with (-)-epigallocatechin-3-gallate (EGCG) or polyphenon E in a cisplatin-induced lung tumorigenesis model. Four-week-old female A/J mice were divided into seven groups: (i) Control, (ii) 150 mg/kg celecoxib (150Cel), (iii) 1,500 mg/kg celecoxib (1500Cel), (iv) EGCG+150 mg/kg celecoxib (EGCG+150Cel), (v) EGCG+1,500 mg/kg celecoxib (EGCG+1500Cel), (vi) polyphenon E+150 mg/kg celecoxib (PolyE+150Cel), and (vii) polyphenon E+1,500 mg/kg celecoxib (PolyE+1500Cel). All mice were administered cisplatin (1.62 mg/kg of body weight, i.p.) 1×/week for 10 weeks and sacrificed at week 30; the numbers of tumors on the lung surface were then determined. The tumor incidence and multiplicity (no. of tumors/mouse, mean±SD) were respectively 95% and 2.15±1.50 in Control, 95% and 2.10±1.29 in 150Cel, 86% and 1.67±1.20 in 1500Cel, 71% and 1.38±1.24 in EGCG+150Cel, 67% and 1.29±1.38 in EGCG+1500Cel, 80% and 1.95±1.36 in PolyE+150Cel, and 65% and 1.05±0.10 in PolyE+1500Cel. The combination of high-dose celecoxib with EGCG or polyphenon E significantly reduced multiplicity in cisplatin-induced lung tumors.

The neuroprotective effect of pterostilbene on oxaliplatin-induced peripheral neuropathy via its anti-inflammatory, anti-oxidative and anti-apoptotic effects: Comparative study with celecoxib

BackgroundOxaliplatin is one of the first-line drugs in solid tumors treatment. However, neuropathy is a devastating side effect leading to poor compliance and treatment cessation. AimThe current study explored pterostilbene plausible neuroprotective effects aiming to ascertain the potential mechanisms involved in relieving oxaliplatin-induced peripheral neuropathy (OIPN) and investigating whether pterostilbene and celecoxib combination could show better relief. Main methodsRats were divided into six groups; control, pterostilbene (40 mg/kg/day, p.o. for 5 weeks), oxaliplatin (4 mg/kg, i.p. twice per week for 4.5 weeks), celecoxib (30 mg/kg/day, p.o. for 5 weeks) and combination of pterostilbene and celecoxib. Behavioral tests and histopathological analysis of sciatic nerves were done. MAPKs, cytokines, COX-2, and PGE2 gene and protein expressions were estimated using qRT-PCR, western, and ELISA techniques. Malondialdehyde (MDA) and total antioxidant capacity (TAC) were assessed by colorimetric assay while apoptotic markers by immunohistochemical analysis and qRT-PCR. Key findingsThe study revealed that pterostilbene and celecoxib averted oxaliplatin-induced behavioral and motor impairments along with restoration of histopathological changes. Moreover, pterostilbene and celecoxib have significantly attenuated sciatic nerve: p38 MAPK, JNK, ERK1/2, NF-κB, COX-2, PGE2, TNF-α, and interleukins levels. Pterostilbene and celecoxib have reduced caspase-3, Bax, and MDA while increasing Bcl-2 level and TAC. SignificanceAltogether, Pterostilbene mitigates OIPN by interrupting the vicious cycle of inflammation, oxidation, and apoptosis. Furthermore, pterostilbene and celecoxib show comparable attenuation on MAPKs cascades, inflammatory cytokines, oxidative and apoptotic markers. Likewise, co-administration of pterostilbene and celecoxib shows further relief of neuropathic pain.

A Novel Anti-Inflammatory Formulation Comprising Celecoxib and Cannabidiol Exerts Antidepressant and Anxiolytic Effects.

Background: Ample research shows that anti-inflammatory drugs, particularly celecoxib, exert antidepressant effects, especially in patients with microglia activation. However, substantial cardiovascular adverse effects limit celecoxib's usefulness. Given that cannabidiol (CBD) exerts anti-inflammatory, microglia-suppressive, and antidepressant effects, we hypothesized that it may potentiate the therapeutic effects of celecoxib. Methods: The effects of celecoxib, CBD, and their combination were examined in murine models of antidepressant- and anxiolytic-like behavioral responsiveness, including the forced swim test (FST), elevated plus maze (EPM), lipopolysaccharide (LPS)-induced neuroinflammation, and chronic social defeat stress (CSDS), as well as in microglia cell cultures. Results: Acute administration of a combination of celecoxib plus CBD, at doses that had no effects by themselves (10 and 5 mg/kg, respectively), produced significant antidepressant- and anxiolytic-like effects in the FST and EPM, in male and female mice. In the LPS model, combinations of celecoxib (10 or 20 mg/kg) plus CBD (30 mg/kg) reversed the anxiety-like behavior in the open-field test (OFT) and anhedonia in the sucrose preference test (SPT), with minimal effects of celecoxib or CBD by themselves. In the CSDS paradigm, a combination of celecoxib plus CBD (each at 30 mg/kg) reversed the deficits in the OFT, EPM, social exploration, and SPT, whereas celecoxib or CBD by themselves had partial effects. In BV2 microglia cultures stimulated with LPS or α-synuclein, CBD markedly potentiated the suppressive effects of celecoxib over TNFα (tumor necrosis factor-α) and IL (interleukin)-1β secretion. Conclusions: Combinations of celecoxib plus CBD produce efficacious antidepressant- and anxiolytic-like effects, which may depend on their synergistic microglia-suppressive effects.

Novel Validated LC-MS/MS Method For Simultaneous Estimation of Celecoxib and Amlodipine in Rat Plasma and Its Application to A Pharmacokinetic Study

The combination of celecoxib (CLX) and Amlodipine (AMD) was approved for hypertensive patients with osteoarthritis by US-FDA. Hence, a potential analytical method that can simultaneously quantify these two drugs is required. In view of this, a novel and fully validated liquid chromatography-electrospray ionization-tandem mass spectrometric (LC-ESI-MS/MS) method has been established for the quantification of CLX and AMD in rat plasma simultaneously. protein precipitation extraction technique was employed for the extraction of analytes and their deuterated analogues from rat plasma quantitatively. The analytes were separated using the mobile phase comprising of acetonitrile–water with 0.1% formic acid buffer (70:30 v/v) and a flow-rate of 1.0 mL/min and 10 min run time on Agilent SB-C18 analytical column. The multiple reaction monitoring transitions, m/z 504.7→98.1 for CLX, 492.8→129.3 for AMD; 385.6→102.8 for CLX-D4 and 496.8.5→412.3 for AMD-D4 were utilized for the analysis in order to attain high selectivity. The method showed good sensitivity and linearity in the range of the concentration 20–800 ng/mL for CLX and 0.25–10 ng/mL for AMD respectively. Moreover, the method also displayed decent accuracy (87.9-100.27% and 99.28-103.26%) for CLX and AMD and precision according to US-FDA guidelines. The precision values for inter- and intra-day were between 1.92.02-7.085% and 0.083-3.43% and for CLX and AMD respectively. Further, the results of the pharmacokinetic parameters including Cmax, tmax, AUC0-t, AUC0-∞ and t1/2 values of drugs indicated that the developed method is valuable for the successful quantification of the analytes in rat plasma. The developed method is significant and is useful for simultaneous quantification of CLX and AMD.

Mialgia as an adverse effect of polypharmacotherapy celecoxib interaction – case report

Pain may be a consequence of the medication you are taking. In practice, it is not uncommon for analgesics to induce pain, and one of the most frequently found mechanisms is drug interactions, including the summation of side effects. Unfortunately, drug-induced side effects are still a risk factor for inducing the prescription cascade, which in practice means an increased risk of further complications. The paper describes a case of myalgia as an undesirable effect of the combination of celecoxib with other drugs used in polypharmacy. The paper describes a case of myalgia as an undesirable effect of the combination of celecoxib with other drugs used in polypharmacy.

Enabling the drug combination of celecoxib through a spherical co-agglomeration strategy with controllable and stable drug content and good powder properties

Combining celecoxib with other chemopreventive drugs is a promising method of chemoprevention for cancer, especially for colorectal cancer. However, the traditional drug combination approaches are restricted with high-cost apparatus, complex and numerous unit operations. This work aims to develop an efficient spherical co-agglomeration strategy for celecoxib in combination with lovastatin, which can achieve drug combination in a single crystallization unit. The ternary solvent system was determined based on molecular simulation, and then a stable spherical agglomeration process was developed through the design of molar fraction of anti-solvent (MFA) and stirring rate to produce spherical agglomerates with high sphericity (84.2–89.9 %) and narrow size distribution. On this basis, celecoxib-benzoic acid spherical co-agglomerates were designed to form a complete spherical co-agglomeration strategy, which includes solvent system selection, spherical agglomeration and spherical co-agglomeration. Finally, celecoxib-lovastatin spherical co-agglomerates with synergistic efficacy were successfully produced by this strategy, with controllable and stable drug content (fluctuation < 2.7 %), good powder properties, and improved tabletability.

Etanercept/celecoxib on improving MRI inflammation of active ankylosing spondylitis: A multicenter, open-label, randomized clinical trial.

ObjectiveTo investigate the efficacy and safety of clinical, magnetic resonance imaging (MRI) changes in active ankylosing spondylitis (AS) patients with etanercept and celecoxib alone/combined treatment.MethodsA randomized controlled trial was conducted in three medical centers in China. Adult AS patients with BASDAI ≥4 or ASDAS ≥2.1, CRP >6 mg/L, or ESR 28 mm/1st hour were randomly assigned (1:1:1 ratio) to celecoxib 200 mg bid or etanercept 50 mg qw or combined therapy for 52 weeks. The primary outcomes were SPARCC change of the sacroiliac joint (SIJ) and spine and the proportion of patients achieving ASAS20 response at 52 weeks.ResultsBetween September 2014 and January 2016, we randomly assigned 150 patients (mean age, 32.4 years; mean disease duration, 109 months), and 133 (88.6%) completed the study. SPARCC inflammation scores of the SIJ and spine decreased in the three groups, and significant differences were found between the combined group and the celecoxib group [between-group difference: −6.33, 95% CI (−10.56, −2.10) for SIJ; −9.53, 95% CI (−13.73, −5.33) for spine] and between the etanercept group and the celecoxib group [between-group difference: −5.02, 95% CI (−9.29, −0.76) for SIJ; −5.80, 95% CI (−10.04, −1.57) for spine]. The ASAS20 response rates were 44%, 58%, and 84% in the celecoxib, etanercept, and combined groups, respectively, and a significant difference was only found between the combined and the celecoxib groups.ConclusionEtanercept with or without celecoxib decreases inflammation detected by MRI at 1 year compared to celecoxib alone in active AS patients. The combination of etanercept and celecoxib was superior to celecoxib alone for the primary clinical response.Clinical Trial Registration ClinicalTrials.gov, identifier NCT01934933.

Beware-of-triple-whammy

The term “triple whammy” refers to a drug interaction following the concurrent use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers, diuretics and non-steroidal anti-inflammatory drugs, the combination of which greatly increases the odds of acute kidney injury. Here, we report a case of a 66-year-old gentleman who was admitted into a tertiary care hospital for elective orthopaedic intervention. He had previously been prescribed sacubitril/valsartan and frusemide and had newly been started on celecoxib during hospitalisation. Upon the initiation of celecoxib, a mild increase in his serum creatinine was immediately observed, and this occurrence is believed to be due to the “triple whammy” combination. The combination of perindopril, frusemide and celecoxib continued to be overlooked throughout his hospitalisation. He was subsequently planned to be discharged with celecoxib on top of his existing chronic medications. However, upon discharge, the dispensing pharmacist took notice of the drug interaction and successfully intervened to withhold celecoxib.

Treatment with the soluble guanylate cyclase activator BAY 60–2770 normalizes bladder function in an in vivo rat model of chronic prostatitis

Background and purposeChronic pelvic pain syndrome (CPPS) is a common and bothersome condition for which no pharmacological treatment options with acceptable efficacy exist. The aim of this study was to investigate the effects of the soluble guanylate cyclase (sGC) activator BAY 60–2770 and the COX-2 inhibitor celecoxib on bladder function in a rat model of CPPS. Experimental approachForty-eight male Sprague-Dawley rats were intraprostatically injected with either saline, serving as control, or zymosan, to induce prostatitis. On days 8–20, the rats were treated with either dimethylsulphoxide (DMSO; vehicle), celecoxib, BAY 60–2770 or a combination of celecoxib and BAY 60–2770. Thereafter, micturition parameters were assessed in a metabolic cage and urine samples were collected. The following day, cystometry was performed. Subsequently, the urinary bladder and prostate were removed and examined histopathologically. Key resultsInduction of prostatitis led to a significant increase of micturition frequency and corresponding decrease of volume per micturition. These alterations were ameliorated by celecoxib, and completely normalized by BAY 60–2770. Induction of prostatitis led to a significantly increased number of non-voiding contractions, decreased bladder compliance and increased voiding time. These parameters were normalized by treatment with BAY 60–2770, either alone or in combination with celecoxib. The immunohistochemical analysis showed signs of prostate inflammation, but not bladder inflammation. Conclusion and implicationsInduction of prostatitis led to significant impairment in bladder function. These alterations could be prevented by BAY 60–2770, alone or in combination with celecoxib. This is the first study to show that sGC activators could be a promising option for the treatment of CPPS.

Quantitative Spectrophotometric Analysis of Celecoxib and Tramadol in Their Multimodal Analgesia Combination Tablets.

Pain is a global, complex health problem that includes physical, emotional, and social components. The pain management process has many goals, including patient satisfaction, reducing clinical complications, and lowering costs. The physician describes pain medications in terms of the proven cause and classification of the severity of the pain. The combination of celecoxib and tramadol was recently approved by the Food and Drug Administration (FDA) in October 2021 for the treatment of acute pain in adults. This paper presents the first published quantitative analytical methods for celecoxib and tramadol. The UV absorption spectra of celecoxib and tramadol showed strong overlap. Mathematical simultaneous equation and ratio difference methods were developed to resolve the spectral overlap and quantify the drugs in the combination mixture. In the simultaneous equation method, the absorbance and absorptivity values at 252 and 217 nm were used to construct two mathematical equations that were used for the simultaneous mathematical quantification of the above drugs. The mathematical manipulation of the ratio difference based on the calculation of the differences in the amplitude values between 250 and 280 nm enabled the quantitative analysis of celecoxib, and the differences in the amplitude values between 221 and 272 nm enabled the quantitative analysis of tramadol. The proposed methods were successfully applied to the selective quantitative analysis of celecoxib and tramadol in the synthetic mixtures and in the pharmaceutical tablets without interference from the tablet additives. The applied methods demonstrated good linearity in the concentration range of 1-20 µg/mL and 3-45 µg/mL for celecoxib and tramadol, respectively, with acceptable accuracy and precision. The methods were found to be sensitive with LOD values of 0.183 µg/mL and 0.626 µg/mL for celecoxib and tramadol, respectively, in simultaneous equation method and of 0.275 µg/mL and 0.772 µg/mL for celecoxib and tramadol, respectively, in ratio difference method. The first established simple and validated UV spectrophotometric methods were described for concurrent quantification of the celecoxib and tramadol in their recently approved pharmaceutical formulation.

Optimization of nanoemulsified systems containing lamellar phases for co-delivery of celecoxib and endoxifen to the skin aiming for breast cancer chemoprevention and treatment

We proposed an innovative nanoemulsified system containing lamellar phases (NLP) produced by a low-energy method to enable the local-transdermal co-delivery of celecoxib and endoxifen as a potential strategy for breast cancer local chemoprevention. The NLPs were composed of surfactant:oil phase at 1:1 (w/w) and 80% water. Oleic or caprylic acid was added (2% or 5% w/w) as penetration enhancer. NLP droplet size was influenced by the type and concentration of the penetration enhancer, ranging from 290 to 450 nm with negative zeta potential. They presented pseudoplastic behavior, and after drug addition, elastic and bioadhesive properties were displayed. Compared to water (control), all formulations increased transepidermal water loss by 8.5–12.9 times, with the NLP containing 5% oleic acid promoting a more pronounced effect. No signs of vascular toxicity were observed in the HET-CAM model, suggesting safety. All NLPs increased the penetration of celecoxib and endoxifen in the skin, but the formulation containing 5% oleic acid was more effective, promoting ~ 3–22-fold increases in cutaneous delivery and ~ 11–20-fold increases in transdermal drug delivery. Combination of celecoxib and endoxifen in this NE reduced the viability of cancer cells in a synergistic manner compared to the use of isolated drugs. These results suggest the potential applicability of the NE for topical delivery and breast cancer chemoprevention.

CC-01 (chidamide plus celecoxib) modifies the tumor immune microenvironment and reduces tumor progression combined with immune checkpoint inhibitor

Immune checkpoint inhibitors (ICIs) have shown clinical benefit in solid tumors, with modest rates of clinical response. Hence, improved therapeutic approaches need to be investigated. Herein, we assessed a combination of chidamide plus celecoxib (called CC-01) combined with programmed cell death protein 1 (PD-1) blockade in a CT26 model as potent tumor microenvironment (TME) regulator. The antitumor activity was assessed by measuring tumor size, overall response rate, and survival rate. Immune profiling of tumor-infiltrating lymphocytes was performed by flow cytometry. Tumor tissues were assessed by chip assay to predict the possible pathway. Tumor size was significantly reduced in mice treated with CC-01 combined with or without anti-PD-1 antibody, however the triple combination therapy consistently demonstrated that it significantly increased both the ORR and survival rate in term of clinical applications. In the combination group, immune landscape profiling revealed decreased populations of immunosuppressive regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Analysis of the mouse tumor chip data using Gene Ontology enrichment analysis of biological processes revealed that the triple combination upregulated genes associated with responses to interferon-gamma. Our results demonstrated that CC-01 possessed potent TME regulatory properties, augmenting the antitumor effect when combined with ICIs. This antitumor effect was achieved by altering the immune landscape in TILs (tumor-infiltrating lymphocytes) and was associated with immune cell activation in the TME. Furthermore, CC-01 demonstrated potent anticancer immune response activity, mainly reducing the number and function of several immunosuppressive cells. The combination of CC-01 with an ICI will further enhance the anticancer effect and boost the immune response rate. Collectively, our results support the clinical evaluation of CC-01 in combination with ICIs in several advanced cancers.