Myeloid-derived suppressor cells (MDSCs) play a crucial role in T cell dysfunction, which is related to poor outcome in patients with severe trauma. Cyclooxygenase-2 (Cox-2) contributes to immune disorder in trauma and infection via production of prostaglandin E2. However, the role of Cox-2 in the accumulation and function of MDSCs after traumatic stress has not been fully elucidated. In the present study, we treated murine trauma model with NS398, a selective Cox-2 inhibitor. Then the percentages of CD11b+/Gr-1+ cells, proliferation and apoptosis of CD4+ T cells were determined. Arginase activity and arginase-1 (Arg-1) protein expression of splenic CD11b+/Gr-1+ cells, and delayed-type hypersensitivity (DTH) response were analyzed. The results showed that Cox-2 blockade significantly decreased the percentages of CD11b+/Gr-1+ cells in the spleen and bone marrow 48 and 72 h after traumatic stress. NS398 inhibited arginase activity and down-regulated the Arg-1 expression of splenic CD11b+/Gr-1+ cells. Moreover, NS398 could promote proliferation and inhibit apoptosis of CD4+ T cells. It also restored DTH response of traumatic mice. Taken together, our data revealed that Cox-2 might play a pivotal role in the accumulation and function of MDSC after traumatic stress.
Animals ; Apoptosis ; drug effects ; Arginase ; biosynthesis ; CD11b Antigen ; biosynthesis ; CD4-Positive T-Lymphocytes ; drug effects ; metabolism ; Cell Proliferation ; drug effects ; Cyclooxygenase 2 ; biosynthesis ; Cyclooxygenase 2 Inhibitors ; administration & dosage ; Gene Expression Regulation ; drug effects ; Humans ; Mice ; Myeloid Progenitor Cells ; metabolism ; pathology ; Nitrobenzenes ; administration & dosage ; Stress Disorders, Traumatic ; drug therapy ; genetics ; pathology ; Sulfonamides ; administration & dosage

BACKGROUNDMultimodal cocktail periarticular injection (MCPI) with a large volume of low concentration local anesthetics, adrenaline, and anti-inflammatory agents such as non-steroidal anti-inflammatory drug or steroids have shown good pain control and improvement in range of motion after surgery. This study compares the efficacy of pain control after total knee arthroplasty, using multimodal cocktail periarticular injection with steroid or without steroid.

METHODSThis is a prospective, double-blinded, randomized and control study. Seventy-two patients with osteoarthritis that met clinical criteria for total knee arthroplasty were recruited into the study, and were randomized to receive either multimodal cocktail periarticular injection with steroid or without steroid. Pain was assessed by visual analogue scale (VAS) at preoperative and postoperative at rest, and during activity. The range of motion was recorded preoperatively and postoperatively. The amount of daily and cumulative morphine consumption were measured by patient-controlled analgesia in the first 72 hours postoperatively. The duration of celecoxib usage was also recorded at the last follow-up.

RESULTSThere were no differences between the non-steroid and steroid groups with regard to VAS at rest and during activity, or range of motion, at any postoperative observation time. The postoperative Knee Society Knee Score in the steroid group improved significantly as compared with that in non-steroid group at the one-month (84.1±13.1 and 65.9±12.1; P < 0.0045), three-month follow-up (90.2±16.3 and 72.5±16.6; P < 0.0027), but after postoperative six-month the Knee Society Knee Score showed no significant difference between the groups. There was no significant difference in consumption of the morphine about daily or total consumption within 72 hours between the two groups. The duration of celecoxib usage in patients in the steroid group was significantly shorter than that in the non-steroid group ((7.2±0.7) compared with (10.5±1.9) weeks; P = 0.012).

CONCLUSIONThe patients who received the steroid injection had faster rehabilitation and less non-steroidal antiinflammatory drugs consumption.

Aged ; Arthroplasty, Replacement, Knee ; methods ; Celecoxib ; Cyclooxygenase 2 Inhibitors ; administration & dosage ; therapeutic use ; Female ; Humans ; Injections, Intra-Articular ; Male ; Pain Measurement ; Pyrazoles ; administration & dosage ; therapeutic use ; Steroids ; administration & dosage ; therapeutic use ; Sulfonamides ; administration & dosage ; therapeutic use

It has been proposed that the pro-inflammatory catalytic activity of cyclooxygenase-2 (COX-2) plays a key role in the aging process. However, it remains unclear whether the COX-2 activity is a causal factor for aging and whether COX-2 inhibitors could prevent aging. We here examined the effect of COX-2 inhibitors on aging in the intrinsic skin aging model of hairless mice. We observed that among two selective COX-2 inhibitors and one non-selective COX inhibitor studied, only NS-398 inhibited skin aging, while celecoxib and aspirin accelerated skin aging. In addition, NS-398 reduced the expression of p53 and p16, whereas celecoxib and aspirin enhanced their expression. We also found that the aging-modulating effect of the inhibitors is closely associated with the expression of type I procollagen and caveolin-1. These results suggest that pro-inflammatory catalytic activity of COX-2 is not a causal factor for aging at least in skin and that COX-2 inhibitors might modulate skin aging by regulating the expression of type I procollagen and caveolin-1.
Animals ; Aspirin/administration & dosage ; Catalysis ; Caveolin 1/genetics/metabolism ; Collagen Type I/genetics/metabolism ; *Cyclooxygenase 2/metabolism/physiology ; Cyclooxygenase 2 Inhibitors/*administration & dosage ; Gene Expression Regulation ; Mice ; Nitrobenzenes/*administration & dosage ; Pyrazoles/administration & dosage ; Skin Aging/*drug effects/physiology ; Sulfonamides/*administration & dosage ; Tumor Suppressor Protein p53/genetics/metabolism

Celecoxib ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cyclin-Dependent Kinase Inhibitor p16 ; genetics ; metabolism ; Cyclin-Dependent Kinase Inhibitor p21 ; genetics ; metabolism ; Cyclooxygenase 2 Inhibitors ; administration & dosage ; pharmacology ; Dose-Response Relationship, Drug ; Humans ; Kidney Neoplasms ; metabolism ; pathology ; Pyrazoles ; administration & dosage ; pharmacology ; RNA, Messenger ; metabolism ; Sulfonamides ; administration & dosage ; pharmacology ; Wilms Tumor ; metabolism ; pathology

This study involves mathematical simulation model such as in vitro-in vivo correlation (IVIVC) development for various extended release formulations of nimesulide loaded hydroxypropylmethylcellulose (HPMC) microparticles (M1, M2 and M3 containing 1, 2, and 3 g HPMC, respectively and 1 g drug in each) having variable release characteristics. In vitro dissolution data of these formulations were correlated to their relevant in vivo absorption profiles followed by predictability worth analysis of these Level A IVIVC. Nimaran was used as control formulation to validate developed formulations and their respective models. The regression coefficients of IVIVC plots for M1, M2, M3 and Nimaran were 0.834 9, 0.831 2, 0.927 2 and 0.898 1, respectively. The internal prediction error for all formulations was within limits, i.e., < 10%. A good IVIVC was found for controlled release nimesulide loaded HPMC floating M3 microparticles. In other words, this mathematical simulation model is best fit for biowaiver studies which involves study parameters as those adopted for M3 because the value of its IVIVC regression coefficient is the closest to 1 as compared to M1 and M2.
Anti-Inflammatory Agents, Non-Steroidal ; administration & dosage ; pharmacokinetics ; Cross-Over Studies ; Cyclooxygenase 2 Inhibitors ; administration & dosage ; pharmacokinetics ; Delayed-Action Preparations ; Humans ; Hypromellose Derivatives ; Methylcellulose ; analogs & derivatives ; Microspheres ; Models, Chemical ; Sulfonamides ; administration & dosage ; pharmacokinetics

OBJECTIVETo investigate the postoperative analgesic effect of parecoxib sodium in patients with posterior spinal surgery.

METHODSEighty patients undergoing posterior spinal surgery under general anesthesia were randomly divided into parecoxib sodium group and placebo group (n=40). All the patients received a single dose of m ml morphine (1.0 mg/ml) as the background analgesia immediately after the operation. The patients in parecoxib sodium group were given 40 mg parecoxib sodium intravenously, and those in the placebo group received an equivalent volume of saline instead, and at 24 and 48 h after the operation, the same dose was repeated. The visual analog pain score, patient satisfaction and adverse reactions were recorded after the administrations.

RESULTSCompared with the placebo group, the patients in parecoxib sodium group had significantly lowered VAS score at 6, 12, 24, and 48 h after the operation (P<0.05). No significant differences were noted in the patient satisfaction and adverse reactions between the two groups.

CONCLUSIONPostoperative short-term use of parecoxib sodium can can provide good postoperative analgesic effect in patients undergoing posterior spinal surgery.

Analgesics, Non-Narcotic ; therapeutic use ; Anesthesia, General ; Cyclooxygenase 2 Inhibitors ; therapeutic use ; Female ; Humans ; Injections, Intravenous ; Isoxazoles ; administration & dosage ; therapeutic use ; Male ; Pain, Postoperative ; drug therapy ; Spinal Diseases ; surgery

OBJECTIVETo evaluate effects of celecoxib (a selective cox-2 inhibitor)combined with fluvastatin (a HMG-CoA reductase inhibitor) on tumor growth and cell apoptosis in hepatocellular carcinoma xenograft in nude mice.

METHODSHepatocellular carcinoma BEL-7402 cells were inoculated subcutaneously into the left armpit of nude mice, the mice (n = 32) were then randomly divided into 4 groups: the control group, the celecoxib group,the fluvastatin group and the combination group. At the end of the study, Tumor Tissues were collected for analysis. Cell apoptosis was determined by flow cytometry analysis and TUNEL assay. Akt, p-Akt and survivin protein levels were measured by Western blot. Statistical comparisons were made using factorial analysis of variance (ANOVA) and multiple comparisons between each two groups were calculated using SNK-q test.

RESULTSThe combination of Celecoxib and fluvastatin resulted in a greater inhibition of tumor growth than either agent alone, the tumor inhibitory rate was 34.0% in the Celecoxib group, 25.0% in the fluvastatin group and 72.2% in the combination group. The percentages of TUNEL--positive cancer cells in the celecoxib and fluvastatin alone treatment groups were 8.5%+/-1.4% and 9.4%+/-1.7% respectively as compared to the control group which was 3.5%+/-0.8%. Combination therapy showed a significantly greater increase in tumor cell apoptosis in comparison with the control and single-therapy groups (apoptotic index: 19.4%+/-3.0%; P value is less than 0.01 versus celecoxib or fluvastatin groups). The results of flow cytometry analysis also showed the same tendency. a small number of apoptotic cells were detected in the control tumours (4.1%+/-1.6%), whereas a large number of apoptotic cells were detected in tumours treated with celecoxib (9.1%+/-2.1%) or fluvastatin (10.1%+/-2.3%) alone; and the combination therapy resulted in even more apoptotic cells (23.6%+/-5.8%; P value is less than 0.01 versus celecoxib or fluvastatin groups). Western blot analysis demonstrated that the combination of celecoxib and fluvastatin significantly down-regulated p-Akt (0.23+/-0.08 versus 1.12+/-0.07 and surviving (0.50+/-0.07 versus 1.47+/-0.19) in BEL-7402 tumours compared with the control (P value is less than 0.01 for all).

CONCLUSIONThe present study provided evidence that treatment with celecoxib in combination with fluvastatin resulted in the inhibition of HCC tumour growth in an in vivo mouse model.

Animals ; Apoptosis ; drug effects ; Carcinoma, Hepatocellular ; drug therapy ; metabolism ; pathology ; Celecoxib ; Cell Line, Tumor ; Cyclooxygenase 2 Inhibitors ; administration & dosage ; pharmacology ; Fatty Acids, Monounsaturated ; administration & dosage ; pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; administration & dosage ; pharmacology ; Indoles ; administration & dosage ; pharmacology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Pyrazoles ; administration & dosage ; pharmacology ; Sulfonamides ; administration & dosage ; pharmacology ; Xenograft Model Antitumor Assays

OBJECTIVETo assess the effect of perioperative administration of a selective cyclooxygenase 2 inhibitor (celecoxib) on pain management and recovery of function after total knee arthroplasty (TKA).

METHODSRandomized, controlled trial conducted from January 2005 through February 2006, 60 patients underwent TKA for osteoarthritis or rheumatoid arthritis were randomly divided into group of perioperative, administration of celecoxib (Study group, n = 30) and postoperative administration of celecoxib (Control group, n = 30). Patients in Study group were given oral celecoxib 3 d before TKA, 200 mg twice daily, and extended to 5 d postoperatively; patients in Control group were given oral celecoxib 2 h after TKA, 200 mg twice daily, and extended to 5 d postoperatively. All operations were finished by the same surgeon group.

RESULTSThe postoperative patient-controlled analgesia (PCA) consumption was significantly less in Study group than in Control group [(43 +/- 12) ml vs. (53 +/- 12) ml, P < 0.05]. The pain scores of postoperative 4, 8, 12 h, 1, 2 d in Study group were 6.1 +/- 1.2, 5.0 +/- 1.3, 4.3 +/- 1.1, 3.4 +/- 1.2, significantly less than in Control group (P < 0.05); There were no intergroup significant differences in the pain scores of postoperative 3, 4, 5 d (P > 0.05). There were no intergroup significant differences in respect to the side-effect occurrence, operation time and postoperative drainage, postoperative analgesic consumption (P > 0.05). The time to achieve 90 degrees knee flexion was significantly shorter in Study group than in Control group [(6.2 +/- 1.7) d vs. (8.6 +/- 1.8) d, P < 0.05].

CONCLUSIONSPerioperative administration of the selective Celecoxib holds the effect of preemptive analgesia. Compared with postoperative administration, perioperative administration of celecoxib can alleviate the early postoperative pain score, reduce the consumption of postoperative analgesic, accelerate the recovery of joint motion and thus increase the patient satisfaction.

Aged ; Arthroplasty, Replacement, Knee ; Celecoxib ; Cyclooxygenase 2 Inhibitors ; administration & dosage ; Female ; Humans ; Male ; Middle Aged ; Pain, Postoperative ; drug therapy ; Perioperative Care ; Pyrazoles ; administration & dosage ; Sulfonamides ; administration & dosage

OBJECTIVESTo observe the effects of NS-398 on proliferation of hepatic stellate cells (HSCs) in vitro, and to investigate the possible molecule mechanism.

METHODSHSCs were incubated with different concentrations of NS-398. The effects of NS-398 on cell proliferation was detected by MTT colormetric assay. The cell cycle of HSCs was analyzed by Flow Cytometry (FCM), cyclooxygenase-2 (COX-2) and proliferating cell nuclear antigen (PCNA) proteins in HSCs were detected by immunocytochemistry.

RESULTSAdministration of 20-160 micromol/L NS-398 significantly inhibited HSCs proliferation in dose-dependent manner compared with the control group (P less than 0.01). After treated with NS-398 at concentrations of 90, 120, and 150 micromol/L for 48 h, the number of HSCs in G(2)/M phase increased and the number of HSCs in G(0)/G(1) phase decreased (P less than 0.05); Incubated with 120 micromol/L NS-398 for 48 h, percentage of masculine cell of PCNA was 28.91%+/-0.11%, which was significantly lower than that of the control group (85.99%+/-0.13%) (P less than 0.01). Percentage of masculine cell of COX-2 was 13.80%+/-0.43%, which was not significantly different from that of the control group (14.07%+/-0.59%) (P more than 0.05).

CONCLUSIONSNS-398 could inhibit the proliferation of HSC-T6 and arrest HSCs in G2/M phase. Down-regulation of PCNA protein may partially accounted for the proliferation inhibition effect on HSCs induced by NS-398.

Animals ; Apoptosis ; drug effects ; Cell Cycle ; drug effects ; Cell Line ; Cell Proliferation ; drug effects ; Cyclooxygenase 2 ; metabolism ; Cyclooxygenase Inhibitors ; administration & dosage ; pharmacology ; Dose-Response Relationship, Drug ; Flow Cytometry ; Hepatic Stellate Cells ; drug effects ; metabolism ; Liver Cirrhosis ; pathology ; prevention & control ; Nitrobenzenes ; pharmacology ; Proliferating Cell Nuclear Antigen ; metabolism ; Rats ; Sulfonamides ; pharmacology

OBJECTIVE: To determine the multimodal postoperative analgesia effect of celecoxib combined with patient-controlled analgesia (PCA) and its clinical efficacy and related adverse events in orthopaedic procedures. METHODS: Sixty patients undergoing orthopaedic surgery were randomly divided into 2 groups. The observation group received 400 mg of celecoxib from POD0 to POD5 and 200 mg until POD14 plus IV PCA (fentanyl 1.0 mg/100 mL) postoperatively. The control group only took IV PCA postoperatively plus placebo. Visual analogue scale (VAS) scores and cumulative volumes of the opioid were assessed every 4 hours postoperatively until 48 hours. Sleep disturbance, vital signs and side effects including nausea, emesis, et al. were observed for 2 days. Blood-R and coagulation function were tested preoperatively and postoperatively. Blood loss, satisfied score, and chronic pain situation at 1 month were also measured. RESULTS: VAS scores, sleep disturbance, PCA cumulative volumes of the fentanyl were significantly better in the multimodal groups compared with the simple analgesia group (P<0.05), the opioid and celecoxib related adverse effects were not statistically lower in the multimodal groups (P>0.05). The observation group was more satisfied with analgesia treatment and experienced less pain 1 month after discharge (P<0.05). CONCLUSION The multimodal use of the specific COX-2 inhibitor celecoxib in the postoperative period of orthopaedic procedures clearly improves postoperative pain, reduces the opioid consumption, releases the sleep disturbance, demonstrates more satisfaction in patients and lower chronic pain rate after discharge, without affecting the platelet and coagulation function.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Analgesia, Patient-Controlled ; methods ; Analgesics, Opioid ; administration & dosage ; Celecoxib ; Cyclooxygenase 2 Inhibitors ; therapeutic use ; Drug Therapy, Combination ; Female ; Fentanyl ; administration & dosage ; Humans ; Male ; Middle Aged ; Orthopedics ; Pain, Postoperative ; drug therapy ; Pyrazoles ; therapeutic use ; Sulfonamides ; therapeutic use ; Young Adult