塞来昔布超前镇痛在经腹前列腺切除术中的应用

目的研究术前口服塞来昔布辅助经腹前列腺切除术后硬膜外自控镇痛（PCEA）的效果。方法40例行经腹前列腺切除术的患者被随机分为两组。术前30min分别口服塞来昔布200mg和维生素C100mg，术后行硬膜外自控镇痛。于术后1、4、8、16、20和24h行VAS评分，并记录PCEA药物用量、按压次数、实进次数和D／D比值，于术后8、16和24h评估下肢运动神经阻滞程度，在术后24h由患者对术后镇痛的总体印象进行评估。结果两组患者的一般情况和术后各时间点的生命体征、VAS评分比较，差异无显著性（P〉0.05）。与C组比较，V组术后4、8、16、20和24h的镇痛药剂量、按压次数、实进次数高（P〈0．05），两组各时间点D／D比值比较，差异无显著性（P〉0.05）。两组患者改良Bromage评分均为0分，差异无显著性（P〉0．05）。两组患者膀胱痉挛发生率和对术后镇痛的总体印象比较，差异无显著性（P〉0．05）。V组有2例（10%）发生恶心、呕吐，而C组无，差异无显著性（P〉0.05）。结论塞来昔布可明显减少经腹前列腺切除术后PCEA的用药量，增加镇痛效果，适于辅助术后硬脊膜外自控镇痛。     

Antimutagenic and anti-oxidant activities of the non-steroidal anti-inflammatory drug celecoxib

1. Tumors arise and progress through the accumulation of serial genetic changes, including successive mutations, which involve activation of proto-oncogenes and inactivation of tumour suppressor genes, leading to the uncontrolled proliferation of progeny cells. The human body is continuously and unavoidably exposed to structurally diverse chemicals with established carcinogenic activity in animal models and/or mutagenic activity in short-term tests. 2. Celecoxib, a non-steroidal anti-inflammatory drug that specifically inhibits the enzyme cyclo-oxygenase-2, has been reported to be effective against certain types of cancers. The in vitro anti-oxidant and antimutagenic activities of the celecoxib were investigated in the present study using standard procedures. 3. The antimutagenic activity of celecoxib was determined using histidine mutant Salmonella typhimurium strains TA98, TA100, TA102 and TA1535 against directly acting mutagens (sodium azide (NaN3), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 4-nitro-o-phenylenediamine (NPDA) and doxorubicin) and mutagens needing activation (2-acetamidofluorene (2-AF) and 7,12-dimethylbenz [a] anthracene (DMBA)). 4. Celecoxib inhibited NaN3-, MNNG- and NPDA-induced mutations of TA100. The antimutagenicity of celecoxib (0.2 mg/plate) against the NaN3-induced mutation of TA1535 was 39.8% (P < 0.001). The MNNG-induced mutation of TA1535 was also inhibited by 0.3 mg/plate celecoxib (46.0%; P < 0.05). At concentrations of 0.2 mg/plate, celecoxib significantly inhibited NPDA- and doxorubicin-induced mutations of TA98 by 52.5 and 58.0%, respectively (P < 0.001 and P < 0.05, respectively). 5. The antimutagenic activity of 0.3 mg/plate celecoxib against 2-AF- and DMBA-induced mutations of TA98 was 81.76 and 98.1%, respectively (P < 0.001). 6. The anti-oxidant activity of celecoxib was determined by the inhibition of lipid peroxidation and superoxide and hydroxyl radical-scavenging activities. 7. The IC50 values of celecoxib for hydroxyl radical-scavenging and the inhibition of lipid peroxidation were 1.97 +/- 0.06 and 1.99 +/- 0.05 micromol/mL, respectively. Celecoxib had no superoxide radical scavenging-activity up to a concentration of 2.6 micromol/mL. 8. The in vitro antimutagenic and anti-oxidant activities of celecoxib indicate its possible therapeutic use as a cancer chemopreventive agent.     

Effects of the Celecoxib on the Acute Necrotizing Pancreatitis in Rats

The investigation of the effects of the celecoxib as a cylooxygenase-2 (COX-2) inhibitor on the course of the acute necrotising pancreatitis (ANP) in rats. ANP was induced in 72 rats by standardized intraductal glycodeoxycholic acid infusion and intravenous cerulein infusion. The rats were divided into four groups (six rats in each group): Sham + saline, sham + celecoxib, ANP + saline, ANP + celecoxib. Six hours later after the ANP induction, celecoxib (10 mg/kg) or saline was given i.p. In the 12th hour, routine cardiorespiratuar, renal parameters were monitored to assess the organ function. The serum amylase, alanine amino transferase (ALT), interleukin 6 (IL-6), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, the serum concentration of the urea, the tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in pancreas and lungs were measured. The pancreas histology was examined. In the second part of the study, 48 rats were studied in four groups similar to the first part. Survival of all the rats after the induction of ANP was observed for 24 h. The induction of the pancreatitis increased the mortality from 0/12, in the sham groups to 4/12 (30%) in the acute pancreatitis with saline group, 5/12 (42%) in the acute pancreatitis with celecoxib group respectively, heart rate, the serum activities of amylase, ALT, the tissue activities of MPO, MDA in the pancreas and lung, and LDH in BAL fluid, the serum concentration of the urea and IL-6, the degree of the pancreatic damage and decreased the blood pressure, the urine production, pO₂ and the serum concentration of calcium. The use of celecoxib did not alter these changes except the serum IL-6 concentration, urine production and MPO, MDA activities in the tissue of the lungs and pancreas. Serum urea concentration and pancreatic damage in ANP + celecoxib group were insignificantly lesser than ANP + saline group. Whereas treatment with celecoxib improves lung and renal functions, the degree of pancreatic damage partially and the serum IL-6 level completely, it does not improve the cardiovascular and liver functions, the mortality rate and the calcium level. Celecoxib may be useful for the support of some organ functions during ANP in rats.     

Pharmacological and pharmacokinetic evaluation of celecoxib prodrugs in rats

This study demonstrates the utility of an in vitro - in vivo correlative approach in the selection and optimization of a prodrug candidate of celecoxib (CBX), a COX(2) inhibitor. As an initial screening step, a comparative single oral dose pharmacokinetic study was conducted in rats for CBX and its three aliphatic acyl water-soluble prodrugs viz., CBX-acetyl (CBX-AC), CBX-propionyl (CBX-PR) and CBX-butyryl (CBX-BU) at high equimolar dose, 100 mg/kg. Only CBX-BU and CBX-PR converted rapidly to CBX and yielded approximately five-fold greater systemic exposure of CBX than CBX alone or CBX-AC. Rank order of systemic exposure of prodrugs in its intact form was CBX-AC >CBX-PR >CBX-BU. Further in vitro hydrolysis studies of CBX prodrugs in intestinal mucosal suspensions and liver homogenates indicated that CBX-BU is rapidly and completely converted to CBX, whereas CBX-PR and CBX-AC require longer incubation period for complete conversion to CBX. There was a very good correlation of the in vitro and in vivo data supporting CBX-BU as the prodrug of choice. Further in vitro pharmacological studies showed that COX(2) selective inhibition is improved for CBX-BU as compared to CBX-AC and CBX-PR. Dose proportionality in pharmacokinetic studies of CBX-BU and CBX at equimolar oral doses confirmed that relative oral bioavailability of CBX was improved following CBX-BU administration and there was linearity in pharmacokinetics of CBX over a wide dose range (10-100 mg/kg), whereas CBX in its conventional form showed poor bioavailability and lack of dose linearity in pharmacokinetics. The oral bioavailability of CBX from CBX-BU was dose independent and was in the range 78-96%. At a 50% reduced molar dose, CBX-BU showed an equivalent efficacy to that of CBX in the in vivo carrageenan model. Based on the study, water-soluble CBX-BU prodrug can be considered for clinical development in view of its potential advantages.     

COX-2抑制剂Celecoxib的合成

以对甲基苯乙酮为原料,经缩合、环合反应合成选择性ＣＯＸ－２抑制剂Ｃｅｌｅｃｏｘｉｂ,总收率３７．７％。     

Celecoxib and Heterotopic Bone Formation After Total Hip Arthroplasty

We assessed the effectiveness of celecoxib in the prevention of heterotopic ossification (HO) following primary total hip replacement (THR). We studied 170 consecutive THRs. Sixty-three patients received celecoxib after surgery (200 mg twice/daily) for 28 days and 84 did not. HO was more common in non-celecoxib patients than in the celecoxib-group at 3, 6, and 12 months (P = 0.005, 0.004 and 0.01, respectively). At 1 year, fewer celecoxib recipients had Brooker classes II or III. None of the celecoxib patients developed HO Brooker class IV, while 2% in the non-celecoxib group did. No patient discontinued treatment or had revision for aseptic loosening. A short course of celecoxib for pain aids in the prevention of HO after primary THR, and could be a useful and safe option that does not interfere with anticoagulation.     

塞来昔布预防根管治疗期间急症的临床评价

目的 比较一次性和二次性根管治疗后根管治疗期间急症(EIAE)的发生率及急性发作程度(FUI),评价应用塞来昔布的预防效果.方法 按纳入标准选取在湖南旺旺医院口腔科就诊的225例牙髓坏死并有根尖周X线透射阴影需行根管治疗的患牙,采用逐步后退法制备根管,随后将患者随机分为两组:塞来昔布组113例,根管预备后口服塞来昔布,其中55例行一次性根管治疗,58例行二次性根管治疗；安慰剂组112例,根管预备后口服外形和颜色一致的安慰剂,一次性根管治疗和二次性根管治疗各56例.记录两组患者根管治疗后l周内出现的症状.结果 一次性根管治疗组EIAE的发生率及FUI均值均明显高于二次性根管治疗组(P＜0.05).塞来昔布组EIAE的发生率及FUI值分别为5.31％、(2.58±0.64),明显低于安慰剂组的13.39％、(4.08±0.79),差异有统计学意义(P＜0.05).塞来昔布对一次性根管治疗术后的EIAE发生率及FUI值具有明显的抑制作用(P＜0.05).结论 根管制备后预防性服用塞来昔布可显著降低EIAE的发生率、减轻术后疼痛及肿胀程度.