Effect of COX-2 inhibitors and non-steroidal anti-inflammatory drugs on a mouse fracture model

A randomised, blinded, prospective animal study with 296 male C57BL/6N mice was performed to evaluate the biomechanical, biomolecular, biochemical, and histological impact of anti-inflammatory medications on fracture healing. A reproducible closed tibia fracture was created and stabilised with an intramedullary pin. Animals were randomised to placebo, ketorolac, ibuprofen, celecoxib, or rofecoxib treatment groups with biomechanical and biochemical testing at 4, 8, and 12 weeks. A second arm of the study was conducted in which animals were randomised to indomethacin or placebo treatment with biomechanical testing at 12 weeks. Histological and biomolecular studies were performed at 2 weeks on all groups in the first arm of the study. Biomechanical testing consisted of three-point bending evaluating maximum load, energy absorbed to maximum load, and stiffness. Safranin O-Fast Green stain was performed for histology. Biochemical quantifications of chondroitin and dermatan sulphate, hydroxyproline, total protein, and DNA content were performed. Osteocalcin and collagen types II and X were evaluated by in situ hybridisation. Some mechanical differences were seen between ketorolac and placebo at 4 weeks with respect to energy absorbed, but there were no differences in maximum load or stiffness seen between any treatment group and placebo at any time point. Indomethacin, celecoxib, rofecoxib, ibuprofen, and ketorolac did not significantly affect fracture healing in this young murine model.     

RP—HPLC法测定布洛芬-聚乙二醇6000固体分散体中布洛芬的含量

目的 建立反相高效液相色谱法测定布洛芬-聚乙二醇6000固体分散体中布洛芬的含量.方法 色谱柱为Shimadzu C18柱,流动相为0.02 mol·L^-1醋酸钠（冰醋酸调节pH至3.0±0.1）-乙腈（40：60）,流速1.0ml·min^-1,检测波长为264nm,进样量为20μl.结果 布洛芬质量浓度在0.051～1.02 mg·ml^-1范围内与相应峰面积呈良好线性关系（r=0.999 9,n=6）,平均加样回收率为98.40%,RSD为0.92%（n=9）.结论 所用方法准确、简便、快速,适用于布洛芬-聚乙二醇6000固体分散体中布洛芬的含量测定.     

尼美舒利与布洛芬治疗高热患儿疗效比较

目的对非甾体类解热镇痛药尼美舒利颗粒、布洛芬混悬液治疗高热患儿效果和不良反应的比较。方法选择1～13岁的高热患儿120例,随机分为两组,在常规治疗基础上,一组使用尼美舒利颗粒口服3mg/kg,另一组使用布洛芬混悬液口服5mg/kg。测定治疗前、治疗后30min、1h、2h、6h体温,并观察疗效及不良反应。结果尼美舒利组在1h内体温下降幅度比布洛芬组大,而且维持时间长。结论口服尼美舒利颗粒治疗高热患儿较布洛芬混悬液起效快,不良反应小,使用较安全,临床上值得推广使用。     

Ibuprofen is a non-competitive inhibitor of the peptide transporter hPEPT1 (SLC15A1): possible interactions between hPEPT1 substrates and ibuprofen

BACKGROUND AND PURPOSE

Recently, we identified etodolac as a possible ligand for the human intestinal proton-couple peptide transporter (hPEPT1). This raised the possibility that other non-steroidal anti-inflammatory drugs, and especially ibuprofen, could also interact with hPEPT1. Here, we have assessed the interactions of ibuprofen with hPEPT1.

EXPERIMENTAL APPROACH

The uptake of [¹⁴C]Gly-Sar, [³H]Ibuprofen and other radio-labelled compounds were investigated in Madin–Darby canine kidney cells (MDCK)/hPEPT1, MDCK/Mock, LLC-PK₁ or Caco-2 cells. The transepithelial transport of ibuprofen and hPEPT1 substrates was investigated in Caco-2 cell monolayers.

KEY RESULTS

Ibuprofen concentration dependently inhibited hPEPT1-mediated uptake of Gly-Sar in MDCK/hPEPT1 cells (K_i^app= 0.4 mM) but uptake of ibuprofen in Caco-2 cells and MDCK/hPEPT1 cells was not inhibited by hPEPT1 substrates. The maximum uptake rate for Gly-Sar uptake was reduced from 522 pmol·min⁻¹·cm⁻² to 181 pmol·min⁻¹·cm⁻² and 78 pmol·min⁻¹·cm⁻² in the presence of 0.5 mM and 1 mM ibuprofen, respectively. The interaction between ibuprofen and hPEPT1 was thus non-competitive. In LLC-PK1 cells, ibuprofen (1 mM) did not influence the transporter-mediated uptake of glycine or α-methyl-D-glycopyranoside. In Caco-2 cell monolayers the absorptive transport of δ-aminolevulinic acid was reduced by 23% and 48% by ibuprofen (1 and 10 mM), respectively. Likewise the transport of Gly-Sar was reduced by 23% in the presence of ibuprofen (1 mM).

CONCLUSIONS AND IMPLICATIONS

Ibuprofen is a non-competitive inhibitor of hPEPT1. As ibuprofen reduced the transepithelial transport of δ-aminolevulinic acid, drug–drug interactions between ibuprofen and hPEPT1 drug substrates at their site of absorption are possible if administered together.     

布洛芬分散片的药效学研究

目的研究布洛芬分散片的药效学。方法应用布洛芬分散片探索对角叉胶所致大鼠足跖炎性肿胀的抗炎作用以及解热镇痛作用、内毒素致家兔发热的解热作用与醋酸致小鼠疼痛的镇痛效果。结果用布洛芬分散片低、中和高剂量组分别与空白组比较,动物关节肿胀程度明显减轻（P〈0．01）,小鼠扭体次数显著减少（P〈0．01）,家兔体温显著降低（JP〈0．01）。结论布洛芬分散片药效与片剂相同,可以作为一种新剂型开发。     

Section 3 A multi-centre clinical evaluation,with proctoscopic control,of the use of ibuprofen suppositories in rheumatic conditions

Summary

Sixty-three patients, suffering from osteoarthrosis, rheumatoid arthritis and allied disorders, were admitted to a multi-centre, open study using 500?mg. ibuprofen suppositories. The results indicate that this is an effective form of therapy, night pain being relieved in 75% of the patients. Proctoscopic examinations carried out during the study confirmed good local tolerance.     

Section 3 Clinical evaluation of ibuprofen given orally and rectally,in degenerative arthroses

Summary

In an open assessment in 46 patients with chronic arthritic and allied disorders, ibuprofen was administered in both oral and suppository form for an average of 10 days. Total daily dosage ranged from 1300?mg. to 1700?mg. ibuprofen depending on the weight of the patient. Pain relief was assessed as very good or good in 56.5 % and moderate in 26 % of patients. General side-effects were reported by 10 patients and 6 were withdrawn. Poor local tolerance of the suppository was reported by 19 patients, 9 of whom stopped treatment.     

Section 1 Ibuprofen (‘Brufen’) tested with bilateral oral surgery as a model for evaluation of anti-inflammatory effects

Summary

Twenty-four healthy patients, who had two separate operations for the removal of an impacted 3rd molar from one side or the other of the lower jaw, took part in a double-blind crossover study of ibuprofen (1200?mg. daily) and placebo given for 5 days, commencing the day before surgery. A number of objective and subjective assessments were recorded for paired comparison of the post-operative course, including swelling (measured by a special device), trismus, and pain. Ibuprofen significantly reduced pain on the day of the operation, which might have accounted in part for less trismus and patient preference for ibuprofen treatment. Patients with less swelling after ibuprofen were not always those with high serum concentrations of the drug. Side-effects were infrequent and ibuprofen did not have any significant effect on wound healing, bleeding, or various haematological parameters investigated.     

布洛芬混合液直肠给药在治疗小儿高热惊厥中的应用价值研究

目的研究布洛芬混合液直肠给药在治疗小儿高热惊厥中的应用价值。方法采用随机分组法将64例高热惊厥患者随机分为观察组和对照组,各32例。对照组采用常规用药方法和物理降温措施进行治疗,观察组应用布洛芬混合液直肠给药进行治疗,比较两组治疗效果。结果观察组止惊时间和退热时间明显提前,组间比较差异具有统计学意义(P<0.05),观察组总体治疗效果评价结果优于对照组,组间比较差异有统计学意义(P<0.05)。结论在常规药物治疗的基础上联合应用布洛芬混合液直肠给药进行治疗,可有效降低药物不良反应发生率,缩短病程,值得临床进一步研究应用。