酮咯酸氨丁三醇联合盐酸哌替啶治疗肾绞痛的临床观察

目的:观察酮咯酸氨丁三醇联合盐酸哌替啶治疗肾绞痛的临床疗效。方法:将我院2008年5月-2010年5月收治的中、重度疼痛的肾绞痛患者120例随机均分为3组,均采取肌肉注射药物进行镇痛治疗。其中,Ⅰ组应用酮咯酸氨丁三醇60mg;Ⅱ组应用盐酸哌替啶100mg;Ⅲ组应用酮咯酸氨丁三醇30mg+盐酸哌替啶50mg。记录用药前以及用药后3h内(0、0.5、1、1.5、2、2.5、3h)的疼痛强度、疼痛强度差、疼痛缓解度以判断镇痛效果,并观察各组治疗中的不良反应情况。结果:用药后,3组均在0.5h起效,在中度疼痛的镇痛方面,Ⅲ组在用药3h内的所有观察点均优于Ⅰ、Ⅱ组(P<0.05),在2h时差异最为显著(P<0.01);在重度疼痛的镇痛方面,Ⅲ组在用药1.5、2、2.5、3h时效果优于Ⅰ、Ⅱ组(P<0.05);Ⅲ组的中度以上疼痛缓解程度除0.5h外,其余各点与Ⅰ、Ⅱ组比较,差异均有统计学意义(P<0.05)。Ⅲ组不良反应的发生率小于其他2组(P<0.05)。结论:酮咯酸氨丁三醇联合盐酸哌替啶治疗肾绞痛效果显著,同时可减少盐酸哌替啶的使用量,并可延长镇痛时间,且安全性较好。     

Validated Stability-indicating Reverse-phase Ultra-performance Liquid Chromatography Method for Simultaneous Determination of Sodium Methylparaben,Sodium Propylparaben and Ketorolac Tromethamine in Topical Dosage Forms

A sensitive, fast, and stability-indicating isocratic reverse-phase ultra-performance liquid chromatography method was developed and validated for quantitative simultaneous determination of sodium methylparaben, sodium propylparaben and ketorolac tromethamine in topical dosage forms. Separation of all peaks was achieved by using acquity ethylene bridged hybrid C18 (50×2.1 mm, 1.7 μ) as stationary phase, mobile phase used was triethylamine buffer (pH 2.5):tetrahydrofuran:methanol (665:35:300, v/v/v) with isocratic mode at a flow rate of 0.40 ml/min. All component were detected at 252 nm with 10 min run time. The described method was found to be linear in the concentration range of 248-744 μg/ml for ketorolac tromethamine, 20.8-62.4 μg/ml for sodium methylparaben and 2.38-7.13 μg/ml for sodium propylparaben with correlation coefficients more than 0.999. Method was validated in terms of specificity, linearity, accuracy, precision, solution stability, filter equivalency, and robustness as per International Conference on Harmonization guideline. Formulation was exposed to the stress conditions of peroxide, acid, base, thermal, and photolytic degradation and proven all components were well separated in the presence of degradants.     

静脉注射小剂量酮咯酸氨丁三醇联合间苯三酚治疗肾绞痛的观察

目的探讨静脉注射小剂量酮咯酸氨丁三醇联合间苯三酚解除肾绞痛的临床疗效。方法将140例肾绞痛患者随机分为三组,I组46例静脉注射酮咯酸氨丁三醇30mg,II组47例肌注酮咯酸氨丁三醇60mg,同时两组均静脉滴注间苯三酚80mg;III组47例在肌注哌替啶100mg的同时静脉滴注山莨菪碱10mg,观察比较各组给药后10、20、40min的疼痛缓解效果、不良反应等情况。结果给药后10minI组患者疼痛解除率及总有效率（19．56％,76．9％）明显高于Ⅱ组（0,40．42％）、III组（8．51％,55．31％）,差异有统计学意义（P=0．005,P=0．002）,给药后40min各组间比较差异无统计学意义（P=0．861,P=0．869）;I组患者的平均疼痛解除时间为（14．3±9．5）min,短于Ⅱ组（23．8±5．4）min、Ⅲ组（18．2±8．3）min,差异有统计学意义（F=46．32,P〈0．05）;I、Ⅱ组的不良反应率（8．69％,14．89％）低于Ⅲ组（82．97％）,差异有统计学意义（P=0．000）。结论小剂量（30mg）酮咯酸氨丁三醇静脉注射联合间苯三酚静脉滴注对肾绞痛疗效好,起效快,不良反应少。     

Rapid pain relief using transdermal film forming polymeric solution of ketorolac

Context: Ketorolac is one of the most potent nonsteroidal anti-inflammatory drugs and is an attractive alternative to opioids for pain management.

Objective: Development and evaluation of transdermal ketorolac film forming polymeric solution.

Materials and methods: Eudragits^® RLPO, RSPO and E100 as well as polyvinyl pyrrolidone K30 dissolved in ethanol were used as film forming solutions. In vitro experiments were conducted to optimize formulation parameters. Different permeation enhancers were monitored for potentiality of enhancing drug permeation across excised pigskin.

Results: The use of 10% oleic acid, Lauroglycol^® 90 or Azone^® with 5% Eudragit^® RSPO, showed the highest enhancement effect on ketorolac skin permeation and showed faster analgesic effect compared to the ketorolac tablet. The formula comprising 5% Eudragit^® RSPO and 10% Lauroglycol^® 90 showed the greatest pharmacodynamic effect and thus was subjected to pharmacokinetic studies. The pharmacodynamic and pharmacokinetic results didn’t run paralleled to each other, as the ketorolac tablets showed higher plasma concentrations compared to the selected ketorolac transdermal formulation. This might be due to the induction of analgesia by the available ethanol in the transdermal preparation.

Conclusion: Optimized transdermal ketorolac formulation showed marked ability to ensure fast and augmented analgesic effect that is an essential request in pain management.     

【In Press】Impact of topical nonsteroidal anti-inflammatory drugs in prevention of macular edema following cataract surgery in diabetic patients

AIM: To evaluate the efficacy of prophylactic administration of topical non-steroidal anti-inflammatory drugs on macular edema following cataract surgery in diabetic patients, and comparing between types of non-steroidal anti-inflammatory drugs (ketorolac tromethamine 0.4% and nepafenac 0.1%). METHODS: Group1 (control) received artificial tears substitute as a placebo group, group 2 (Nepafenac) received topical nepafenac 0.1%, and group 3 (Ketorolac) received topical ketorolac tromethamine 0.4%. Patients were examined postoperatively after completing one week, one month, two months and three months’ intervals for evaluating cystoid macular edema (CME) development. The main study outcomes were achieving the best corrected visual acuity (BCVA) and change in the central macular thickness measured with optical coherence topography (OCT). RESULTS: Eighty eyes of 76 patients were included in this study. BCVA showed a statistically significant difference at the third month postoperative follow up between the control group and the nonsteroidal anti-inflammatory (NSAIDs) groups. There was an increase in the central macular thickness (CMT) in all cases starting from postoperative first week until third month. CMT showed a statistically significant difference between control group and NSAIDs groups from postoperative first month until third month. There was no statistically significant difference between Nepafenac and Ketorolac groups in BCVA and OCT CMT. CONCLUSION: Prophylactic preoperative and postoperative NSAIDs may have a role in reducing the frequency and severity of CME in diabetic eyes following cataract surgery.     

酮咯酸氨丁三醇致过敏性休克

1例26岁男性患者因腹痛给予酮咯酸氨丁三醇30mg肌内注射。注射完毕后约5min,患者感头晕、乏力,并出现全身出汗、晕厥。血压65／40mmHg（1mmHg=0．133kPa）,心率108次／min。立即予吸氧、静脉给予肾上腺素、地塞米松、间羟胺及肌内注射异丙嗪等治疗。约30min后,患者神志恢复正常,症状逐渐好转,血压105／75mmHg,心率80次／min。其后未再出现不适。     

Utilization of Ketorolac for Pain Control During Nephrostomy and Nephroureteral Stent Exchange: A Quality Improvement Study

Patients with nephrostomy/nephroureteral stents undergo exchange procedures every 6 to 8 weeks to maintain patency. This procedure is commonly performed with moderate sedation. These medications are not without risks relating to maintenance of airway and rate of breathing. A quality improvement study was conducted to evaluate the effectiveness of adding ketorolac to a reduced amount of opioid administration during this procedure to examine pain scores. Pain scores were measured by the Visual Analog Scale before, during, and after procedure. Ketorolac has shown to be effective in other areas of pain management but there was a gap in research related to this procedure. Six of the 10 patients required half of the previous total of medications. Four of the 10 patients received the full dose of medications. There were no significant differences between these groups in pre-procedure pain score or the post-procedure pain score. The patients receiving half the dose of medications were able to achieve similar pain control compared to those patients receiving the full dose.     

Comparison of ketorolac and morphine for postoperative pain after major surgery

This study was designed to determine the relative analgesic efficacy and safety of single intramuscular injections of ketorolac (10 mg or 30 mg) and morphine (10 mg) in patients of either sex with moderate to severe pain after major surgery. In a single-dose, randomised, double-blind study of parallel design, pain was assessed immediately before injection of test medication and at regular intervals for 8 h thereafter. One hundred and seventeen patients (109 undergoing cardiac surgery; 8 lung surgery) were randomized to one of the three treatment groups. Pain intensity was assessed using a 5-point verbal scale before administration of study drugs. Postadministration, at 30 min and hourly for 8 h, pain intensity and pain relief were assessed, again using the 5-point verbal scale. Additionally, as a measure of analgesia, forced expiratory volume (FEV1) was obtained in all patients. Vital signs including blood pressure, pulse, temperature, respiratory rate and blood gases (PaCO2) were recorded prior to and after study medication. Based on hourly pain intensity differences and hourly pain relief observations, ketorolac 10 mg was generally more effective than morphine 10 mg, and ketorolac 30 mg was generally more effective than ketorolac 10 mg. The results of this study show that ketorolac is an effective and safe (with regard to arterial pressure, blood gases and lung function) analgesic for relief of postoperative pain after major surgery in stable patients. No clinically significant adverse effects occurred during the study. One cannot exclude an influence on patients with organ system dysfunction or on parameters not measured in this study.     

Comparative bioavailability of two oral formulations of ketorolac tromethamine: Dolac® and Exodol®

The bioavailability of ketorolac after administration of two oral formulations containing 10 mg of ketorolac tromethamine, Exodol^® and Dolac^®, to 12 healthy Mexican volunteers was compared. Subjects received both formulations according to a randomized crossover design and blood samples were drawn at selected times during 24 h. Ketorolac plasma concentrations were determined by HPLC and individual plasma-concentration-against-time curves were constructed. Maximal plasma concentration and AUC_0-24. values were compared by analysis of variance followed by Westlake's confidence interval test. 90% confidence limits ranged from 80 to 125% for C_max and from 85 to 118% for AUC_0-24. It is concluded that the two assayed formulations are bioequivalent.     

Ketorolac tromethamine floating beads for oral application: Characterization and in vitro/in vivo evaluation

The floating beads have been employed to make a sustained release of the drug in the stomach and to decrease the dose of the drug and hence overcome its side effects. The common benefits of the floating beads were it is easy preparation, without the need of a high temperature, and high percentage of the drug entrapment. In the present work, the Ketorolac tromethamine (KT) floating beads were prepared by extrusion congealing method utilizing calcium carbonate as a gas forming agent. The physical characters of the produced beads were investigated such as KT yield, KT loading, and entrapment efficiency of the drug. In addition, floating behavior, swelling, particle size, morphology and KT stability were also evaluated. In vitro drug release study was carried out, and the kinetics of the release was evaluated using the linear regression method. Furthermore, the in vivo analgesic effect of KT after oral administration of the selected formula of floating beads (F10) was carried out using hot plate and tail flick methods. Oral commercial KT tablets and KT solution were used for the comparison. The prepared beads remained floated for more than 8 h. The optimized formulation (F10) exhibited prolonged drug release (more than 8 h) and the drug release follows the Higuchi kinetic model, with a Fickian diffusion mechanism according to Korsmeyer-Peppas (n = 0.466). Moreover, F10 showed a sustained analgesic effect as compared to the commercial tablet.