Formulation and Optimization of a Sustained-Release Tablet of Ketorolac Tromethamine

The objective of our study was to formulate a sustained-release tablet of Ketorolac tromethamine, which is a nonsteroidal anti-inflammatory agent. A 2 3 full factorial design (8 runs) was selected. The variables studied were the amount of drug (30 and 40 mg), ratio of hydroxypropyl methylcellulose (HPMC)/sodium carboxymethylcellulose (NaCMC) (240/40 and 140/140 mg), and amount of ethylcellulose (140 and 180 mg). Swelling-controlled matrix tablets were manufactured by direct compression of formulation ingredients using a Stokes single punch tablet press. Dissolution tests were performed using USP apparatus 3 (Bio-Dis II), at various pHs to mimic the conditions that exist in the gastrointestinal tract. Responses studied included time for 50% of the drug to dissolve (T 50), diffusional exponent (n) that characterizes the release mechanism, and percent friability of the tablets. Analysis of variance indicated that the release rate (T 50) was affected by the HPMC/NaCMC ratio, amount of drug, and two-way and three-way interactions; whereas the amount of drug, HPMC/NaCMC ratio, ethylcellulose, and the interaction between drug and HPMC/NaCMC and HPMC/NaCMC and ethylcellulose and also three-way interactions were significantly affecting the diffusional exponent (n) . The release mechanism was found to be super-case II transport. The friability of the tablets was significantly affected by all three factors: amount of drug, HPMC/NaCMC ratio, and amount of ethylcellulose. The formulation giving the best release characteristics was identified.     

Comparison of analgesic effect of locally and systemically administered ketorolac in mastectomy patients

Background: Ketorolac is a parenteral nonsteroidal antiinflammatory drug (NSAID). Two features have limited its clinical utility: tendency to elicit kidney failure and inability to produce complete analgesia. Because most NSAIDs are weak acids (pKa 3–5) and become concentrated in acidic tissues, such as injured and inflamed tissues, we hypothesized that local administration may enhance its analgesic efficacy while lowering the potential for systemic complications. Methods: We conducted a randomized, placebo-controlled study of 60 group I–III (American Society of Anesthesiology criteria) mastectomy patients, 20 in each group. Near the end of surgery and every 6 h postoperatively, 20 ml of the study solution containing normal saline with or without 30 mg of ketorolac were administered simultaneously either via a Jackson-Pratt drain or intravenously in a double-blind fashion. The quality of pain control, the amount and character of the drain fluid, incidence of nausea and vomiting, length of stay in the postoperative care unit, and amount of morphine used for treatment of breakthrough pain were recorded. Results: Intraoperative administration of ketorolac resulted in better quality of pain control in the immediate postoperative period regardless of route of administration. The incidence of nausea was significantly higher in the placebo group, and drain output in the ketorolac groups did not exceed the output in the placebo group. Conclusion: Analgesic of the locally administered ketorolac is equally effective to the efficacy of ketorolac administered intravenously. Presented at the 48th Annual Meeting of the Society of Surgical Oncology, Boston, Massachusetts, March 23–26, 1995.     

酮咯酸氨丁三醇复合酒石酸布托啡诺用于治疗骨折术后急性疼痛的临床效果观察

目的比较单用酮咯酸氨丁三醇和酮咯酸氨丁三醇联合酒石酸布托啡诺用于治疗骨折术后急性疼痛的效果。方法 80例骨折术后急性疼痛患者,拟采用酮咯酸氨丁三醇或酮咯酸氨丁三醇联合酒石酸布托啡诺治疗,随机均分为两组。两组镇痛负荷剂量均为酮咯酸氨丁三醇30 mg。并继以2 ml/h静脉持续泵注酮咯酸氨丁三醇0.5 mg/kg（A组）及酮咯酸氨丁三醇0.25 mg/kg联合酒石酸布托啡诺10 mg（B组）。采用视觉模拟量表（VAS法）评分法评价给药前（T1）、给药后10 min、1 h、2 h、4 h、6 h（分别为T2、T3、T4、T5、T6）时的镇痛效果,并记录胃部不适、干呕或呕吐等不良反应的发生情况。结果与T1时点相比,两组T2、T3、T4、T5、T6时点VAS评分明显降低（P〈0.05）。与T2-T5时点相比,两组的VAS评分在T6时点升高（P〈0.05）。T6时点A组的VAS评分低于B组（P〈0.05）。B组胃部不适、干呕或呕吐等不良反应发生率明显低于A组（P〈0.05）。结论采用酮咯酸氨丁三醇酮或酮咯酸氨丁三醇联合酒石酸布托啡诺可有效控制骨折术后急性疼痛,其中酮咯酸氨丁三醇联合酒石酸布托啡诺的使用可明显降低相关不良反应发生率,但有效镇痛时间稍短。     

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.     

酮咯酸氨丁三醇预防瑞芬太尼全麻苏醒期疼痛及躁动临床效果观察

目的:观察酮咯酸氨丁三醇预防瑞芬太尼全麻苏醒期疼痛及躁动的临床效果。方法:选择40～60岁择期行腹腔镜胆囊手术患者100例,ASA I～II级,随机分为两组,每组50例,观察组手术结束前30min静脉滴注酮咯酸氨丁三醇30mg,对照组手术结束前30min静脉滴0.9%氯化钠1mL,观察两组患者自主呼吸恢复时间、苏醒时问、拔管时间以及拔管后15、30min疼痛评分和烦躁程度评级。结果:两组自主呼吸恢复时间、苏醒时间、拔管时间差异均无统计学意义(P>0.05);观察组拔管后15、30min疼痛评分及躁动程度评级明显低于对照组,差异有统计学意义(P均<0.01)。结论:酮咯酸氨丁三醇可以预防瑞芬太尼全麻苏醒期疼痛和躁动。     

Comparison of Pain-relieving Effects of Fentanyl versus Ketorolac after Eye Amputation Surgery

Purpose

To investigate the analgesic effect and incidence of postoperative nausea and vomiting (PONV) between the opioid fentanyl and the non-steroidal anti-inflammatory drug ketorolac in patients who underwent eye amputation surgery.

Methods

Retrospective observational case series. Eighty-two patients underwent evisceration or enucleation surgery by one surgeon over a 2-year period. Fentanyl by intravenous patient-controlled analgesia (IV-PCA) at 20 µg/kg with 12 mg/kg ondansetron or intravenous ketorolac at 2 mg/kg/day was administered to patients at postoperative days 0, 1, and 2. The pain score was measured using an 11-point visual analog scale (VAS). The incidence of severe nausea requiring anti-emetics and the incidence of vomiting were reviewed.

Results

The mean postoperative VAS in the fentanyl group was significantly lower than that in the ketorolac group on the day of operation for both types of surgery (p = 0.001 and p = 0.004, respectively). At postoperative days 1 and 2, the mean VAS was not different between the two groups for either surgical type (p > 0.05 for both days). The mean VAS was significantly higher in eviscerated patients than in enucleated patients at postoperative days 0 and 1 in the fentanyl group (p = 0.023 and p = 0.016, respectively). However, this was not observed in the ketorolac group. The incidence of PONV was higher in the fentanyl group than in the ketorolac group, although this was not statistically significant for either surgical type (p > 0.05 for both groups).

Conclusions

Fentanyl was more effective as an analgesic than was ketorolac on the day of operation for both surgical types. There was no difference between the two analgesics on postoperative day 1. The analgesic effect of fentanyl in enucleated patients was significantly higher than in eviscerated patients at postoperative days 0 and 1. The use of fentanyl by IV-PCA was associated with greater PONV despite co-administration with anti-emetics, although this finding was not significant.     

酮咯酸预先镇痛联合罗哌卡因局部浸润用于腹腔镜胆囊切除术患者术后镇痛的效果

目的 探讨酮咯酸预先镇痛联合罗哌卡因局部浸润用于腹腔镜胆囊切除术患者术后镇痛的效果.方法 全凭静脉麻醉腹腔镜下胆囊切除术患者90例,随机分为3组（n=30）：生理盐水组（S组）、0.375％罗哌卡因组（L组）和0.375％罗哌卡因加酮咯酸组（T组）,各组均加舒芬太尼.其中T组于麻醉诱导前15 min静脉注射酮咯酸30 mg.观察术后镇痛效果与不良反应.结果 S组和L组苏醒时间显著短于T组（P＜0.05）.拔管后口述疼痛评分与VAS评分S组最高,L组次之,T组最低（P＜0.05）.S组要求辅助镇痛药者较其他两组多（P＜0.05）.结论 腹腔镜胆囊切除术患者,酮咯酸预先镇痛可优化罗哌卡因局部浸润麻醉的术后镇痛效果.     

无痛肠镜检查中使用酮咯酸氨丁三醇的效果评价

目的：评价酮咯酸氨丁三醇联合丙泊酚静脉麻醉用于无痛肠镜检查的麻醉效果及安全性。方法：选择120例自愿实施无痛肠镜检查患者,随机分为两组,A组仅使用丙泊酚,B组先静脉滴注酮咯酸氨丁三醇30 mg,5 min后静脉推注丙泊酚。记录两组患者在不同时间点的平均动脉压（MAP）、心率（HR）、呼吸（RR）及血氧饱和度（SpO2）数值,比较两组患者的丙泊酚用量、手术时间、术中肢动、清醒时间、疼痛评分。结果：所有患者均顺利完成手术,两组术中的MAP、HR均较术前显著降低（P<0.05）,但两组间比较差异无统计学意义（P>0.05）。B组的丙泊酚用量、疼痛评分、麻醉效果显著优于A组（P<0.05）。两组手术时间、清醒时间比较差异无统计学意义（P>0.05）。结论：在无痛肠镜检查中联合应用酮咯酸氨丁三醇-丙泊酚能增强麻醉效果,不增加麻醉风险,术后腹痛减少,患者满意,是一种安全、有效的麻醉方法,值得在临床上推广应用。     

国产酮咯酸氨丁三醇分散片的人体相对生物利用度研究

目的评价酮咯酸氨丁三醇分散片剂的人体相对生物利用度,并与胶囊剂比较其生物等效性。方法 18名男性健康受试者随机、自身对照交叉单剂量口服酮咯酸氨丁三醇分散片和胶囊,采用RP-HPLC法测定血浆中酮咯酸氨丁三醇的浓度。结果单剂量口服含酮咯酸氨丁三醇20 mg的受试和参比制剂,其达峰时间Tmax分别为(0.68±0.30)、(0.80±0.38)h;血药浓度峰值Cmax分别为(3 124.44±382.96)、(3 170.28±289.03)ng/mL;药时曲线下面积AUC(0→24)分别为(13 939.32±2 471.53)、(14 312.29±2 268.26)ng.h/mL。两种制剂的药物动力学参数比较差异无统计学意义(P>0.05),受试制剂的相对生物利用度(F)为97.86%±11.62%。结论两种制剂具有生物等效性。