Use of intravenous ketorolac in the neonate and premature babies

BACKGROUND: Ketorolac is a powerful nonsteroidal anti-inflammatory drug widely used for pain control in children and adults. The aim of this study was to evaluate its safety and analgesic efficacy in the neonate. METHODS: Ketorolac was used in a group of 18 spontaneously breathing neonates presenting with chronic lung disease, for the control of postsurgical pain and pain from invasive procedures. Pain scores (Neonatal Infant Pain Scale) were assessed before and after i.v. administration of 1 mg.kg(-1) of ketorolac. RESULTS: Total pain control was achieved in 94.4% of the neonates. None of the neonates had haematological, renal or hepatic changes prior to treatment, and these complications did not occur after treatment. No neonate had systemic haemorrhage or bleeding from injection and blood withdrawal sites. CONCLUSIONS: Ketorolac could represent an efficacious analgesic alternative to opioids, particularly in neonates. It would avoid the side-effects associated with opioid analgesics, especially respiratory depression.     

Pretreatment with ketorolac and venous occlusion to reduce pain on injection of propofol

We performed a randomised, double-blind, prospective trial to discover whether intravenous ketorolac 10 mg made up to 2 ml with saline, with or without venous occlusion for 2 min, reduces the pain on injection of propofol. In 90 patients, pain scores were obtained during injection of propofol following pretreatment of the vein with saline, ketorolac or ketorolac with venous occlusion. Pain on injection of ketorolac was more common than with saline (p = 0.02). The incidence of severe pain following propofol was reduced by ketorolac with venous occlusion (p = 0.019) compared with saline or ketorolac without venous occlusion. There was no difference in venous sequelae at 7 days postoperatively between the groups. Our results suggest that pain on injection of propofol may be related to release of local kininogens and that nonsteroidal anti-inflammatory drugs may have a role in reducing that pain.     

The effects of ketorolac injected via patient controlled analgesia postoperatively on spinal fusion

Lumbar spinal fusions have been performed for spinal stability, pain relief and improved function in spinal stenosis, scoliosis, spinal fractures, infectious conditions and other lumbar spinal problems. The success of lumbar spinal fusion depends on multifactors, such as types of bone graft materials, levels and numbers of fusion, spinal instrumentation, electrical stimulation, smoking and some drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs). From January 2000 to December 2001, 88 consecutive patients, who were diagnosed with spinal stenosis or spondylolisthesis, were retrospectively enrolled in this study. One surgeon performed all 88 posterolateral spinal fusions with instrumentation and autoiliac bone graft. The patients were divided into two groups. The first group (n=30) was infused with ketorolac and fentanyl intravenously via patient controlled analgesia (PCA) postoperatively and the second group (n=58) was infused only with fentanyl. The spinal fusion rates and clinical outcomes of the two groups were compared. The incidence of incomplete union or nonunion was much higher in the ketorolac group, and the relative risk was approximately 6 times higher than control group (odds ratio: 5.64). The clinical outcomes, which were checked at least 1 year after surgery, showed strong correlations with the spinal fusion status. The control group (93.1%) showed significantly better clinical results than the ketorolac group (77.6%). Smoking had no effect on the spinal fusion outcome in this study. Even though the use of ketorolac after spinal fusion can reduce the need for morphine, thereby decreasing morphine related complications, ketorolac used via PCA at the immediate postoperative state inhibits spinal fusion resulting in a poorer clinical outcome. Therefore, NSAIDs such as ketorolac, should be avoided after posterolateral spinal fusion.     

高效液相色谱法测定酮咯酸氨丁三醇注射液的含量

目的 :建立一种用高效液相色谱法测定酮咯酸氨丁三醇注射液含量的方法。方法 :采用HypersilODS2C185 μm柱 ,甲醇 水 冰醋酸 (5 5∶4 4∶1)为流动相 ,流速约为 1.2mL·min-1,检测波长为 2 4 9nm。结果 :该方法酮咯酸氨丁三醇含量线性范围为 0 .0 96～ 0 .336g·L-1,r =0 .9999,回收率为 99.38% ,RSD为 0 .4 2 % (n =6 )。结论 :该方法简便、准确 ,能满足制剂质量标准的要求。     

Ketorolac inhibits choroidal neovascularization by suppression of retinal VEGF

We assessed the effect of topical ketorolac on laser-induced choroidal neovascularization (CNV), measured retinal PGE₂ and VEGF levels after laser treatment, and determined the effect of ketorolac on PGE₂ and VEGF production. Six laser burns were placed in eyes of rats which then received topical ketorolac 0.4% or artificial tears four times daily until sacrifice. Fluorescein angiography (FA) was performed at 2 and 3 weeks and retinal pigment epithelium-choroid-sclera flat mounts were prepared. The retina and vitreous were isolated at 1, 3, 5, 7, and 14 days after laser treatment and tested for VEGF and PGE₂. Additional animals were lasered and treated with topical ketorolac or artificial tears and tested at 3 and 7 days for retinal and vitreous VEGF and PGE_2. Ketorolac reduced CNV on FA by 27% at 2 weeks (P < 0.001) and 25% at 3 weeks (P < 0.001). Baseline retina and vitreous PGE₂ levels were 29.4 μg/g and 16.5 μg/g respectively, and reached 51.2 μg/g and 26.9 μg/g respectively, 24 h after laser treatment (P < 0.05). Retinal VEGF level was 781 pg/g 24 h after laser treatment and reached 931 pg/g by 7 days (P < 0.01). Ketorolac reduced retinal PGE₂ by 35% at 3 days (P < 0.05) and 29% at 7 days (P < 0.001) and retinal VEGF by 31% at 3 days (P = 0.10) and 19% at 7 days (P < 0.001). Topical ketorolac inhibited CNV and suppressed retinal PGE₂ and VEGF production.     

Prinomide Tromethamine Pharmacokinetics: Mutually Dependent Saturable and Competitive Protein Binding Between Prinomide and Its Own Metabolite

Prinomide tromethamine, a nonsteroidal antiinflammatory drug, was orally administered at doses of 250, 500, and 1000 mg every 12 hr for 28 days to healthy male volunteers. The pharmacokinetic behavior of prinomide and its primary plasma metabolite displayed nonlinear characteristics, while those of free prinomide and its metabolite were dose proportional. The nonlinear pharmacokinetic behavior of total prinomide and p-hydroxy metabolite was found to be caused by both saturable and mutually dependent competitive Langmuir-type plasma protein binding between prinomide and its p-hydroxy metabolite. The extent of the protein interaction displayed at steady state was due to the extensive accumulation of the p-hydroxy metabolite. While ligand–protein interactions are known for xenobiotic competitors, the characteristic behavior of prinomide is the first known example to be reported for a competitive protein interaction between a xenobiotic and its own in vivo generated metabolite. The findings of this study may have implications regarding the disposition of other extensively bound nonsteroidal antiinflammatory drugs with long-lived metabolites.     

Coordinate production of PGE,and IL-1β in the gingival crevicular fluid of adults with periodontitis: its relationship to alveolar bone loss and disruption by twice daily treatment with ketorolac tromethamine oral rinse

The inflammatory mediators prostaglandin E₂ (PGE₂) and interleukin-1β (IL-1β) play critical roles in the inflammatory process leading to alveolar bone and connective tissue loss in periodontal disease. Data from a previously published 6-month clinical study demonstrated that twice daily use of 0.1% ketorolac tromethamine oral rinse prevented alveolar bone loss in adults with periodontitis. We further analyzed data from this study to examine the relationship between PGE₂, IL-1β and bone loss. Patient mean PGE₂, and IL-1β levels in gingival crevicular fluid (M-GCF) measured throughout the course of the study were directly compared to the maximum amount of alveolar bone height loss observed at a single study site in each patient. The maximum amount of bone loss measured was chosen for the analysis since the pattern of bone loss was clearly episodic in nature. A statistically significant correlation (r = 0.73, p = 0.001) exists between M-GCF PGE₂ concentration and the maximum amount of bone height lost at individual patient study sites. The correlation between M-GCF IL-1β concentration and maximum bone height lost is also statistically significant (r = 0.66, p = 0.005). Over the 6-month duration of the study, both PGE, and IL-1β were coordinately expressed in the placebo treatment group as reflected in the significant correlation between M-GCF concentrations of the 2 mediators (r=0.81, p<0.001). Treatment of patients with 0.1% ketorolac tromethamine twice daily for 6 months resulted in reductions of PGE, in GCF and a negligible correlation between M-GCF PGE, and M-GCF IL-1β (r=0.42, p=0.088). This lack of a strong association between the 2 mediators in the ketorolac treatment group provides a direct biochemical readout of the anti-inflammatory efficacy of ketorolac tromethamine oral rinse in patients with periodontitis. Further studies are warranted to determine the full diagnostic potential of M-GCF levels of PGE₂, and IL-1β for predicting risk of alveolar bone loss in patients with periodontitis and monitoring periodontal therapy effectiveness.     

高效液相色谱法测定人体血浆中酮咯酸含量及其药动学

目的：建立高效液相色谱法测定血浆中酮咯酸浓度的方法.方法：色谱柱为Waters sunfire C18色谱柱（150 mm× 4.6mm,5 μm）,流动相为（0.02 mol·L^-1磷酸二氢钾溶液-乙腈（70∶30）,用磷酸调至pH 4.5,检测波长315 nm,测定酮咯酸的含量.结果：血样酮咯酸的保留时间为6.35 min,最低定量限为0.05 mg·L^-1,RSD小于20%,在0.05～8.0 mg·L^-1范围内呈良好线性关系,平均方法学回收率为95.40%～100.28%关系,平均提取回收率为95.79%～106.01%,批内和批间变异＜10%.结论：本法简便、快捷、灵敏,适用于酮咯酸人体临床药动学研究.     

Effect of Ketorolac Tromethamine on Lymph Circulation, Contractile Activity of the Lymphangion and Lymphatic Microvessels, and Cellular Composition and Toxicity of the Lymph during Fever

Single parenteral administration of ketorolac tromethamine produced a lymphotropic effect, which was manifested in acceleration of lymph flow in the thoracic duct and increase in contractile activity of the wall and valves in mesenteric lymphatic microvessels of rats with fever. These changes improved lymph circulation. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 140, No. 10, pp. 394–397, October, 2005