I.v. intraoperative ketoprofen in small children during adenoidectomy: a dose-finding study.
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We have investigated if a low dose of ketoprofen (0.3 mg kg-1) i.v., provided as good analgesia with less adverse effects than higher doses (1.0 and 3.0 mg kg-1) in 220 children, aged 1-7 yr, undergoing adenoidectomy, in a prospective, randomized, double-blind, placebo-controlled, parallel group study. The postoperative analgesic effect was notable even after the lowest dose of ketoprofen. However, the higher doses seemed to provide better analgesia with no increase in adverse events or intraoperative bleeding. None of the children experienced postoperative bleeding which would have required intervention or delayed discharge from hospital. This study confirms the efficacy and safety of intraoperative ketoprofen in children during adenoidectomy. (+info)
Ketoprofen, diclofenac or ketorolac for pain after tonsillectomy in adults?
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We have compared the analgesic and opioid sparing effect of three i.v. non-steroidal anti-inflammatory drugs with placebo in a randomized, double-blind, placebo-controlled study in 80 adult patients after elective tonsillectomy. A standard anaesthetic was used. After induction of anaesthesia, patients received ketoprofen 100 mg, diclofenac 75 mg or ketorolac 30 mg by i.v. infusion over 30 min. Patients in the placebo group received saline. Ketoprofen and diclofenac infusions were repeated after 12 h and ketorolac infusion at 6 h and 12 h. Oxycodone was used as rescue analgesic. Patients in the ketoprofen group requested 32% less opioid and patients in the diclofenac and ketorolac groups 42% less opioid than those in the placebo group (P < 0.05). There were one, two and six patients in the placebo, diclofenac and ketorolac groups, respectively, but none in the ketoprofen group, who did not request opioid analgesia during the study (P < 0.05, ketorolac vs placebo and ketoprofen). Visual analogue pain scores were similar in all groups. Visual analogue satisfaction scores were significantly higher in the diclofenac group compared with the placebo group. The incidence of nausea was 44-54%. There were no differences in the incidence of other adverse reactions. We conclude that all three non-steroidal anti-inflammatory drugs were superior to placebo after tonsillectomy. (+info)
Human and rat liver UDP-glucuronosyltransferases are targets of ketoprofen acylglucuronide.
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Acylglucuronides formed from carboxylic acids by UDP-glucuronosyltransferases (UGTs) are electrophilic metabolites able to covalently bind proteins. In this study, we demonstrate the reactivity of the acylglucuronide from the nonsteroidal anti-inflammatory drug, ketoprofen, toward human and rat liver UGTs. Ketoprofen acylglucuronide irreversibly inhibited the glucuronidation of 1-naphthol and 2-naphthol catalyzed by human liver microsomes or by the recombinant rat liver isoform, UGT2B1, which is the main isoform involved in the glucuronidation of the drug. A decrease of about 35% in the glucuronidation of 2-naphthol was observed when ketoprofen acylglucuronide was produced in situ in cultured V79 cells expressing UGT2B1. Inhibition was always associated with the formation of microsomal protein-ketoprofen adducts. The presence of these covalent adducts within the endoplasmic reticulum of cells expressing UGT2B1 was demonstrated following addition of ketoprofen to culture medium by immunofluorescence microscopy with antiketoprofen antibodies. Immunoblots of liver microsomes incubated with ketoprofen acylglucuronide and probed with antiketoprofen antibodies revealed the presence of several protein adducts; among those was a major immunoreactive protein at 56 kDa, in the range of the apparent molecular mass of UGTs. The adduct formation partially prevented the photoincorporation of the UDP-glucuronic acid (UDP-GlcUA) analog, [beta-32P]5N3UDP-GlcUA, on the UGTs, suggesting that ketoprofen glucuronide covalently reacted with the UDP-GlcUA binding domain. Finally, UGT purification from rat liver microsomes incubated with ketoprofen glucuronide led to the isolation of UGT adducts recognized by both anti-UGT and antiketoprofen antibodies, providing strong evidence that UGTs are targets of this metabolite. (+info)
Intra-articular absorption and distribution of ketoprofen after topical plaster application and oral intake in 100 patients undergoing knee arthroscopy.
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OBJECTIVE: The primary objective of this study was to assess the kinetics of ketoprofen in synovial fluid and intra-articular tissues in relation to plasma. The secondary objective was to study whether intra-articular tissues act as reservoirs. METHODS: The ketoprofen concentration was analysed in plasma, synovial fluid and intra-articular tissues after single application of a 30 mg plaster (n = 40), multiple applications for 5 days (n = 30) or oral intake of 50 mg (n = 30) in patients undergoing knee arthroscopy. RESULTS: Median CMax values after topical application were 12.8 ng/ml in synovial fluid, 56.7 ng/g in synovial tissue, 349.3 ng/g in meniscus and 568.9 ng/g in cartilage. CONCLUSION: Topical applications of ketoprofen allow the attainment of high intra-articular tissue concentrations. (+info)
Interferon alfa-2b alone or in combination with ketoprofen as treatment for interferon-naive chronic hepatitis C patients.
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BACKGROUND: Non-steroidal anti-inflammatory drugs may amplify the anti-viral effect of alpha-interferon in vitro but in vivo data are still controversial. AIM: : To test the hypothesis that ketoprofen may increase the rate of response to alpha-interferon of chronic hepatitis C patients. METHODS: Fifty patients with chronic hepatitis C who had never received alpha-interferon were randomly assigned to receive 3-8 MU of alpha2b-interferon, three times weekly for 6 months, alone or in association with ketoprofen at a dose of 200 mg/day five times weekly. The virological response to treatment (undetectable HCV RNA in serum) was evaluated after 3 months and at the end of treatment, and 6 and 12 months after therapy withdrawal. RESULTS: One patient under combination therapy stopped the ketoprofen for persisting epigastric pain. Complete response under treatment was observed in 15 out of 24 (62.5%) patients receiving alpha2b-interferon alone and in 14 out of 26 (53.8%) patients under combination therapy (P=N.S.). One year after the end of treatment, a sustained response was seen in 4 out of 24 (16.2%) patients treated with alpha2b-interferon and in 5 out of 26 (19.2%) patients having received the combination (P=N.S.). CONCLUSION: Administration of ketoprofen does not increase either the primary or the sustained response to alpha2b-interferon therapy of interferon-naive chronic hepatitis C patients. (+info)
Helix 6 of subdomain III A of human serum albumin is the region primarily photolabeled by ketoprofen, an arylpropionic acid NSAID containing a benzophenone moiety.
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It is well known that the subdomain III A (site II) of human serum albumin (HSA) binds a variety of endogenous and exogenous substances. However, the nature of the microenvironment of the binding site remains unclear. Ketoprofen (KP), an arylpropionic acid NSAID which contains a benzophenone moiety, was used as a photoaffinity labeling agent to label the binding region. Subsequent CNBr cleavage of the photolabeled HSA revealed that the 11.6 kDa and 9.4 kDa fragments contained most of the incorporated radioactivity. Competition experiments showed that the 11.6 kDa fragment contains the common binding region for site II ligands. This fragment was redigested with Achromobacter lyticus protease I (AP-I) and the amino acid sequence of the photolabeled peptide was determined to be XCTESLVNRR, which corresponds to the sequence 476C-485K of HSA. The complete amino acid sequence of the corresponding AP-I digested HSA peptide encompasses residues 476 to 499, which form helices 5 and 6 of subdomain III A. The HSA-Myr X-ray crystallography data showed that helix 5 is involved to the least extent in ligand binding. A docking model provided further support that helix 6 represents the photolabeled region of KP. (+info)
Postoperative pain after adenoidectomy in children.
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We have investigated if pain intensity or analgesic requirements in hospital predicted pain intensity, pain duration or analgesic requirements at home in 611 children, aged 1-7 yr, after day-case adenoidectomy. We also investigated if ketoprofen 0.3-3.0 mg kg-1, administered pre-emptively i.v. during operation, modified pain at home. In hospital, a prospective, randomized, double-blind, placebo-controlled study design was performed. A standard anaesthetic technique was used in all children and fentanyl i.v. was available for rescue analgesia. After discharge, the study design was open, experimental, prospective and longitudinal. On return home, children were prescribed ketoprofen tablets 5 mg kg-1 day-1. Parents were asked to complete an analgesia diary; non-responders were contacted by telephone. The response rate was 91%. The number of doses of fentanyl given in hospital correlated with pain intensity at home (P < 0.001). There were no other correlations and no pre-emptive effect of ketoprofen. (+info)
Stereoselective pharmacokinetics of ketoprofen and ketoprofen glucuronide in end-stage renal disease: evidence for a 'futile cycle' of elimination.
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AIMS: To assess if futile cycling of ketoprofen occurs in patients with decreased renal function. METHODS: Ketoprofen was administered to six haemodialysis-dependent patients with end-stage renal disease as single (50 mg) or multiple doses (50 mg three times daily, for 7 days). Plasma and dialysate concentrations of the unconjugated and glucuronidated R- and S-enantiomers of ketoprofen were determined using h.p.l.c. following the single and multiple dosing. RESULTS: The oral clearance was decreased and terminal elimination half-lives of R- and S-ketoprofen and the corresponding acyl glucuronides were increased in functionally anephric patients compared with healthy subjects. In contrast with the R-isomers, S-ketoprofen and S-ketoprofen glucuronide exhibited an unexpected accumulation (2.7-3. 8 fold) after repeated dosing achieving S:R ratios of 3.3+/-1.7 and 11.2+/-5.3, respectively. The plasma dialysis clearances for R- and S-ketoprofen glucuronides were 49.4+/-19.8 and 39.0+/-15.9 ml min-1, respectively, and 10.8+/-17.6 and 13.3+/-23.5 ml min-1 for unconjugated R- and S-ketoprofen. CONCLUSIONS: The selective accumulation of S-ketoprofen and its acyl glucuronide are consistent with amplification of chiral inversion subsequent to futile cycling between R-ketoprofen and R-ketoprofen glucuronide. Severe renal insufficiency, and possibly more modest decrements, results in a disproportionate increase in systemic exposure to the S-enantiomer which inhibits both pathologic and homeostatic prostaglandin synthesis. (+info)