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Clinical Pharmacology and Therapeutics Apr 1999To compare the pharmacokinetics and metabolism of R(+)- and S(-)- ketorolac in children. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
OBJECTIVE
To compare the pharmacokinetics and metabolism of R(+)- and S(-)- ketorolac in children.
METHODS
Children from 3 to 18 years old received 0.6 mg/kg racemic ketorolac intravenously. Serial blood samples were obtained for 12 hours, and urine was collected for 12 to 24 hours. Racemic ketorolac was measured in plasma, and racemic ketorolac, para-hydroxyketorolac, and ketorolac glucuronide were measured in urine by HPLC. S(-)- and R(+)-ketorolac were measured in plasma; S(-)- and R(+)-ketorolac and ketorolac glucuronide were measured in urine by chiral HPLC separation. Plasma pharmacokinetic parameters for racemic drug and both enantiomers were determined for each patient.
RESULTS
Clearance of racemic ketorolac in children was approximately 2 times the clearance reported in adults. Clearance of the S(-) enantiomer was 4 times that of the R(+) enantiomer. Terminal half-life of S(-)-ketorolac was 40% that of the R(+) enantiomer, and the apparent volume of distribution of the S(-) enantiomer was greater than that of the R(+) form. Recovery of S(-)-ketorolac glucuronide was 2.3 times that of the R(+) enantiomer.
CONCLUSION
The higher clearance in children suggests that the weight-adjusted dose of ketorolac may have to be greater for children to achieve plasma concentrations comparable to those of adults. Because of the greater clearance and shorter half-life of S(-)-ketorolac, pharmacokinetic predictions based on racemic assays may overestimate the duration of pharmacologic effect. Enantiomeric pharmacokinetic differences are best explained by stereoselective plasma protein binding. Selective glucuronidation of the S(-) enantiomer suggests that stereoselective metabolism may also be a contributing factor.
Topics: Adolescent; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Child; Child, Preschool; Chromatography, High Pressure Liquid; Double-Blind Method; Female; Humans; Injections, Intravenous; Ketorolac; Male; Morphine; Pain, Postoperative; Stereoisomerism; Tolmetin
PubMed: 10223774
DOI: 10.1016/S0009-9236(99)70131-1 -
CMAJ : Canadian Medical Association... May 1993
Topics: Advertising; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Costs and Cost Analysis; Drug Combinations; Humans; Ketorolac Tromethamine; Tolmetin; Tromethamine
PubMed: 8485673
DOI: No ID Found -
Archives of Emergency Medicine Dec 1984A prospective controlled trial involving over 1000 patients did not reveal any difference between four drugs commonly used in accident and emergency departments for the... (Clinical Trial)
Clinical Trial Comparative Study
A prospective controlled trial involving over 1000 patients did not reveal any difference between four drugs commonly used in accident and emergency departments for the relief of mild to moderate pain. There were no significant variations in therapeutic effect, side-effects or patient compliance. When considering the supply of analgesics which may be no more potent than those available without prescription from retail chemists, cost and safety are more important than analgesic effect. By restricting the choice of analgesics available, the accident and emergency department should be able to increase awareness among its staff of the actions and side-effects of a small number of prescribed drugs and to contain costs.
Topics: Acetaminophen; Analgesics; Clinical Trials as Topic; Costs and Cost Analysis; Emergencies; Emergency Service, Hospital; England; Fenoprofen; Humans; Mefenamic Acid; Prospective Studies; Tolmetin
PubMed: 6399444
DOI: 10.1136/emj.1.4.197 -
British Journal of Pharmacology Jul 19811 The site of the analgesic action of tolmetin sodium was investigated by use of the acetic acid writhing test in rats. 2 Tolmetin sodium was administered to the rat... (Comparative Study)
Comparative Study
1 The site of the analgesic action of tolmetin sodium was investigated by use of the acetic acid writhing test in rats. 2 Tolmetin sodium was administered to the rat between 15 and 60 min after intraperitoneal injection of 1 ml of a 1% acetic acid aqueous solution. Number of writhing was counted for 20 min beginning from 60 min after acetic acid injection. 3 When the rat was given tolmetin sodium 5 mg/kg orally, a relatively large quantity of tolmetin was found in the peritoneal exudate and there was a rough correlation between anti-writhing activity and the exudate tolmetin content. 4 Anti-writhing ED50 of tolmetin sodium was 1.42 (0.82-2.91) and 92.0 (57.0-140) microgram/kg when given intraperitoneally and intravenously, respectively, and the potency ratio of intraperitoneal to intravenous tolmetin sodium was 40.0 (18.5-80.2). This potency ratio for salicylic acid and morphine hydrochloride was 19.4 and 1.0, respectively. 5 When equipotent doses ( 5 microgram/kg i.p.; 200 microgram/kg i.v.) of tolmetin sodium were administered to the rat, the plasma tolmetin level after the intraperitoneal administration was less than one-fortieth that after the intravenous administration during the counting time of 20 min, while both the peritoneal exudate contents of tolmetin were nearly equal. 6 From these results, it is concluded that the site of anti-writhing action of tolmetin sodium is in the peritoneum and that tolmetin sodium produces its anti-writhing action mainly by a peripheral mechanism in the rat.
Topics: Administration, Oral; Animals; Ascitic Fluid; Injections, Intraperitoneal; Injections, Intravenous; Male; Pain; Peritoneum; Pyrroles; Rats; Tolmetin
PubMed: 7248666
DOI: 10.1111/j.1476-5381.1981.tb16815.x -
Proceedings of the National Academy of... May 1993Acyl glucuronide metabolites of bilirubin and many drugs can react with serum albumin in vivo to form covalent adducts. Such adducts may be responsible for some toxic...
Acyl glucuronide metabolites of bilirubin and many drugs can react with serum albumin in vivo to form covalent adducts. Such adducts may be responsible for some toxic effects of carboxylic nonsteroidal antiinflammatory agents. The mechanism of formation of the adducts and their chemical structures are unknown. In this paper we describe the use of tandem mass spectrometry to locate binding sites and elucidate the binding mechanism involved in the formation of covalent adducts from tolmetin glucuronide and albumin in vitro. Human serum albumin and excess tolmetin glucuronide were coincubated in the presence of sodium cyanoborohydride to trap imine intermediates. The total protein product was reduced, carboxymethylated, and digested with trypsin. Six tolmetin-containing peptides (indicated by absorbance at 313 nm) were isolated by high-pressure liquid chromatography and analyzed by liquid secondary-ion mass spectrometry and collision-induced dissociation, using a four-sector tandem mass spectrometer. All six peptides contained tolmetin linked covalently via a glucuronic acid to protein lysine groups. Major attachment sites on the protein were Lys-195, -199, and -525; minor sites were identified as Lys-137, -351, and -541. Our results show unambiguously that the glucuronic acid moiety of acyl glucuronides can be retained within the structure when these reactive metabolites bind covalently to proteins, and they suggest that acyl migration followed by Schiff base (imine) formation is a credible mechanism for the generation of covalent adducts in vivo.
Topics: Acylation; Amino Acid Sequence; Binding Sites; Carbohydrate Conformation; Chromatography, High Pressure Liquid; Glucuronates; Humans; Lysine; Mass Spectrometry; Molecular Sequence Data; Peptide Fragments; Serum Albumin; Tolmetin; Trypsin
PubMed: 8483897
DOI: 10.1073/pnas.90.9.3797 -
Biomedicines Apr 2023Glioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months)....
Glioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months). Resistance to therapy may originate from a subpopulation of tumor cells identified as glioma-stem cells (GSC), and new treatments are urgently needed to target these. The biology underpinning GBM recurrence was investigated using whole transcriptome profiling of patient-matched initial and recurrent GBM (recGBM). Differential expression analysis identified 147 significant probes. In total, 24 genes were validated using expression data from four public cohorts and the literature. Functional analyses revealed that transcriptional changes to recGBM were dominated by angiogenesis and immune-related processes. The role of MHC class II proteins in antigen presentation and the differentiation, proliferation, and infiltration of immune cells was enriched. These results suggest recGBM would benefit from immunotherapies. The altered gene signature was further analyzed in a connectivity mapping analysis with QUADrATiC software to identify FDA-approved repurposing drugs. Top-ranking target compounds that may be effective against GSC and GBM recurrence were rosiglitazone, nizatidine, pantoprazole, and tolmetin. Our translational bioinformatics pipeline provides an approach to identify target compounds for repurposing that may add clinical benefit in addition to standard therapies against resistant cancers such as GBM.
PubMed: 37189838
DOI: 10.3390/biomedicines11041219 -
British Journal of Anaesthesia Apr 1998
Topics: Acute Kidney Injury; Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Evidence-Based Medicine; Humans; Ketorolac; Postoperative Complications; Tolmetin
PubMed: 9640143
DOI: 10.1093/bja/80.4.420 -
British Journal of Anaesthesia Feb 1999We studied intensity of pain, cumulative morphine consumption, ventilatory and renal function, and haemostasis in patients undergoing video-assisted thoracoscopic... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
We studied intensity of pain, cumulative morphine consumption, ventilatory and renal function, and haemostasis in patients undergoing video-assisted thoracoscopic surgery and receiving a 2-day i.v. infusion of diclofenac, ketorolac or saline. Plasma concentrations of the two NSAID were also measured. The study was randomized, double-blind and placebo-controlled, with 10 patients in each group. Patients experienced mainly moderate pain. Mean consumption of i.v. morphine during the first day after operation was 57 (SEM 11) mg in the placebo group. Diclofenac and ketorolac were equally effective in reducing total morphine consumption (61% and 52%, respectively). Adverse events were similar and minor. Greater variability in plasma concentrations of ketorolac were detected compared with diclofenac.
Topics: Adolescent; Adult; Aged; Analgesics, Non-Narcotic; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Double-Blind Method; Endoscopy; Female; Forced Expiratory Volume; Hemostasis; Humans; Ketorolac; Kidney; Male; Middle Aged; Morphine; Pain, Postoperative; Thoracic Surgical Procedures; Thoracoscopy; Tolmetin
PubMed: 10364998
DOI: 10.1093/bja/82.2.221 -
The British Journal of Ophthalmology Feb 1985We have compared the anti-inflammatory efficacy of 5% tolmetin sodium dihydrate, 0.5% prednisolone disodium phosphate, and 0.1% betamethasone disodium phosphate in 71... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
We have compared the anti-inflammatory efficacy of 5% tolmetin sodium dihydrate, 0.5% prednisolone disodium phosphate, and 0.1% betamethasone disodium phosphate in 71 consecutive patients presenting with acute endogenous non-granulomatous uveitis randomly assigned to one of these treatment groups. Inflammatory symptoms and signs were scored during the course of the 21-day trial period. There was no statistically significant difference in the effect on the signs or symptoms of the three drugs tested. 90% of the Betnesol (betamethasone sodium phosphate, benzalkonium chloride) treated group were clinically judged cured compared with 68% of the Predsol (prednisolone sodium phosphate, benzalkonium chloride) treated group, and 57% of the tolmetin treated group.
Topics: Administration, Topical; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Betamethasone; Clinical Trials as Topic; Dexamethasone; Female; Humans; Intraocular Pressure; Male; Middle Aged; Prednisolone; Pyrroles; Tolmetin; Uveitis
PubMed: 3881125
DOI: 10.1136/bjo.69.2.120 -
Frontiers in Chemistry 2018The goal of this study is to provide tools to minimize in the development of novel lipid-based nanotherapeutics, in favor of a rational design process. For this...
The goal of this study is to provide tools to minimize in the development of novel lipid-based nanotherapeutics, in favor of a rational design process. For this purpose, we present case-study examples of biophysical assays that help addressing issues of lipid-based nanotherapeutics' profiling and assist in the design of lipid nanocarriers for therapeutic usage. The assays presented are rooted in spectroscopic methods (steady-state and time-resolved fluorescence; UV-Vis derivative spectroscopy; fluorescence anisotropy and fluorescence lifetime image microscopy) and allow accessing physical-chemical interactions between drugs and lipid nanocarriers, as well as studying interactions between lipid-based nanotherapeutics and membranes and/or proteins, as this is a key factor in predicting their therapeutic and effects. Derivative spectroscopy revealed Naproxen's high distribution (Log ≈ 3) in different lipid-based nanocarriers (micelles and unilamellar or multilamellar vesicles) confirming the adequacy of such systems for encapsulating this anti-inflammatory drug. Fluorescence quenching studies revealed that the anti-inflammatory drugs Acemetacin and Indomethacin can reach an inner location at the lipid nanocarrier while being anchored with its carboxylic moiety at the polar headgroup. The least observed quenching effect suggested that Tolmetin is probably located at the polar headgroup region of the lipid nanocarriers and this superficial location may translate in a fast drug release from the nanocarriers. Fluorescent anisotropy measurements indicated that the drugs deeply buried within the lipid nanocarrier where the ones that had a greater fluidizing effect which can also translate in a faster drug release. The drug binding strength to serum albumin was also compared for a free drug (Clonixin) or for the same drug after encapsulation in a lipid nanocarrier DSPC:DODAP (2:1). Under both conditions there is a strong binding to serum albumin, at one binding site, suggesting the need to produce a stealth nanosystem. Finally the cellular uptake of lipid nanocarriers loaded with Daunorubicin was investigated in cancer cells using fluorescence lifetime imaging microscopy. From the images obtained it was possible to conclude that even at short incubation times (15 min) there was a distribution of the drug in the cytoplasm, whereas for longer incubation periods (4 h) the drug has reached the nucleus.
PubMed: 30109226
DOI: 10.3389/fchem.2018.00323