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Journal of Physiology and Pharmacology... Dec 2012We previously reported that delta-9-tetrahydrocannabinol (delta-9-THC), the primary psychoactive constituent of Cannabis sativa, inhibited gastric motor activity and...
We previously reported that delta-9-tetrahydrocannabinol (delta-9-THC), the primary psychoactive constituent of Cannabis sativa, inhibited gastric motor activity and evoked bradycardia and hypotension upon its parenteral administration in the rat. As prostanoids are important mediators of the actions of cannabinoids, we hypothesized that the inhibitory gastric motor and cardiovascular effects of delta-9-THC could depend on cyclooxygenase (COX) activation in the hindbrain and/or in the periphery. To test this hypothesis, vehicle or delta-9-THC (0.2 mg/kg, i.v.) were administered before and 15-min after the COX inhibitor tolmetin (50 mg/kg, i.v.) or 15 min after topical application of tolmetin to the surface of the dorsal medulla (0.5 mg/rat) in chloralose-anesthetized rats. Delta-9-THC-evoked gastric motor inhibition and bradycardia were abolished by parenteral and were attenuated by hindbrain administration of tolmetin. Moreover, administration of delta-9-THC after parenteral tolmetin evoked marked and long-lasting hypertension. We concluded that the inhibitory gastric motor and cardiovascular effects of systemically administered delta-9-THC depend on the hindbrain and peripheral activation of COX.
Topics: Animals; Arterial Pressure; Cyclooxygenase Inhibitors; Dronabinol; Gastrointestinal Motility; Heart Rate; Hemodynamics; Injections, Intravenous; Male; Prostaglandins; Psychotropic Drugs; Rats; Rats, Sprague-Dawley; Rhombencephalon; Tolmetin
PubMed: 23388474
DOI: No ID Found -
Anesthesiology May 1998Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with hemostasis during the perioperative period, and the combination of NSAID and enoxaparin could increase... (Comparative Study)
Comparative Study
BACKGROUND
Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with hemostasis during the perioperative period, and the combination of NSAID and enoxaparin could increase this effect. The aim of this prospective, blinded experimental study was to assess these effects using a model of arterial thrombosis and bleeding in the rabbit.
METHODS
After anesthesia was induced and monitors placed, the common carotid arteries were exposed, and 60% stenosis of the right common carotid artery was produced. Twenty minutes later, a compression injury of the artery was produced that triggered a series of cyclic episodes of thrombosis and clot lysis. This was manifested as cyclic flow reductions (CFR; measured with an electromagnetic flow meter). After the first flow reduction was noted, the rabbits were immediately and randomly assigned to one of four groups (n = 10 each) that received intravenous infusions: control, ketorolac (2 mg/kg), enoxaparin (0.5 mg/kg), and ketorolac plus enoxaparin (2 mg/kg and 0.5 mg/kg, respectively). The number of CFRs that occurred in the subsequent 20-min period was used as a measure of treatment effect. The contralateral common carotid artery was exposed, and both stenosis and injury were produced. The ability of the administered drug to prevent thrombosis was assessed as the number of CFRs that occurred during the first 20-min period after vessel injury. In addition, both before and after group assignment and drug injection, bleeding times were noted and a platelet aggregation test was performed. Laparotomy was followed by a spleen section, and the extent of the wound and the amount of splenic bleeding were measured.
RESULTS
The treatment effect was indicated by the median number of CFRs, which was 5.5 in the control group, 1 in the ketorolac group, 2 in the enoxaparin group, and 0 in the ketorolac + enoxaparin group. The prevention effect was indicated by the median number of CFRs, which was 4 in the control group, 0 in the ketorolac group, 2 in the enoxaparin group, and 0.5 in the ketorolac + enoxaparin group. Bleeding time was significantly lengthened in the enoxaparin and in the ketorolac + enoxaparin groups. Splenic and wound bleeding was greater in the ketorolac group. Platelet aggregation was completely inhibited in the ketorolac and the ketorolac + enoxaparin groups.
CONCLUSIONS
Ketorolac had an important antithrombotic activity. The association of enoxaparin with ketorolac seemed to lengthen the bleeding time observed with ketorolac.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Bleeding Time; Blood Coagulation; Carotid Artery Thrombosis; Drug Interactions; Enoxaparin; Ketorolac; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Rabbits; Tolmetin
PubMed: 9605692
DOI: 10.1097/00000542-199805000-00023 -
Reactive & Functional Polymers Jan 2021Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used over-the-counter drugs and their uncontrolled disposal is a significant environmental concern. Although...
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used over-the-counter drugs and their uncontrolled disposal is a significant environmental concern. Although their fluorescent sensing is a desirable method of detection for its sensitivity and simplicity, the structural similarity of the drugs makes the design of selective sensors highly challenging. A thiourea-based fluorescent functional monomer was identified in this work to enable highly efficient synthesis of molecularly imprinted nanoparticle (MINP) sensors for NSAIDs such as Indomethacin or Tolmetin. Micromolar binding affinities were obtained in aqueous solution, with binding selectivities comparable to those reported for polyclonal antibodies. The detection limit was ~50 ng/mL in aqueous solution, and common carboxylic acids such as acetic acid, benzoic acid, and citric acid showed negligible interference.
PubMed: 33716552
DOI: 10.1016/j.reactfunctpolym.2020.104759 -
Transactions of the American... 1998
Review
Topics: Acetazolamide; Administration, Oral; Aged; Aged, 80 and over; Cataract Extraction; Chronic Disease; Humans; Incidence; Ketorolac Tromethamine; Macular Edema; Male; Middle Aged; Ophthalmic Solutions; Postoperative Care; Postoperative Complications; Tolmetin; Tromethamine; Visual Acuity
PubMed: 10360304
DOI: No ID Found -
Academic Emergency Medicine : Official... Feb 1998
Topics: Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Humans; Ibuprofen; Ketorolac; Musculoskeletal System; Pain; Research Design; Tolmetin
PubMed: 9492125
DOI: 10.1111/j.1553-2712.1998.tb02589.x -
Acta Crystallographica. Section E,... Feb 2021The asymmetric unit of the title compound, sodium 2-[1-methyl-5-(4-methyl-benzo-yl)-1-pyrrol-2-yl]acetate dihydrate, Na·CHNO ·2HO, contains two sodium cations, two...
The asymmetric unit of the title compound, sodium 2-[1-methyl-5-(4-methyl-benzo-yl)-1-pyrrol-2-yl]acetate dihydrate, Na·CHNO ·2HO, contains two sodium cations, two organic anions ( and ) and two water mol-ecules. The coordination geometry around the sodium cations corresponds to a distorted octa-hedron. Each pair of sodium cations (- or -) is chelated by two bridging anions coordinated by the O atoms of the deprotonated carb-oxy-lic groups, and each sodium atom is coordinated by an O atom of a third anion, which connects pairs of sodium atoms, and a water mol-ecule. As a result, a two-dimensional polymer is formed in the crystal. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to analyze the inter-molecular contacts present in the crystal.
PubMed: 33614141
DOI: 10.1107/S2056989021000414 -
The Biochemical Journal Oct 1995Human serum albumins modified by covalently bound tolmetin or zomepirac were synthesized as models for similar products formed in vivo from acyl glucuronides. Activated... (Comparative Study)
Comparative Study
Synthesis and mass-spectrometric characterization of human serum albumins modified by covalent binding of two non-steroidal anti-inflammatory drugs: tolmetin and zomepirac.
Human serum albumins modified by covalently bound tolmetin or zomepirac were synthesized as models for similar products formed in vivo from acyl glucuronides. Activated esters of both drugs were prepared with 1-ethyl-3-(3-dimethylaminopropyl)-carbodi-imide, and then allowed to react with human serum albumin. Tryptic digests of both protein products were analysed by HPLC to identify peptides containing covalently bound drugs, and binding sites on albumin were identified by high-performance tandem MS. Three binding sites were common to both products, i.e. lysine-195, -199 and -351. Three further modified residues were identified for the tolmetin-albumin product, i.e. aspartic acid 1, and lysine-524 and -536.
Topics: Amino Acid Sequence; Anti-Inflammatory Agents, Non-Steroidal; Binding Sites; Chromatography, High Pressure Liquid; Humans; Mass Spectrometry; Molecular Sequence Data; Peptide Fragments; Protein Binding; Serum Albumin; Tolmetin
PubMed: 7487878
DOI: 10.1042/bj3110431 -
Angewandte Chemie (International Ed. in... Sep 2022H O -driven enzymes are of great interest for industrial biotransformations. Herein, we show for the first time that oxalate oxidase (OXO) is an efficient in situ source...
H O -driven enzymes are of great interest for industrial biotransformations. Herein, we show for the first time that oxalate oxidase (OXO) is an efficient in situ source of H O for one of these biocatalysts, which is known as unspecific peroxygenase (UPO). OXO is reasonably robust, produces only CO as a by-product and uses oxalate as a cheap sacrificial electron donor. UPO has significant potential as an industrial catalyst for selective C-H oxyfunctionalisations, as we confirm herein by testing a diverse drug panel using miniaturised high-throughput assays and mass spectrometry. 33 out of 64 drugs were converted in 5 μL-scale reactions by the UPO with OXO (conversion >70 % for 11 drugs). Furthermore, oxidation of the drug tolmetin was achieved on a 50 mg scale (TON 25 664) with 84 % yield, which was further improved via enzyme immobilization. This one-pot approach ensures adequate H O levels, enabling rapid access to industrially relevant molecules that are difficult to obtain by other routes.
Topics: Carbon Dioxide; Mixed Function Oxygenases; Oxalates; Oxidoreductases; Tolmetin
PubMed: 35916874
DOI: 10.1002/anie.202207831 -
Journal of Clinical Anesthesia Aug 1997To examine the effect of timing of an intravenous (i.v.) dose (intraoperative vs. postoperative) of ketorolac tromethamine on pain scores and overall outcome after total... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
STUDY OBJECTIVES
To examine the effect of timing of an intravenous (i.v.) dose (intraoperative vs. postoperative) of ketorolac tromethamine on pain scores and overall outcome after total abdominal hysterectomy (TAH) and myomectomy.
DESIGN
Prospective, randomized, placebo-controlled study.
PATIENTS
248 ASA physical status I and II adult female patients scheduled for elective hysterectomy or myomectomy.
INTERVENTIONS
General anesthesia was administered that consisted of thiopental sodium for induction, enflurane or isoflurane in nitrous oxide-oxygen for maintenance, and small doses of fentanyl and midazolam. Patients were randomized into three groups to receive toradol/placebo on a dosing schedule of dose 1 given one-half hour prior to expected end of surgery, dose 2 given on awakening in the postanesthesia care unit, and doses 3, 4, and 5 given at 6, 12, and 18 hours, respectively, after dose 2; Group 1 patients received placebo (saline) for dose 1, ketorolac 60 mg i.v. for dose 2, and ketorolac 30 mg i.v. for doses 3, 4, and 5. Group 2 patients received ketorolac 60 mg i.v. for dose 1, placebo for dose 2, and ketorolac 30 mg i.v. for doses 3, 4, and 5. Group 3 patients received placebo for all doses. All patients were given i.v. morphine PCA postoperatively, and morphine usages, visual analog pain intensity (VAS) scores, as well as adverse events and median times to recovery milestones were recorded.
MEASUREMENTS AND MAIN RESULTS
VAS scores (mean) before dose 2 were significantly lower in Group 2 than Group 1, as were at-rest evaluations at 15 minutes and one hour. Group 2 patients also had decreased morphine requirements as compared to placebo. Both ketorolac groups (Groups 1 and 2) had significantly higher values for patient and observer overall ratings, case of nursing care, and tolerability as compared to placebo (Group 3). There were no significant differences among groups in adverse events or median times to recovery milestones.
CONCLUSIONS
Although it is possible to demonstrate an improvement in early postoperative pain scores with intraoperative ketorolac and better overall ratings of ketorolac both intraoperatively and postoperatively as compared with placebo, the lack of clinically significant differences in analgesic efficacy in the two active study groups indicates the need for a careful consideration by the clinician of the risks versus benefits involved in the administration of antiplatelet medication in the perioperative period.
Topics: Adult; Analysis of Variance; Anti-Inflammatory Agents, Non-Steroidal; Combined Modality Therapy; Double-Blind Method; Elective Surgical Procedures; Female; Humans; Hysterectomy; Intraoperative Care; Ketorolac Tromethamine; Middle Aged; Myometrium; Postoperative Care; Tolmetin; Treatment Outcome
PubMed: 9257200
DOI: 10.1016/s0952-8180(97)00062-7 -
World Journal of Gastroenterology Dec 2004To investigate the gastroprotective effect and mechanism of amtolmetin guacyl (AMG, MED15) in mice.
AIM
To investigate the gastroprotective effect and mechanism of amtolmetin guacyl (AMG, MED15) in mice.
METHODS
Male and female Kunming strain mice, weighing 18-22 g, were utilized in the experiment. Normal or ethanol-induced gastric mucosal damage models in mice were successfully established to investigate the gastroprotective effect and mechanism of AMG. In the experiment of gastric mucosal damage after repeated treatment with AMG, the mice were randomly divided into 5 groups: normal group, 3 AMG groups receiving (75, 150 and 300 mg/kg), and tolmetin group receiving 90 mg/kg. The mice were randomly divided into 6 groups as follows: normal group, model group, AMG groups with doses of 75, 150 and 300 mg/kg, respectively, and tolmetin group with a dose of 90 mg/kg in ethanol-induced gastric mucosal damage experiment. The severity of gastric mucosal lesions was scored from 0 to 5. Gastric tissue sections were stained with hematoxylin and eosin (HE) and examined under light microscopy. Also gastric tissue sections were stained with uranyl acetate and lead citrate, and examined under electron microscopy. In addition, nitric oxide (NO) and malondialdehyde (MDA) contents, and nitric oxide synthase (NOS) and superoxide dismutase (SOD) activities in the stomach tissue homogenates were measured by biochemical methods.
RESULTS
Repeated treatment with AMG (75, 150 and 300 mg/kg) for 7 d did not induce any appreciable mucosal damage, and the average score was not significantly different from that of normal mice. In contrast, tolmetin (90 mg/kg) produced significant gastric mucosal lesions compared with the normal group (P<0.01). AMG (75, 150 and 300 mg/kg) significantly reduced the severity of gastric lesions induced by ethanol in a dose-dependent manner as compared with the model group (P<0.05, AMG 75 and 150 mg/kg vs model; P<0.01, AMG 300 mg/kg vs model). Light and electron microscopy revealed that AMG (150 and 300 mg/kg) induced minimal changes in the surface epithelium layer, without vascular congestion or leucocyte adherence. AMG (75,150 and 300 mg/kg) demonstrated dose-dependent gastroprotective effects on mice in our study. AMG (75, 150 and 300 mg/kg) could significantly increase NO content and NOS level in the stomach homogenates of mice compared with the model group (P<0.05, AMG 75 mg/kg and 150 mg/kg groups vs model group; P<0.01, AMG 300 mg/kg vs model group) respectively. Moreover, AMG (150 and 300 mg/kg) not only significantly increased SOD activities but also obviously decreased the MDA content in the stomach homogenates of mice.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Central Nervous System Depressants; Ethanol; Female; Gastric Mucosa; Gastritis; Glycine; Male; Malondialdehyde; Mice; Mice, Inbred Strains; Microscopy, Electron, Transmission; Microvilli; Nitric Oxide; Nitric Oxide Synthase; Pyrroles; Superoxide Dismutase
PubMed: 15534917
DOI: 10.3748/wjg.v10.i24.3616