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Tolmetin: a review of its pharmacological properties and therapeutic efficacy in rheumatic diseases.Drugs Jun 1978
Review
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Juvenile; Arthritis, Rheumatoid; Blood Platelets; Endocrine Glands; Humans; Intestinal Absorption; Intestinal Mucosa; Kinetics; Osteoarthritis; Prostaglandin Antagonists; Pyrroles; Rats; Rheumatic Diseases; Skin Tests; Spondylitis, Ankylosing; Tolmetin
PubMed: 350558
DOI: 10.2165/00003495-197815060-00002 -
Clinical Pharmacology and Therapeutics Dec 1978The protein binding of the new nonsteroidal anti-inflammatory agent tolmetin to human serum albumin (HSA) and to the plasma of 8 healthy subjects was studied by...
The protein binding of the new nonsteroidal anti-inflammatory agent tolmetin to human serum albumin (HSA) and to the plasma of 8 healthy subjects was studied by equilibrium dialysis at 37 degrees and pH 7.4 with 14C-tolmetin. Over the total concentration (Ct) range 3.0 to 28.7 microgram/ml (therapeutic range), the fraction of tolmetin unbound to 4% HSA was largely invariant at 0.3%. At 100 microgram/ml the unbound fraction rose to 0.8 and at 434 microgram/ml to 3.6%. Within the therapeutic concentration range, tolmetin binding to 0.4% HSA was reduced in accordance with the law of mass action and at Ct = 26.2 microgram/ml, 10.5% was free. Analysis of the 0.4% HSA data showed tolmetin had 3 classes of binding sites (n1 = 1, K1 = 8.3 X 10(5) M-1; n2 = 4, K2 = 2.4 X 10(4) M-1; n3 = 44, K1 = 7.9 X 10(1) M-1). By studying the binding to 0.4% HSA at 23 degrees, it was established that the free energy change in binding for the first two classes of sites was entirely entropic in nature. Albumin accounted for almost all the binding of tolmetin in human plasma. The effect of other drugs, the tolmetin metabolite McN 2987 (5-p-carboxybenzoyl-1-methylpyrrole-2-acetic acid), tryptophan, and oleic acid on tolmetin binding to 4% HSA was studied using ultrafiltration and 14C-tolmetin. Aspirin and salicyclic acid decreased tolmetin binding and a combination of aspirin and salicyclic acid exerted a synergistic displacing effect. Indomethacin and ibuprofen had no effect while phenylhbutazone and acetaminophen increased tolmetin binding slightly. Tolmetin binding was decreased slightly by McN 2987 and tryptophan and markedly increased by oleic acid. McN 2987 was not bound as extensively as tolmetin. Binding of 14C-tolmetin to the plasma of 4 arthritic patients was studied by ultrafiltration and found to be less than to normal plasma and 4% HSA. Distribution of tolmetin in the whole blood of 8 healthy subjects using a centrifugation technique showed that the drug was not taken up by red blood cells at therapeutic concentrations.
Topics: Adult; Aged; Arthritis, Rheumatoid; Binding Sites; Binding, Competitive; Erythrocytes; Female; Humans; In Vitro Techniques; Male; Middle Aged; Oleic Acids; Plasma; Protein Binding; Pyrroles; Serum Albumin; Tolmetin; Tryptophan
PubMed: 710027
DOI: 10.1002/cpt1978246694 -
JAMA Jul 1978
Topics: Adult; Anaphylaxis; Arthritis, Rheumatoid; Female; Humans; Pruritus; Pyrroles; Tolmetin
PubMed: 660851
DOI: No ID Found -
Drug Metabolism Reviews 1981
Review
Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Biological Availability; Guinea Pigs; Humans; Kinetics; Mice; Pyrroles; Rats; Species Specificity; Tissue Distribution; Tolmetin
PubMed: 7040019
DOI: 10.3109/03602538108994037 -
Connecticut Medicine May 1991
Comparative Study Review
Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Drug Combinations; Humans; Injections, Intramuscular; Ketorolac Tromethamine; Morphine; Pain, Postoperative; Tolmetin; Tromethamine
PubMed: 1860314
DOI: No ID Found -
Anesthesia and Analgesia Feb 1993
Topics: Anti-Inflammatory Agents, Non-Steroidal; Bronchial Spasm; Drug Combinations; Hernia, Hiatal; Humans; Ketorolac Tromethamine; Male; Middle Aged; Tolmetin; Tromethamine
PubMed: 8424524
DOI: No ID Found -
The Journal of Pharmacology and... Dec 1988The glycine amide of tolmetin sodium (TGA) functions as a prodrug and was demonstrated to be more potent than the parent compound as an inhibitor of developing and...
The glycine amide of tolmetin sodium (TGA) functions as a prodrug and was demonstrated to be more potent than the parent compound as an inhibitor of developing and established adjuvant arthritis in the female Lewis rat. In contrast, the glycine amide of indomethacin was less potent than indomethacin. The superiority of TGA relative to tolmetin sodium in alleviating this condition was demonstrated by inhibition of paw swelling and reduction of the degenerative bone changes that are associated with the progression of this chronic animal model of rheumatoid arthritis in humans. These properties were not evident when equimolar mixtures of tolmetin sodium and glycine were administered concurrently. Pharmacokinetic analyses revealed that TGA was absorbed completely and hydrolyzed to tolmetin in the female adjuvant arthritic rat. The combined effects of absorption, distribution and hydrolysis of TGA produced lower peak plasma tolmetin levels than an equivalent dose of tolmetin sodium, but plasma concentrations were sustained for a longer period of time contributing to an apparent increase in potency. Furthermore, TGA displayed a decreased propensity to cause gastrointestinal irritation compared to tolmetin sodium. Several additional amino acid amides of tolmetin were similar to the glycine amide in exhibiting increased potency and reduced gastrointestinal toxicity in comparison to equivalent doses of tolmetin sodium.
Topics: Animals; Arthritis; Arthritis, Experimental; Bone and Bones; Digestive System; Female; Indomethacin; Prodrugs; Pyrroles; Rats; Tolmetin
PubMed: 3204521
DOI: No ID Found -
Journal of the American Geriatrics... Oct 1976The effectiveness of tolmetin sodium in the treatment of rheumatoid arthritis was evaluated by: 1) a 12-week, double-blind study with a dosage range of 800-1600 mg... (Clinical Trial)
Clinical Trial
The effectiveness of tolmetin sodium in the treatment of rheumatoid arthritis was evaluated by: 1) a 12-week, double-blind study with a dosage range of 800-1600 mg daily; and 2) an open 2-year study with a dosage range of 400-2400 mg daily. The double-blind study involved 14 patients (7 tolmetin sodium, 7 placebo), and the long-term study involved 24 patients. At frequent intervals, evaluations were made of joint pain, swelling, stiffness and inflammation; grip strength; walking time; and subjective well-being. Various laboratory tests were also performed. In the double-blind study, tolmetin sodium proved superior to placebo and produced moderate improvement. In the long-term study, 5 patients improved markedly, 14 moderately, and 3 minimally. Severe side effefts were notably absent. Some mild side effects occurred but they were transient and did not interfere with therapy. Tolmetin sodium seems effective and safe in the management of rheumatoid arthritis.
Topics: Adult; Aged; Arthritis, Rheumatoid; Blood Pressure; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Locomotion; Male; Middle Aged; Palliative Care; Placebos; Pyrroles; Time Factors; Tolmetin
PubMed: 61224
DOI: 10.1111/j.1532-5415.1976.tb03256.x -
Journal of Toxicology. Clinical... 1994
Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Ketorolac; Kidney; Risk Factors; Tolmetin
PubMed: 8007039
DOI: 10.3109/15563659409017965 -
Journal of Pharmaceutical and... Mar 2003Non-steroidal anti-inflammatory drugs (NSAIDs) are prohibited by the International Federation of Horse Racing Authorities but are commonly used in veterinary practice....
Non-steroidal anti-inflammatory drugs (NSAIDs) are prohibited by the International Federation of Horse Racing Authorities but are commonly used in veterinary practice. Plasma and urinary concentrations of the NSAID tolmetin were determined by a high-performance liquid chromatographic procedure with UV detection following oral administration of a dose of 1 g to six fasted untrained standard bred mares. With a limit of quantitation (LOQ) of 0.05 microg/ml tolmetin was present in plasma for 9-12 h post-administration. Maximum concentrations of 2.1+/-0.89 microg/ml were found after 0.7+/-0.25 h. The elimination half-life was 2+/-1.25 h. Plasma protein binding at concentrations of 0.25 and 2.5 microg/ml was 92+/-4.9 and 84+/-4.2%, respectively. As early as 1 h after dosage, tolmetin could be detected in unhydrolysed urine and remained detectable up to 48 h (LOQ=0.5 microg/ml). The maximum concentrations occurred 1.8+/-0.4 h after administration. The percentage of the dose excreted as unchanged tolmetin within 12 h was 58+/-7.9%. Neither conjugates nor metabolites could be detected under the experimental conditions studied. For confirmatory analysis in doping control, an LC-MS method was developed. Analysis was performed on an ion trap LC-MS system equipped with an ESI probe in positive MS(2) mode.
Topics: Administration, Oral; Animals; Chromatography, High Pressure Liquid; Female; Horses; Tolmetin
PubMed: 12644199
DOI: 10.1016/s0731-7085(02)00687-8