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At least 19 recordsLinked to original sources
PubMed1988

Effect of tolmetin glycine amide (McN-4366), a prodrug of tolmetin sodium, on adjuvant arthritis in the rat.

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.

Animals↗
PubMed1979

Effects of tolmetin, paracetamol, and of two combinations of tolmetin and paracetamol as compared to placebo on experimentally induced pain. A double blind study.

Previous studies in animals suggested that a coadministration of the anti-rheumatic/anti-inflammatory agent tolmetin (Tolectin) and of paracetamol potentiates the effects of these two drugs. The present study was carried out to assess whether or not the dosis of tolmetin necessary to obtain an analgesic effect can be reduced when paracetamol is coadministered in a model with experimentally induced pain in healthy human subjects. The effects of tolmetin 200 mg (T 200), paracetamol 400 mg (P 400), tolmetin 150 mg plus paracetamol 300 mg (T 150 + P 300), and of tolmetin 100 mg plus paracetamol 400 mg (T 100 + P 400) on pain threshold to electrical and thermal stimuli and on pain tolerance to electrical stimuli were compared to the effects of placebo under double blind conditions. Each of 20 healthy volunteers received all of the 5 treatments randomised according to four 5 X 5 Latin squares. The results showed that the combination T 100 + P 400 had better analgesic effects than the double dose of tolmetin, T 200, alone, while the effects of P 400 could not be discrminated from placebo. In a sequential t-test the effects of T 100 + P 400 could be discriminated from placebo already after 14 Ss. The effects of T 200, T 150 + P 300, and T 100 + P 400 respectively could not be differentiated, indicating that the dose of tolmetin can be reduced markedly by simultaneous administration of paracetamol without a loss in analgesic potency. Coadministration of tolmetin and paracetamol permits a marked reduction of the dose of tolmetin without any loss of analgesic potency as measured in a model with experimentally induced pain in healthy subjects.

Acetaminophen↗
PubMed1990

Comparative evaluation of tolmetin & tolmetin-zinc on wound-repair & inflammation.

In view of the reported healing-suppressant activity of some NSAIDs and absence of this adverse effect in their zinc-complexes, tolmetin (Tol), a recently introduced NSAID and its zinc-complex (Tol-Zn) were compared for their wound healing and antiinflammatory profiles in male albino rats. Tolmetin-zinc (Tol-Zn) significantly reversed (P less than 0.01) the suppressant effect of Tol on gain in breaking strength of skin incisions and dead space wounds (breaking strength, g: for control, Tol and Tol-Zn were: 313 +/- 7, 250 +/- 11, 294 +/- 16 in skin wounds; 244 +/- 7, 137 +/- 18, 195 +/- 16 in dead space wounds). Tol-Zn shared the significant (P less than 0.001) suppressant effect of Tol on granuloma formation (granuloma weight, mg: control - 69 +/- 3, Tol - 36 +/- 3.03, Tol-Zn - 37 +/- 2.75) and its collagen content (total hydroxyproline per tissue, microgram: control - 1955 +/- 55, Tol - 1400 +/- 200, Tol-Zn - 1410 +/- 150). Rat paw edema induced by carrageenin was significantly (P less than 0.001) reduced by Tol as well as Tol-Zn. In the chronic model both the agents suppressed significantly (P less than 0.001) granuloma formation by 50 per cent. Zinc sulphate by itself reduced the rat paw edema by 39 per cent (P less than 0.02) and did not affect the other parameters. Zinc-complex appears to be an improved version of tolmetin as an antiinflammatory agent with no adverse effect on the healing process. Tolmetin-zinc promotes gain in breaking strength, not by increasing the collagen content, but by favouring better maturation of available collagen at the wound site.

Animals↗
PubMed1987

High-performance liquid chromatographic determination of tolmetin, tolmetin glucuronide and its isomeric conjugates in plasma and urine.

A rapid and sensitive analytical procedure is described for the simultaneous measurement of tolmetin (T), tolmetin glucuronide (1 beta-TG) and the isomers of tolmetin glucuronide in plasma and urine. A reversed-phase liquid chromatographic system is used with an ion-pairing mobile phase of methanol-tetrabutylammonium hydrogensulfate buffered to pH 4.5 and kept at a constant temperature of 50 degrees C. Detection is by UV at 313 nm. Plasma (0.5 ml) and urine (0.1 ml) are collected in pre-cooled containers and immediately adjusted to pH 3.0 to minimize TG isomerization and hydrolysis. Samples are then deproteinated with acetonitrile, the supernatant is evaporated to dryness and reconstituted in an acetate buffer (pH 4.5), and 50 microliters are injected onto the system. Using zomepirac as the internal standard, the measurable, linear concentration ranges are 0.05-50 micrograms/ml for T in plasma and 0.025-50 micrograms/ml for T in urine. Chromatographic peaks representing T,1 beta-TG and three isomers of TG were identified, all with retention times less than 10 min. The need for special handling of biological samples is discussed.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Studies on disposition and metabolism of tolmetin, a new anti-inflammatory agent, in rats and mice. I. Absorption, distribution, and excrection of [14C]tolmetin radioactivity.

[14C]Tolmetin was rapidly and almost completely absorbed in both rats and mice. The major portion of the drug was shown to be absorbed from the upper part of the duodenum, and a small portion from the stomach. Tissue levels of radioactivity comparable to blood levels were found only in liver and kidney, and other tissue levels were lower than those in blood, possibly because of the considerable plasma protein binding of the drug. Radioactivity disappeared from most tissues at rates similar to that from blood, and no appreciable radioactivity was found in rat and mouse tissues 24 hr after dosing. Correspondingly, radioactivity was excreted mostly in urine within this time period. Mouse fetuses contained significantly less radioactivity than did maternal tissues in autoradiography. No significant differences were found in absorption, distribution, and excretion of radioactivity when single or five consecutive daily doses of [14C]tolmetin were administered to rats.

Animals↗
PubMed1978

Protein binding of tolmetin.

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.

Adult↗
PubMed1979

Absorption and excretion of tolmetin in arthritic patients.

The absorption, kinetics, biotransformation, and excretion of tolmetin and its metabolites were studied in patients with rheumatoid arthritis (RA) to evaluate the effects of the disease on tolmetin disposition. Five RA patients were stabilized on tolmetin sodium (300 mg, 4 times daily for 14 days) before receiving a single oral solution dose of tolmetin-14C sodium (300 mg as the acid) on day 15. Tolmetin was rapidly and completely absorbed (peak time, 20 to 60 min) and eliminated rapidly from plasma with a biphasic decay curve (t1/2beta congruent to 2.1 hr). MCPA, the oxidative metabolite, appeared more slowly (peak time, 40 to 90 min) but was eliminated rapidly in a biphasic manner (t1/2beta congruent to 1.7 hr). The terminal elimination phases for both tolmetin and MCPA demonstrated a curvature which suggested possible nonlinearity in the kinetic disposition of the drug. There were no apparent effects of the disease on the kinetics of tolmetin or MCPA. Tolmetin, MCPA, and tolmetin glucuronide were recovered quantitatively in urine (0 to 72 hr) with most of the exretion occurring in the 0- to 24-hr period. A significant increase, relative to data on normal subjects, in the renal clearance of both tolmetin and MCPA was noted. Concomitant increase in the apparent volume of distribution secondary to reported decreases in the plasma protein binding of tolmetin appeared to be the reason for increased renal clearance of tolmetin.

Arthritis, Rheumatoid↗
PubMed1981

Site of analgesic action of a non-steroidal, anti-inflammatory drug, tolmetin sodium, in rats.

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.

Administration, Oral↗
PubMed1983

Tolmetin uptake into inflamed tissue in the rat.

Concentrations of the antiinflammatory agent tolmetin have been measured by HPLC in inflamed and non-inflamed rat tissues after oral administration of tolmetin sodium dihydrate in solution (100 mg free acid/kg) and after topical administration of tolmetin (Tolectin gel, 1 g of a 5% gel, 250 mg free acid/kg). After oral administration of tolmetin, there was marked localisation of the drug in inflamed rat paws. Concentrations of tolmetin were significantly greater in inflamed paws than those in non-inflamed paws at each time studied (e.g. at 3 h after dosing, inflamed paw 30.5 micrograms/g, non-inflamed paw 14.9 micrograms/g). After a single topical application of tolmetin gel to the shaved backs of rats, tolmetin was well absorbed percutaneously into the non-inflamed dorsal muscle. After repeated topical application of tolmetin gel to the shaved backs of rats, daily for 4 consecutive days, concentrations of tolmetin (total micrograms/paw) similar in inflamed paws and in non-inflamed paws. After topical administration of tolmetin gel to rat paws, tolmetin was transported from treated paws to untreated paws, e.g. from non-inflamed paws to inflamed paws and vice versa. These studies showed that tolmetin applied topically reaches inflamed tissues in concentrations that exceed those in plasma.

Administration, Topical↗
PubMed1983

Clinical pharmacology of tolmetin: comparisons in rheumatoid arthritis patients and normal volunteers.

The pharmacokinetics of tolmetin sodium were studied in five patients with rheumatoid arthritis (RA) and five normal volunteers to determine whether data derived from normals could be applied to RA patients. In addition, prostaglandin E (PGE) levels in synovial fluid were compared with tolmetin levels in serum and synovial fluid. Both groups received 400 mg tolmetin every 6 hours for seven days. During a 24-hour washout period after the dose of tolmetin (400 mg) on day 8, blood and urine samples were obtained from all study participants, and synovial fluid samples from the RA patients only. The patients continued into a second 24-hour drug-free period, after which they received a single 400-mg dose of tolmetin. Blood and urine samples were again collected. No clinically or statistically significant differences in tolmetin kinetics between normal volunteers and RA patients were found. A comparison of multiple-dose and single-dose results in the patient group showed an 11 per cent increase in the tolmetin serum concentration after multiple dosing. Total PGE levels in synovial fluid remained significantly depressed in the patient group for 24 hours after the 400-mg test dose of tolmetin on day 8. These findings suggest that tolmetin serum kinetics may not be an appropriate indicator of the duration of biologic activity of tolmetin.

Adult↗
PubMed1999

Influence of sex on the pharmacokinetics of tolmetin in the rat.

The purpose of this study was to investigate sex-related differences in the pharmacokinetics of tolmetin, a potent nonsteroidal anti-inflammatory drug, in the rat. Male and female Wistar rats received oral tolmetin at two dose levels, 3.2 and 10 mg/kg. Blood samples were drawn at selected times after drug administration, and tolmetin concentration in whole blood was determined. Tolmetin was rapidly absorbed in all cases. C(max) increased with the dose, but was similar in both sexes. Notwithstanding, tolmetin half-life was significantly prolonged in females compared with males. As a result of the prolonged half-life, area under the curve values were significantly higher in females than in males. Tolmetin clearance was significantly reduced in females. The present results strongly suggest sex-related differences in the pharmacokinetics of tolmetin in the rat. Tolmetin elimination appears to be impaired in females, compared with males. The existence of sex-related differences in tolmetin pharmacokinetics in other species, including humans, requires further investigation.

Animals↗
PubMed1988

Disposition and irreversible plasma protein binding of tolmetin in humans.

The pharmacokinetics and irreversible plasma protein binding of tolmetin were studied in six healthy subjects after the administration of a single, 400 mg dose of tolmetin. With HPLC analysis, tolmetin, tolmetin glucuronide, and the isomers of tolmetin glucuronide, which result from intramolecular acyl migration in vivo, were detected in the plasma up to 4 hours after administration, whereas these conjugates were present in the urine up to 24 hours. Irreversible binding of tolmetin to plasma proteins occurred in all subjects. Irreversible binding exhibited a better correlation with exposure to tolmetin glucuronide (r = 0.5618) and the isomers of tolmetin glucuronide (r = 0.8200) than with exposure to tolmetin (-0.3635). This is consistent with the hypothesis that covalent binding occurs via the acyl glucuronide.

Adult↗
PubMed1980

Clinical experience with tolmetin sodium.

Two studies are reported with tolmetin sodium. The first compared tolmetin sodium, phenylbutazone and placebo in rheumatoid arthritis. The second compared tolmetin sodium and aloxiprin in osteoarthritis and soft tissue rheumatism. In the first study, a double-blind crossover trial involving 12 patients, tolmetin sodium (1600 mg daily) was shown to be superior to placebo and comparable to phenylbutazone (400 mg daily). The reductions in morning stiffness and pain were statistically significant when compared to placebo. Tolmetin sodium and aloxiprin were compared in the treatment of osteoarthritis in a single-blind study which investigated efficacy and safety over a 3-month period. Initial dosages were 1600 mg tolmetin sodium and 6 g aloxiprin (equivalent to 5 g aspirin) daily. Thirty-four patients were enrolled in the study. Both drugs produced an improvement over the 3-months treatment period. The reduction in pain was statistically significant. The dosage of tolmetin sodium remained at 1600 mg daily for the 3-month duration of the study but side-effects necessitated the reduction of the dosage of aloxiprin in many patients and after 3-months' treatment the mean dosage was 4 g daily. Five patients withdrew from the tolmetin sodium group and 11 from the aloxiprin group. Adverse reactions including limiting side-effects, were about twice as common with aloxiprin compared to tolmetin sodium.

Arthritis, Rheumatoid↗
PubMedDate not supplied

In vivo administration of tolmetin in hyaluronic acid modulates protease levels in postsurgical macrophage-conditioned media.

Tolmetin sodium in a hyaluronic acid carrier (tolmetin-HA) was previously shown to reduce adhesion formation and alter the kinetics and levels of cellular influx into the peritoneal cavity after surgery. In this study, the effect of tolmetin-HA on the level of protease activity in macrophage-conditioned media was determined. The level of collagenase activity in macrophage-conditioned media was suppressed at 12 and 24 h after administration of tolmetin-HA. Alternatively, the peak level of elastase activity measured in macrophage-conditioned media was unchanged after tolmetin-HA treatment, but the kinetics of expression of maximal protease activity was delayed from 12 h in the control surgical rabbits to 24 h in tolmetin-HA-treated rabbits. Elevated plasminogen activator activity was detected in acid-treated conditioned media from the tolmetin-HA-treated rabbits when compared to control levels. However, no alteration in the level of plasminogen activator inhibitor activity was present in conditioned media of macrophages harvested from tolmetin-HA-treated rabbits compared to controls. These data suggest that tolmetin-HA treatment altered the levels of neutral protease activity secreted by postsurgical macrophages and may therefore elevate the fibrinolytic potential of the peritoneal cavity after surgery.

Animals↗
PubMed1979

[Analgesic activity of a non-steroidal anti-inflammatory agent, tolmetin sodium in experimental animals (author's transl)].

Effect of tolmetin sodium on the pain-like responses caused by various nociceptive stimuli was examined in experimental animals. Tolmetin sodium showed a potent inhibitory activity on the acetic acid-induced writhing in mice and rats, and its potency, (ED50 = 23.4 and 3.01 mg/kg, p.o.) was about 2.4--10.3 times that of ibuprofen and aspirin. The hypertension induced by intraarterial injection of bradykinin toward the spleen of dogs was inhibited by tolmetin sodium (ED50 = 80 mg/kg, i.v.), but the hypertension by a simultaneous injection of bradykinin and PGE1 was not inhibited by tolmetin sodium and sulpyrine, though pentazocine inhibited both hypertensions. The pain-like response caused by pressing mechanically the inflamed paws or joints of rats induced by kaolin-carrageenin or adjuvant was inhibited by tolmetin sodium (30--100 or 20--40 mg/kg, p.o., respectively), and the potency was approximately equal that of ibuprofen and phenylbutazone. Tolmetin sodium produced a significant inhibition of the pain-like response induced by electrical stimulation of tooth pulp of dogs, but showed no effect when the methods of Haffner and D'Amour-Smith were applied to mice. Anti-writhing action of tolmetin sodium was not antagonized by naloxone. From these results, it was concluded that tolmetin sodium has a potent inhibitory activity on the pain-like responses induced by the chemical nociceptive stimuli and by the mechanical pressure stimulus of the inflamed tissue, especially on the writhing. The analgesic activity probably involves a peripheral mechanism.

Analgesics↗
PubMed1983

Long-term efficacy and safety of tolmetin sodium in treatment of geriatric patients with rheumatoid arthritis and osteoarthritis: a retrospective study.

In order to evaluate the effectiveness and safety of tolmetin sodium in the treatment of both rheumatoid arthritis (RA) and osteoarthritis in geriatric patients, a retrospective study was made of patients 65 years and older who participated in long-term, controlled, double-blind and open trials during both the investigational period and since marketing of the drug. Standard entrance criteria, methods of evaluating disease activity, and statistical methods were used in the study of both arthritic diseases. A total of 847 geriatric patients were studied for periods of up to one year; 171 had RA, while 676 had osteoarthritis of large or small joints. Average daily dose of tolmetin sodium was 1141 mg for patients with RA and 953 mg for patients with osteoarthritis. The results of this retrospective study of both RA and osteoarthritis patients show that tolmetin was as effective in geriatric patients as in nongeriatric patients. Symptoms responded rapidly to treatment with tolmetin, and both the inflammatory symptoms of RA and the joint pain and functional parameters of osteoarthritis showed improvement that was both statistically and clinically significant throughout the major course of therapy. Tolmetin was also found to be safe and well tolerated by the elderly patient population. The major complaints were gastrointestinal, but serious or limiting side effects occurred in few patients. The dropout rates due to adverse effects during the entire year of therapy were 15.8 per cent in the RA population and 15.4 per cent in osteoarthritis patients. This retrospective evaluation of tolmetin therapy shows significant relief of the symptoms of both RA and osteoarthritis in a geriatric population and fails to reveal any unusual or serious conditions which would contraindicate its use in the elderly patient. Tolmetin, which is an antiinflammatory agent with a short half-life, can provide adequate, safe therapy in the geriatric population.

Aged↗
PubMed1985

The effect of tolmetin on the chronic pain and decreased functional capacity associated with degenerative joint disease.

Degenerative joint disease (DJD) is a common disorder characterized by chronic pain and limitation of activity, for which treatment with a nonsteroidal anti-inflammatory drug (NSAID) is often useful. The anti-inflammatory activity of the NSAID tolmetin sodium has been well described, being comparable in efficacy to indomethacin and effective for the relief of the acute and chronic symptoms that accompany DJD. To examine specifically the effect of tolmetin in controlling the pain and functional limitation in DJD of the spine, tolmetin was tested against placebo in a double-blind, two-segment, crossover study. Twenty-six patients (mean age, 62.5 years; range, 42-79 years) received three weeks of tolmetin 1,200 mg/d and three weeks of placebo. The results showed that tolmetin provided significantly greater relief of symptoms than placebo in virtually all measurements of joint pain and stiffness: tenderness, pain at rest, pain on motion, intensity of joint pain (P less than 0.001), and duration of morning stiffness (P = 0.002). Statistically significant improvement was noted in two of the three measures of cervical range of motion (P less than or equal to 0.01) and in all assessments of daily living activities (P = 0.001 in four parameters; P = 0.02 in a fifth parameter). Global evaluations of response to treatment by both patients and investigator also demonstrated significant effects (P less than or equal to 0.002). Significantly more placebo patients (13 of 26) than tolmetin patients (two of 26) found the medication ineffective and discontinued treatment prematurely (P = 0.01). No serious or limiting adverse reactions were seen during placebo or tolmetin therapy. The most frequently reported side effects on both therapies were gastrointestinal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗