tolfenamic-acid and Arthritis--Rheumatoid

The pharmacokinetics of tolfenamic acid is well described by a two-compartment model with relatively short half-lives (T/2 beta 1-2 hours) and tolfenamic acid is highly protein-bound with small volumes of distribution. It is cleared relatively fast (150-200 ml/min), mainly by hepatic metabolism and the metabolites are renally cleared as glucuronic acid conjugates. The peroral absorption is good and the peroral bioavailability is about 75%, as first pass metabolism accounts for about 20%. Tolfenamic acid shows linear pharmacokinetics and during multiple dosage regimen, i.e. thrice daily, no accumulation beyond the second dose is observed. The bioavailability in dependence of age and disease has been studied and only in the case of severe liver or kidney impairment, a change in dosage regimen seems warranted. The development of different formulations will be outlined, mainly on rectal delivery, on sustained release and rapid release oral formulations, on topical ointment, and on parenteral delivery. The problems with tolfenamic acid in pharmaceutical formulation caused mainly by poor solubility will be discussed. Formulations ready for the market now or very soon are Clotam capsules (tablets). Clotam retard tablets, Clotam suppositories, and Clotam oral suspension, whereas rapid tablets, topical ointments, and parenteral formulations need further development to be ready for marketing in the years to come.

Topics: Absorption; Aging; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Biological Availability; Dosage Forms; Drug Administration Routes; Half-Life; Humans; Liver Cirrhosis; Migraine Disorders; ortho-Aminobenzoates

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Diclofenac; Double-Blind Method; Drug Tolerance; Female; Humans; Male; Middle Aged; Naproxen; ortho-Aminobenzoates; Osteoarthritis; Pain

The analgesic effect of 10 anti-inflammatory drugs was compared using a single-blind method in 90 patients with rheumatoid arthritis. Each patient received two different drugs, for three days each and each drug was evaluated in 18 patients. After the trial, the patients considered which of the drugs they preferred. The greatest relief from pain was achieved by diclofenac, indomethacin, naproxen and tolfenamic acid, each of these being preferred by the majority of patients and being significantly (p less than 0.01) better than the least effective drugs ketoprofen and proquazone. Acetylsalicylic acid, azapropazone, carprofen and ibuprofen were considered intermediate in efficacy.

Topics: Adult; Aged; Analgesics; Anti-Inflammatory Agents; Apazone; Arthritis, Rheumatoid; Aspirin; Carbazoles; Diclofenac; Female; Humans; Ibuprofen; Indomethacin; Ketoprofen; Male; Middle Aged; Naproxen; ortho-Aminobenzoates; Quinazolines

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Double-Blind Method; Humans; Ibuprofen; ortho-Aminobenzoates

Prostanoids, found in enhanced concentrations in rheumatic synovial fluid, are involved in the joint destruction seen in rheumatoid arthritis. Adherent cells isolated from rheumatic synovia produce higher amounts of prostanoids in a primary cell culture than cells originating from non-inflamed synovia. In the present study, it was found that exogenous arachidonic acid diminished the differences in prostanoid production between healthy and rheumatic synovial cells. Non-steroidal anti-inflammatory analgesics in clinically relevant concentrations had similar inhibitory effects on arachidonic acid-stimulated prostanoid synthesis in both healthy and rheumatic cells. In the presence of exogenous arachidonic acid, hydrocortisone (0.3-5.0 microM) did not affect prostanoid production in healthy cells. In rheumatic synovial cells hydrocortisone reduced PGE2 and PGF2 alpha synthesis to about half of the control value and the effect was not reversed by adding excess exogenous arachidonic acid. Altered regulation of phospholipase A2 activity in rheumatic synovia could explain the observed differences between healthy and rheumatic synovial cells.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Diclofenac; Humans; Hydrocortisone; Indomethacin; Kinetics; Knee Joint; ortho-Aminobenzoates; Prostaglandin Antagonists; Prostaglandins; Reference Values; Synovial Fluid

The effects of one-day treatment with nine nonsteroidal anti-inflammatory drugs and prednisolone on human synovial fluid concentrations of prostanoids were studied. The doses were calculated so as to be approximately equipotent according to clinical experience and the recommendations of the manufacturers. Most of the drugs used reduced clearly PGE2 and TxB2 levels in synovial fluid, but only a slight diminution in 6-keto-PGF1 alpha values was found. Carprofen, diclofenac, indomethacin, naproxen and tolfenamic acid reduced significantly the synovial fluid PGE2 concentrations. Diclofenac and indomethacin also reduced significantly the synovial TxB2 concentrations.

Topics: 6-Ketoprostaglandin F1 alpha; Acetaminophen; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Aspirin; Carbazoles; Diclofenac; Dinoprostone; Guanidines; Humans; Indomethacin; Naproxen; ortho-Aminobenzoates; Prednisolone; Prostaglandins; Prostaglandins E; Quinazolines; Synovial Fluid; Thromboxane B2