Proquazone

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Abstract
Proquazone 1 is a non-steroidal anti-inflammatory agent (NSAID) which, unlike most other NSAIDs, does not have a free acid group in its structure. It is advocated for use in rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, musculoskeletal disorders, acute inflammatory conditions and acute pain states such as dysmenorrhoea, postoperative pain and headache. Published data in small groups of patients indicate that proquazone 300 to 900 mg/day in 3 divided doses is a possible alternative to aspirin, ibuprofen, indomethacin, and naproxen in rheumatoid arthritis, and to indomethacin and ibuprofen in ankylosing spondylitis. Similarly, proquazone 300 to 900 mg/day is as effective as aspirin, diclofenac, ibuprofen, indomethacin and naproxen in patients with osteoarthritis. Preliminary studies have confirmed the efficacy of proquazone in acute inflammatory disorders, and shown that it provides useful analgesic relief in acute pain states such as dysmenorrhoea, headache and after minor surgery. Evidence from small groups of patients with rheumatoid arthritis treated for a year or more suggests that proquazone may inhibit or arrest progression of bone erosions. However, these encouraging findings clearly need confirmation in a larger number of patients studied under well-controlled conditions. The overall impression from clinical trials to date is that proquazone at dosages of ⩾ 900 mg/day produces a high incidence of gastrointestinal symptoms such as diarrhoea (in approximately 30% of patients). However, these effects were usually of mild to moderate severity and transient in nature and in most comparative studies the overall tolerability of proquazone was assessed as being comparable to that of other NSAIDs tested. Similarly, withdrawal from therapy due to side effects was no greater with proquazone than with other NSAIDs evaluated. Initial experience with lower dosages of proquazone (300 to 450 mg/day) suggest that efficacy is maintained and tolerability markedly improved. Thus, at present, proquazone would seem to be as effective as other NSAIDs used in the management of rheumatoid arthritis and osteoarthritis. However, further studies are needed to fully evaluate the efficacy and tolerability of this agent, especially at the lower daily dosages currently recommended, and to clarify whether it does have significant ‘disease modifying’ potential. Proquazone is a non-steroidal anti-inflammatory drug (NSAID) which possesses analgesic and antipyretic properties. It has been shown to suppress inflammation in various animal models of acute and chronic disease. In carrageenin-induced paw oedema and adjuvant-induced arthritis, it appears to be equipotent with diclofenac but less active than indomethacin. In animal and human models of pain, proquazone has generally been at least as active as indomethacin and other NSAIDs in tests designed to detect ‘non-narcotic-type’ analgesia. Indeed, in man, proquazone 600mg as a single dose was found to be a superior analgesic to phenylbutazone 400mg, naproxen 500mg and diclofenac 100mg and marginally better than indomethacin 100mg. In vitro and in vivo, proquazone is a potent inhibitor of prostaglandin synthesis, comparable in activity to indomethacin and diclofenac and superior to naproxen. It also inhibits collagen-, arachidonic acid- and ADP-induced platelet aggregation. Preliminary results in patients with rheumatoid arthritis suggest that proquazone 600 to 900 mg/day may increase the synovial fluid concentrations of complement components (C3 and C4) and decrease the concentration of immunoglobulins IgG, IgM and IgA, which are indicative of an immunological mechanism. However, in various animal models, proquazone (like indomethacin and phenylbutazone) did not influence cell-mediated or humoral immune mechanisms. Animal studies generally demonstrated that proquazone had a lower ulcerogenic potential than other NSAIDs, although in a study involving healthy volunteers proquazone 600 and 900 mg/day and aspirin 3600 mg/day produced a similar extent of faecal blood loss. Proquazone 100 to 900mg orally is rapidly absorbed from the gastrointestinal tract, peak plasma concentrations being attained in about 1.5 hours. Food appears to markedly increase the bioavailability of proquazone as estimated by area under the plasma concentration-time curve (AUG). Following intravenous administration of proquazone 75 or 122mg to healthy subjects the mean apparent volume of distribution was 10.8L while the volume of distribution at steady-state was 39.5L. Proquazone is extensively bound to plasma protein (> 98%). After oral administration, proquazone is subject to extensive first-pass metabolism — between 80 and 95% of a single dose is metabolised during its first passage through the liver. Hydroxylation of the parent molecule to m-hydroxyproquazone (existing mainly in the conjugated form) seems to be the major metabolic pathway. A number of other metabolites have also been identified in man. Further research is necessary to evaluate the anti-inflammatory and analgesic activity of the metabolites. Proquazone and its metabolites are removed from the body by a combination of urinary (46 to 51%) and biliary (30 to 43%) excretion and the majority is eliminated within the first 24 hours. The total body clearance of proquazone is about 40 L/h while renal clearance is only about 0.004 L/h, highlighting the importance of hepatic extraction in the elimination of proquazone. The elimination half-life of proquazone is usually between 0.6 and 1.3 hours whereas that of its major metabolite, m-hydroxyproquazone, is much longer (6.7 to 13.4 hours). In patients with hydrarthrosis of the knee, the synovial fluid concentrations of proquazone and its metabolites steadily increased over the first 3 hours and were still high after 4 to 7 hours. In another study, the pharmacokinetic properties of proquazone were found to be similar in children with juvenile rheumatoid arthritis to those in healthy subjects. Proquazone 300 to 1200 mg/day produced clinically significant relief from pain, improved grip strength and reduced the number of affected joints in placebo-controlled trials in patients with rheumatoid arthritis. In other comparative studies, proquazone 300 to 900 mg/day was usually shown to be as efficacious as NSAIDs such as aspirin, diclofenac, ibuprofen, indomethacin and naproxen in patients with rheumatoid arthritis. Preliminary results from long term trials (⩾ 12 months) have demonstrated that proquazone 600 to 900 mg/day maintains its efficacy and may arrest the progression of bone erosions, although this encouraging finding needs to be confirmed in well-controlled trials in larger numbers of patients. Short term studies in patients with osteoarthritis usually involved only small groups of patients, and have shown that proquazone 300 to 900 mg/day was of comparable efficacy as indomethacin 75 to 150 mg/day, aspirin 1200 to 3600 mg/day, diclofenac 75 to 150 mg/day and ibuprofen 1200 mg/day and tended to be more effective than naproxen 500 mg/day. Preliminary dose-ranging studies in patients with osteoarthritis showed that lower daily dosages of proquazone (300 to 500mg) did not result in reduced efficacy but were associated with only half the incidence of side effects compared with proquazone 900 mg/day (13.3% vs 27.1%, respectively). Proquazone 900 mg/day was as effective as indomethacin 75 mg/day and ibuprofen 1200 mg/day in patients with ankylosing spondylitis. For treating the pain, swelling and redness associated with acute gouty arthritis, proquazone 900 mg/day was comparable to indomethacin 150 mg/day and superior to phenylbutazone 600 mg/day. In addition to conservative therapy, proquazone 600 to 1500 mg/day was as effective as naproxen 500 to 750 mg/day, diclofenac 50 to 125 mg/day, indomethacin 150 mg/day and ibuprofen 800 to 1600 mg/day in patients suffering from low back pain and sciatica. In these studies proquazone produced analgesic relief more quickly than naproxen and indomethacin, and elicited an overall better global assessment than diclofenac. Proquazone 900 to 1200 mg/day and oxyphenbutazone 300 to 400 mg/day both produced marked improvement in 70 to 80% of patients with acute traumatic injury. The analgesic activity of proquazone in patients with pain associated with dysmenorrhoea, minor surgery or headaches was demonstrated to be significantly superior to that of placebo, oxyphenbutazone and aspirin, and equivalent to that produced by indomethacin. In comparative studies proquazone 900 mg/day appeared to be of similar overall tolerability as indomethacin 150 mg/day, aspirin 1200 to 3600 mg/day and diclofenac 125 to 150 mg/day, but less well tolerated than ibuprofen 1200 mg/day and naproxen 500 mg/day. Reducing the daily dosage of proquazone to 300 to 500 mg/day in patients with rheumatoid arthritis or osteoarthritis resulted in a lower incidence of side effects without significantly altering the efficacy. Gastrointestinal symptoms, especially diarrhoea, occurred frequently with proquazone (diarrhoea in about 30% of patients usually treated with proquazone 900 mg/day); however, the symptoms were usually mild to moderate in severity and infrequently required discontinuation of therapy. Proquazone dosage should be adjusted to suit individual requirements. The recommended adult dosage is 300 to 450 mg/day orally or rectally in 2 or 3 divided doses. This can be increased to 900 mg/day if necessary and, in acute disease, a daily dosage of 1200mg may be administered for a maximum of 7 days. Proquazone is contraindicated in patients with active peptic ulceration or allergy to other NSAIDs. It should be used with caution in patients with a history of gastrointestinal disease, renal insufficiency or hepatic disease.