A double-blind,crossover trial of mefenamic acid,sulindac and flurbiprofen in rheumatoid arthritis

Summary

A double-blind crossover trial was carried out in 24 patients to compare the effects of mefenamic acid, flurbiprofen, sulindac and placebo. Each drug was given for 2 weeks, the treatment sequence being randomized. Daily doses were 1500?mg mefenamic acid, 150?mg flurbiprofen or 150?mg sulindac. All of the active drugs were significantly superior to placebo in terms of pain score, patients' assessment, articular index of joint tenderness, and duration and severity of morning stiffness. There was improvement in grip strength compared with placebo, but the diferences were not statistically significant with sulindac. There was slight reduction in joint circumference but this was only statistically significant in the right hand with flurbiprofen and sulindac. No significant differences were found in technetium uptake in knee joints. The three drugs appeared to be equally effective and tolerated, and no significant differences were noted.     

Flurbiprofen: a review of its pharmacological properties and therapeutic use in rheumatic diseases.

Flurbiprofen, a phenylalkanoic acid derivative, is a non-steroidal anti-inflammatory, antipyretic, analgesic agent advocated for use in rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and allied conditions. Published data suggest that flurbiprofen 120 to 150 mg daily is comparable in effectiveness with therapeutic doses of aspirin (3 to 4 g) in rheumatoid arthritis, but generally causes fewer side effects. Flurbiprofen 150 to 300 mg appears to be comparable with 75 to 150 mg of indomethacin in rheumatoid arthritis and degenerative joint disease, and comparable with phenylbutazone or indomethacin in ankylosing spondylitis. In comparison with other non-steroidal agents, flurbiprofen appears to be at least as effective as naproxen, ibuprofen or sulindac, but generally causes more side effects than these drugs. However, as no one of the non-steroidal anti-inflammatory agents is the most suitable drug for all patients requiring such therapy, flurbiprofen should be considered along with other drugs of its type in the arthritic patient.     

Reply to comments by Gonzalez et al. on the Concerta,Adderall XR Food Evaluation (CAFE) Study

Summary

A double-blind crossover trial of 200?mg flurbiprofen daily and 100?mg indomethacin daily, each given for 2 weeks separated by a 1-week placebo washout period, was carried out in 30 patients with rheumatoid arthritis. The results were analyzed for the 26 patients with complete records. No statistically significant differences were found between the two treatments with regard to subjective impression of pain severity, duration of morning stiffness, grip strength, joint size, haemoglobin and erythrocyte sedimentation rate. When the results for each treatment period were compared to baseline and both drugs considered individually, there was a statistically significant improvement from baseline. During the flurbiprofen treatment period the erythrocyte sedimentation rate showed a statistically significant fall, but not with indomethacin. During the placebo washout period between the active therapies, there was a statistically significant worsening in all parameters apart from the level of haemoglobin and erythrocyte sedimentation rate. These assessments showed little change. Five patients reported side-effects with indomethacin, and 1 with flurbiprofen. No side-effects were reported during the placebo period and although 4 patients were withdrawn, none was withdrawn because of side-effects. Patient preference was for flurbiprofen.     

A double-blind comparative study of 150 mg flurbiprofen daily and 75 mg indomethacin daily in the treatment of osteoarthrosis of the hip joint.

Thirty patients with osteoarthrosis of the hip were studied in a double-blind crossover comparison of 150 mg flurbiprofen daily and 75 mg indomethacin daily, each drug being given for 2 weeks separated by a wash-out period of 1 week on placebo. Statistical analysis of the results from 26 patients with complete records showed that both drugs produced statistically significant improvements over baseline after 1 and 2 weeks in assessments of severity of pain, night pain, duration of morning stiffness, and intermalleolar straddle. No statistical differences, however, were found between the two drugs. There were no reports of side-effects with flurbiprofen, but 6 reports from 3 patients whilst receiving indomethacin.     

Flurbiprofen and indomethacin in the treatment of rheumatoid arthritis: a double-blind crossover study.

A double-blind crossover study was carried out in 30 patients with rheumatoid arthritis to compare the effectiveness of 300 mg flurbiprofen daily with that of 150 mg indomethacin daily. Each drug was given in random order for 2 weeks, each period being preceded by a wash-out period of 2 weeks during which patients received paracetamol. With the exception of joint size and erythrocyte sedimentation rate, both drugs showed a statistically significant improvement when compared individually to baseline in all of the parameters assessed. There were no statistically significant differences between the two drugs when both treatments were compared. Three patients reported side-effects with flubiprofen and 3 with indomethacin, 1 of whom had to be withdrawn from the trial.     

Diclofenac sodium

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of diclofenac sodium are reviewed. Diclofenac, the first nonsteroidal anti-inflammatory agent (NSAID) to be approved that is a phenylacetic acid derivative, competes with arachidonic acid for binding to cyclo-oxygenase, resulting in decreased formation of prostaglandins. The drug has both analgesic and antipyretic activities. Diclofenac is efficiently absorbed from the gastrointestinal tract; peak plasma concentrations occur 1.5 to 2.0 hours after ingestion in fasting subjects. Even though diclofenac has a relatively short elimination half-life in plasma (1.5 hours), it persists in synovial fluid. The drug is metabolized in the liver and is eliminated by urinary and biliary excretion. In clinical trials, diclofenac was as effective as aspirin, diflunisal, indomethacin, sulindac, ibuprofen, ketoprofen, and naproxen in improving function and reducing pain in patients with rheumatoid arthritis. For treatment of osteoarthritis, diclofenac was equivalent in efficacy to aspirin, diflunisal, indomethacin, sulindac, ibuprofen, ketoprofen, naproxen, flurbiprofen, mefenamic acid, and piroxicam. Diclofenac was as effective as indomethacin or sulindac in treating ankylosing spondylitis. The most frequent adverse effects reported for diclofenac were gastrointestinal, but these effects were fewer and less serious than occurred with aspirin or indomethacin; in addition, diclofenac caused fewer central nervous system reactions than indomethacin. Diclofenac is administered in divided doses with meals. The recommended total daily dosage is 100 to 150 mg (osteoarthritis and ankylosing spondylitis) or 150 to 200 mg (rheumatoid arthritis). Diclofenac is effective, but no more so than other NSAIDs. It is structurally distinct and offers another choice in the treatment of rheumatological conditions.     

A controlled endoscopic study comparing the toxic effects of sulindac, naproxen, aspirin, and placebo on the gastric mucosa of health volunteers

Sixty volunteers were endoscopically evaluated to compare gastric mucosal injury following oral administration of sulindac, naproxen, aspirin, or placebo for two consecutive seven-day periods. A single-blind technique was utilized wherein the endoscopist was unaware which drug each volunteer had received. The following dosages were employed for the two study periods: sulindac, 150 and 200 mg, b.i.d., naproxen, 250 and 375 mg, b.i.d., and aspirin, 650 and 975 mg, q.i.d. The only subject who developed a frank ulcer with mucosal bleeding was in the sulindac group, however volunteers taking sulindac demonstrated statistically less significant mucosal injury on endoscopic examination than those receiving naproxen or aspirin.     

Treatment of rheumatoid arthritis with flurbiprofen or ibuprofen.

Flurbiprofen and ibuprofen were compared in a six-week double-blind randomized study in 208 patients with rheumatoid arthritis. Daily dosages were 120 mg flurbiprofen and 2400 mg ibuprofen for six weeks. Both drugs were effective in providing partial control of RA symptoms. Either or both drugs produced statistically significant improvement in mean values of time of onset of fatigue, grip strength and tender and swollen joint counts. All other standard endpoints of efficacy (except ESR) were improved but not at a statistically significant level. Slightly more than half of the patients improved during the trial. There was no statistically significant difference in the efficacy of the drugs. The incidence of side effects was low with both drugs. Most side effects were related to gastrointestinal tract irritation.     

Analgesic effect of graded doses of flurbiprofen in post-episiotomy pain

Our purpose was to evaluate the analgesic efficacy and safety of single oral doses of flurbiprofen 25, 50 and 100 mg, aspirin 600 mg, and placebo in the relief of moderate to severe post-episiotomy pain. One hundred and fifty-two evaluable patients completed a randomized, double-blind, stratified, parallel groups study. They were observed over a six hour period by one nurse-observer. Based upon each of the summary efficacy measures SPID, TOTAL and PEAK % and most of the hourly direct measures of pain intensity and pain relief, each of the four active treatments were statistically superior to placebo. Flurbiprofen 25 mg appeared to be slightly less effective than aspirin 600 mg, but the differences were not statistically significant. Flurbiprofen 50 and 100 mg were quite similar and were significantly more effective than aspirin 600 mg and flurbiprofen 25 mg. There were no observed or reported adverse effects.     

Species differences in inhibition potential of nonsteroidal anti-inflammatory drugs against estradiol 3beta-glucuronidation between rats, dogs, and humans

Differences in the inhibitory potentials against UDP-glucuronosyltransferase (UGT) between species have been reported only rarely, even though the information would be useful for the precise characterization of drug candidates. In this study, the inhibition potentials of nonsteroidal anti-inflammatory drugs (NSAIDs) against UGT-catalyzed estradiol 3beta-glucuronidation (E3G) in the liver microsomes of rats, dogs, and humans were compared. Rat liver microsomes (RLMs) and human liver microsomes (HLMs) exhibited homotropic activation kinetics with S(50) values of 22 and 12 microM, respectively. However, dog liver microsomes (DLMs), exhibited Michaelis-Menten kinetics with no activation. Among the NSAIDs investigated (diclofenac, diflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, niflumic acid, and sulindac), only niflumic acid and mefenamic acid inhibited E3G potently in all three species. The IC(50) values of NSAIDs against E3G in RLMs and HLMs were within a threefold difference of each other, while those in DLMs was more than three times higher than the other two. In conclusion, RLMs showed an inhibitory pattern similar to that of HLMs, whereas DLMs presented a distinct pattern. These results indicate that a rat animal model would be useful for evaluating the inhibitory potentials of drugs against estradiol glucuronidation, but a dog model would not.     

A double-blind comparison of mefenamic acid and piroxicam in acute soft tissue injuries

Thirty patients suffering from strains, sprains or direct soft tissue injuries were entered into a double-blind trial comparing mefenamic acid and piroxicam. Mefenamic acid was given at a dosage of 500 mg 3-times daily and piroxicam as a single daily dose of 20 mg, for a maximum of 10 days. Both drugs were effective in treating the symptoms associated with acute soft tissue injuries. There were statistically significant improvements in all parameters monitored (pain, functional capacity, sleep disturbance, local swelling and tenderness) by Day 2, except for local swelling in the mefenamic acid group and sleep disturbance in the piroxicam group. By Day 5 all parameters showed improvement. Almost all (90%) of the patients had recovered from their injury in less than 1 week. Both drugs were well tolerated, only 5 patients reporting adverse events (3 on mefenamic acid and 2 on piroxicam).     

An evaluation of flurbiprofen, aspirin, and placebo in postoperative oral surgery pain

One hundred sixty-four outpatients with postoperative pain after the removal of impacted third molars were randomly assigned on a double-blind basis, to receive oral doses of flurbiprofen 25, 50, or 100 mg; aspirin 600 mg; or placebo. Using a self-rating record, subjects rated their pain and its relief hourly for 8 hours after medicating. Estimates of sum of pain differences (SPID), peak pain intensity difference (PID), total relief, peak relief, and hours of 50% relief were derived from these subjective reports. All active medications were significantly superior to placebo. Analgesia was similar for flurbiprofen 25 mg and aspirin 600 mg. Flurbiprofen 50 and 100 mg were significantly superior to aspirin for every measure of analgesia except peak PID. There was a significant dose-response regression between flurbiprofen 25 mg and both of the higher dosages. Flurbiprofen 50 and 100 mg did not differ significantly, suggesting a plateau in flurbiprofen's analgesia. The analgesic effect of flurbiprofen was significant by hour 1 and persisted for 8 hours. The frequency of adverse effects was similar for the active medications.     

Influence of H2 receptor antagonists on the disposition of flurbiprofen enantiomers

The effect of oral cimetidine or ranitidine on the pharmacokinetics of the R and S enantiomers of the nonsteroidal anti-inflammatory drug flurbiprofen and its major metabolite, 4'-hydroxyflurbiprofen, was evaluated. Nine healthy volunteers participated in a randomized crossover design study with the following treatments: (A) flurbiprofen 200 mg; (B) flurbiprofen 200 mg plus ranitidine 150 mg bid for 7 days before and for 2 days after receiving flurbiprofen and (C) flurbiprofen 200 mg plus cimetidine 300 mg qid for 7 days before and for 2 days after receiving flurbiprofen. Blood and urine samples were collected at various intervals during a 48-hour period. These samples were assayed stereospecifically for flurbiprofen and its metabolite. Small but statistically significant differences in the terminal elimination rate constant (K), maximum peak serum drug concentration (Cmax), time to reach peak concentration (tmax), oral clearance (Cl/F) and area under the curve (AUC) were noted for flurbiprofen enantiomers. No significant treatment*isomer interactions were observed, indicating that neither cimetidine nor ranitidine interacted stereospecifically with flurbiprofen. Cimetidine, but not ranitidine, resulted in small (less than or equal to 15%) but statistically significant changes in flurbiprofen pharmacokinetic parameters. The interaction between H2-antagonists and flurbiprofen is unlikely to be clinically important.     

A multi-centre,double-blind randomized study to assess the efficacy and tolerance of sulindac versus placebo in the symptomatic treatment of patients with upper respiratory tract infection

Summary

A multi-centre, double-blind, randomized, placebo-controlled study was carried out to compare the efficacy and tolerance of sulindac (200?mg twice daily) with placebo in the symptomatic treatment for 7 days of 312 adult patients with upper respiratory tract infection. Investigators and patients rated sulindac superior to placebo in the overall evaluations of response to treatment, but the differences were not significant. In general, patients treated with sulindac had greater mean decreases from baseline scores for individual signs and symptoms than did placebo patients. Fever was relieved better by sulindac than by placebo. The mean decrease from baseline pain scores was also greater in the sulindac group. More patients receiving sulindac reported clinical adverse experiences compared with those on placebo, the most common adverse experiences reported being in the digestive system.     

A multi-centre, double-blind randomized study to assess the efficacy and tolerance of sulindac versus placebo in the symptomatic treatment of patients with upper respiratory tract infection

A multi-centre, double-blind, randomized, placebo-controlled study was carried out to compare the efficacy and tolerance of sulindac (200 mg twice daily) with placebo in the symptomatic treatment for 7 days of 312 adult patients with upper respiratory tract infection. Investigators and patients rated sulindac superior to placebo in the overall evaluations of response to treatment, but the differences were not significant. In general, patients treated with sulindac had greater mean decreases from baseline scores for individual signs and symptoms than did placebo patients. Fever was relieved better by sulindac than by placebo. The mean decrease from baseline pain scores was also greater in the sulindac group. More patients receiving sulindac reported clinical adverse experiences compared with those on placebo, the most common adverse experiences reported being in the digestive system.     

Tranexamic acid: a review of its use in the management of menorrhagia

Tranexamic acid (Transamin), Cyklokapron, Exacyl, Cyklo-f) is a synthetic lysine derivative that exerts its antifibrinolytic effect by reversibly blocking lysine binding sites on plasminogen and thus preventing fibrin degradation.In a number of small clinical studies in women with idiopathic menorrhagia, tranexamic acid 2-4.5 g/day for 4-7 days reduced menstrual blood loss by 34-59% over 2-3 cycles, significantly more so than placebo, mefenamic acid, flurbiprofen, etamsylate and oral luteal phase norethisterone at clinically relevant dosages. Intrauterine administration of levonorgestrel 20 microg/day, however, produced the greatest reduction (96% after 12 months) in blood loss; 44% of patients treated with levonorgestrel developed amenorrhoea. Tranexamic acid 1.5 g three times daily for 5 days also significantly reduced menstrual blood loss in women with intrauterine contraceptive device-associated menorrhagia compared with diclofenac sodium (150 mg in three divided doses on day 1 followed by 25 mg three times daily on days 2-5) or placebo. Tranexamic acid, mefenamic acid, etamsylate, flurbiprofen or diclofenac sodium had no effect on the duration of menses in the studies that reported such data.In a large noncomparative, nonblind, quality-of-life study, 81% of women were satisfied with tranexamic acid 3-6 g/day for 3-4 days/cycle for three cycles, and 94% judged their menstrual blood loss to be 'decreased' or 'strongly decreased' compared with untreated menstruations. The most commonly reported drug-related adverse events are gastrointestinal in nature. The total incidence of nausea, vomiting, diarrhoea and dyspepsia in a double-blind study was 12% in patients who received tranexamic acid 1g four times daily for 4 days for two cycles (not significantly different to the incidence in placebo recipients). In conclusion, the oral antifibrinolytic drug tranexamic acid is an effective and well tolerated treatment for idiopathic menorrhagia. In clinical trials, tranexamic acid was more effective at reducing menstrual blood loss than mefenamic acid, flurbiprofen, etamsylate and oral luteal phase norethisterone. Although it was not as effective as intrauterine administration of levonorgestrel, the high incidence of amenorrhoea and adverse events such as intermenstrual bleeding resulting from such treatment may be unacceptable to some patients. Comparative studies of tranexamic acid with epsilon - aminocaproic acid, danazol and combined oral contraceptives, as well as long-term tolerability studies, would help to further define the place of the drug in the treatment of menorrhagia. Nevertheless, tranexamic acid may be considered as a first-line treatment for the initial management of idiopathic menorrhagia, especially for patients in whom hormonal treatment is either not recommended or not wanted.     

Lack of interaction between sulindac or naproxen and propranolol in hypertensive patients

Seventeen patients with hypertension and osteoarthritis participated in a single-blind crossover study comparing the effects of sulindac 200 mg twice daily, naproxen 500 mg twice daily, and placebo on blood pressure. All patients were treated for hypertension with propranolol monotherapy. Blood pressures were back-titrated to achieve a baseline diastolic blood pressure of 90 to 100 mm Hg while taking naproxen. There were no significant differences in mean sitting or standing blood pressures among the patients receiving naproxen, sulindac, or placebo treatments. There was no change in pulse, weight, or any of the laboratory measurements at the end of each treatment phase. These results suggest that neither sulindac nor naproxen interferes with propranolol therapy for uncomplicated hypertension.     

Central stimulating effect of the combination of the new quinolone group of antimicrobials and nonsteroidal anti-inflammatory drugs in mice]

Six new quinolones: enoxacin, norfloxacin, ofloxacin, ciproflosacin, lomefloxacin, and tosufloxacin and eight nonsteroidal anti-inflammatory drugs: fenbufen, flurbiprofen, ketoprofen, pranoprofen, ibuprofen, indomethacin, mefenamic acid and aspirin were tested for their ability to produce a central stimulating effect in mice. At 5 min after the oral administration of one of the nonsteroidal anti-inflammatory drugs, a new quinolone was administered orally. The combination of drugs induced convulsions in a dose-dependent manner, and some mice died as a result of the convulsions. The survival time was used as an index to measure the intensity of convulsions induced by the drug combination. The new quinolones in combination with fenbufen at 100 mg/kg produced convulsions in the following order of potencies: enoxacin greater than lomefloxacin greater than norfloxacin. In contrast, administration of fenbufen together with ofloxacin, ciprofloxacin, or tosufloxacin up to a dose of 1000 mg/kg caused no convulsions. Four nonsteroidal anti-inflammatory drugs combined with enoxacin at 100 mg/kg also caused convulsion dose-dependently. The order of potency in producing convulsion was as follows: fenbufen greater than flurbiprofen greater than ketoprofen = pranoprofen. However, no convulsions were produced by treatment of ibuprofen, indomethacin, mefenamic acid or aspirin together with enoxacin. From these results, the important chemical structures of the new quinolones particularly concerned with the appearance of convulsion were discussed.     

A comparative study of flurbiprofen and indomethacin in rheumatoid arthritis.

A double-blind, crossover study was carried out in 30 patients with active, classical or definite rheumatoid arthritis to compare the effect of 200 mg flurbiprofen per day with that of 100 mg indomethacin per day. Patients received, at random, each drug for a period of 2 weeks separated by a weeks' wash-out period on placebo. Assessments were made before the start of the trial and at weekly intervals of pain, morning stiffness, grip strength, articular index, walking time, and finger joint size. Patients' preference for any particular treatment period was recorded at the end of the trial. Laboratory investigations were carried out before and during the trial. Both drugs shows statistically significant improvement over baseline assessments, although there was little difference between the two active treatment periods. More patients preferred the treatment period with flurbiprofen, and this was probably related to the fewer side-effects which were reported with this drug.     

A comparative study of the long-term efficacy of flurbiprofen and indomethacin in the treatment of rheumatoid arthritis, with special reference to iron metabolism.

Preliminary results are reported for the first 23 rheumatoid arthritis patients entered in a long-term, double-blind trial to compare the efficacy of flurbiprofen and indomethacin. It was planned that, unless withdrawn, patients from matched pairs received either flurbiprofen (150 mg to 300 mg daily) or indomethacin (75 mg to 150 mg daily) over a minimum period of 6 months, dosage being adjusted to suit exacerbations and remission of disease. In addition to clinical assessments of severity of pain, duration and severity of morning stiffness, joint size and joint score, routine laboratory measurements were carried out, including estimates of serum iron and total iron binding capacity, rheumatoid factor and immunoglobulin levels. This interim report gives the statistical analysis of results from the 17 patients completing from 2 to 4 months of treatment and shows that both drugs were equally effective in controlling disease activity. Withdrawals due to side-effects or exacerbations of disease were similar for both drugs.