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A controlled double blind study on the incidence of nonsteroidal antiinflammatory drug (NSAID) gastropathy was performed in 29 healthy volunteers administered diclofenac Na (10 subjects) or a prodrug (loxoprofen Na in 10 subjects and proglumetacin maleate in 9 subjects). The incidence of NSAID gastropathy was significantly lower in the subjects administered the prodrugs than in those administered diclofenac Na (p less than 0.05), which suggested the clinical usefulness of the prodrugs.

The efficacy and safety of etodolac and piroxicam were compared in a double-blind, randomized, parallel-group outpatient study at four sites. Patients with active osteoarthritis of the knee were assigned to receive etodolac 600 mg/day (57 patients) or piroxicam 20 mg/day (59 patients) for 6 weeks. Efficacy assessments were made at the pretreatment screening, at baseline, and at treatment weeks 2, 4, and 6 for patient and physician global evaluations, night pain, spontaneous pain intensity, weight-bearing pain variables, measures of inflammation, morning stiffness, and knee flexion. An analysis was also done based on each patient's final evaluation, regardless of the week at which it occurred. Safety assessments were made before treatment and at the completion of therapy. A therapeutic response was obtained in both treatment groups by the end of the second week of treatment. At the final evaluation, both groups showed significant improvement (P less than or equal to 0.05) from baseline for most efficacy assessments. The physician's global assessment indicated improvement in the condition of 60% of the etodolac-treated patients and 39% of the piroxicam-treated patients at the final evaluation. There was no significant difference between treatment groups in the number of patient withdrawals due to adverse reactions or in the number of patients reporting side effects. The results of this study indicate that, compared with piroxicam 20 mg/day, etodolac 600 mg/day is effective and well tolerated in the treatment of patients with osteoarthritis.

The efficacy and safety of etodolac and naproxen were compared in a double-blind, randomized, parallel-group outpatient study. Patients with acute sports injuries were assigned to receive either etodolac 300 mg TID (50 patients) or naproxen 500 mg BID (49 patients) for up to 7 days. Assessments were made at the pretreatment screening (baseline) and at days 2, 3, 4, and 7 of treatment. Assessments included patient and physician global evaluations, spontaneous and induced pain intensity, range of motion, tenderness, heat, degree of swelling, and degree of erythema. Safety assessments, including laboratory profiles, were made at pretreatment and at final evaluation; patients' complaints were elicited at all visits. Both treatment groups showed significant (P less than or equal to 0.05) improvement from baseline for all efficacy parameters by day 2 and thereafter at all time points. Improvement was similar for the two groups. No patients in either group withdrew from the study because of drug-related adverse reactions. The results of this study indicate that etodolac (900 mg/day) is effective and well tolerated as an analgesic and anti-inflammatory in acute sports injuries and is comparable to naproxen (1000 mg/day).

The Authors show the results of a clinical trial carried out on two groups of patients affected by acute periodontitis. Patients were treated with proglumetacin or ketoprofen, respectively; the efficacy and tolerability of these two drugs were analyzed.

Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) effective in the treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis, and in the alleviation of postoperative pain. Etodolac also provides relief of other types of pain, including that arising from gouty conditions and traumatic injury. In all indications, etodolac appears to be at least as effective as other NSAIDs. The incidence of clinical adverse effects other than abdominal pain and dyspepsia is similar to that observed with placebo, and etodolac has been associated with a low rate of gastrointestinal ulceration and other serious events. Data from preliminary animal studies have suggested that etodolac may provide more selective inhibition of prostaglandin synthesis at sites of inflammation than some other currently available NSAIDs. Thus, available evidence indicates that etodolac, with its low incidence of gastrointestinal events, is an effective and well tolerated alternative to other NSAIDs in the treatment of arthritic diseases and pain of various aetiologies and should be considered a first-line therapy.

Etodolac, a new nonsteroidal anti-inflammatory drug, was administered orally at doses of 1 and 5 mg/kg to MRL/MpJ-lpr/lpr (MRL/lpr) mice, and its effect on articular lesions was compared with that of indomethacin. Both etodolac and indomethacin significantly reduced swelling of the hind paw. Histopathological examination showed that etodolac significantly reduced cartilage and bone damage, whereas indomethacin treatment did not achieve a statistically significant effect. Rheumatoid factors were not affected by either etodolac or indomethacin. These results indicate that etodolac delays the development of arthritis in MRL/lpr mice, and reduces cartilage and bone damage.

A study was carried out to compare the efficacy and tolerability of etodolac and piroxicam in patients with rheumatoid arthritis. Sixty patients entered this double-blind, parallel study and after a wash-out period of up to 2 weeks were randomly assigned to receive 200 mg etodolac twice daily or 20 mg piroxicam once daily for 12 weeks. Efficacy and tolerability assessments were made after 2, 4, 6, 8 and 12 weeks. Patients in the etodolac group demonstrated statistically significant improvement in the number of tender joints and the duration of morning stiffness after 12 weeks, as did the piroxicam-treated patients. In addition, the etodolac-treated patients had significant improvement according to the patients' and physician's global evaluations, pain intensity, number of swollen joints, and grip strength. There were significant differences between therapies favouring etodolac for the assessments of the number of tender joints and the physician's global evaluation by the end of the study. Forty-seven percent (47%) of 15 etodolac-treated patients compared with 7% of 15 piroxicam-treated patients showed improvement according to the physician's global evaluation at Week 12. Similarly, the patients' global evaluation showed that 40% of etodolac-treated patients and 19% of piroxicam-treated patients had improved by the end of therapy. Both therapies were well tolerated. There were no significant differences between groups in the incidence of any adverse reactions or the frequency of withdrawals.

Thirty-nine patients with rheumatoid arthritis were randomly assigned to receive 200 mg of etodolac or 500 mg of naproxen twice daily for 12 weeks. In both treatment groups, significant improvements in the number of tender and swollen joints, in the global evaluations of both patients and physician, in pain intensity scores, grip strength, and duration of morning stiffness, and in the erythrocyte sedimentation rate were noted. One etodolac-treated patient withdrew from treatment because of a rash; three etodolac-treated patients and two naproxen-treated patients reported minor upper gastrointestinal discomfort. No abnormal laboratory test results were found. It is concluded that both etodolac and naproxen are safe and effective in the treatment of rheumatoid arthritis.

The efficacy and tolerability of etodolac and piroxicam were compared in patients with osteoarthritis of the knee. Two hundred and twenty patients entered a double-blind, parallel group trial and were randomly assigned to receive 300 mg etodolac twice daily (n = 112) or 20 mg piroxicam once daily (n = 108) for 8 weeks. The etodolac group showed significant improvement (p less than 0.05) from baseline in all efficacy assessments at all evaluations. The piroxicam group showed improvement from baseline in all efficacy assessments at all evaluations except for erythema at Week 2. While mean change from baseline was similar for both groups, the patients' and physicians' final overall evaluations showed that the etodolac-treated patients improved slightly more from baseline than the piroxicam-treated patients. Twenty (18%) patients in the etodolac group reported at least one drug-related study event. In the piroxicam group, 16 (15%) patients reported at least one drug-related study event. Twelve (11%) etodolac-treated patients prematurely withdrew from the study. Of these, 7 had at least one adverse reaction. Two of the 12 patients withdrew because of lack of efficacy. Withdrawals from the piroxicam group were comparable. Thirteen (12%) patients withdrew, 6 of whom had at least one adverse reaction. One of these patients suffered a cardiovascular accident and died. Three patients withdrew because of lack of efficacy. The results of this study indicate that etodolac and piroxicam are comparable in efficacy and tolerability for the treatment of patients with osteoarthritis.

The aim of this clinical, endoscopical study was to evaluate the therapeutic efficacy and the gastric tolerability of etodolac, a new anti-inflammatory, non-steroidal drug, compared with naproxen. The study was conducted on 48 patients suffering from rheumatoid arthritis. 44 of whom completed the trial. After an initial oesophagogastroduodenoscopy to exclude the presence of gastric mucosal lesions, patients were randomly allocated to double-blind treatment with either etodolac 200 mg b.i.d. or naproxen 500 mg b.i.d. for a period of 4 weeks. Endoscopic control followed this treatment period. Both drugs proved effective in relieving clinical symptoms, without a statistically significant difference. Gastric mucosal lesions were observed in 15% of etodolac-treated patients and in 46% of patients treated with naproxen (P less than 0.05) (95% CI 0.01-0.60). Painful dyspepsia was observed in 15% of patients treated with etodolac vs. 38% of patients on naproxen therapy. This study demonstrates that etodolac is at least as active as naproxen in relieving rheumatic symptoms, and its administration results in a significantly lower degree of gastric damage.

The efficacy and tolerability of etodolac and indomethacin were compared in patients with osteoarthritis of the knee. Sixty-four patients entered a double-blind, parallel trial and were randomly assigned to receive 300 mg etodolac twice daily (n = 31) or 50 mg indomethacin 3-times daily (n = 33) for 6 weeks. Both groups showed significant (p less than or equal to 0.05) improvement from baseline in all efficacy assessments at the final evaluation. However, significantly (p less than or equal to 0.05) greater decreases from baseline were seen for etodolac than for indomethacin in patients' global evaluation, pain intensity, night pain, standing pain, walking pain, pain getting up from a chair, tenderness on pressure, and knee flexion. In addition, 67% of the patients in the etodolac group indicated improvement in their condition at the final evaluation, compared with 53% of the patients who received indomethacin. No patients in the etodolac group withdrew because of adverse reactions compared to 4 patients in the indomethacin group. Furthermore, significantly more patients in the indomethacin group (52%) than in the etodolac group (19%) reported drug-related adverse reactions. Thus, the results of this study strongly indicate that etodolac is more effective and produces fewer side-effects than indomethacin in the treatment of patients with osteoarthritis.

Patients affected by osteoarthritis totalling 358 (142 males and 216 females) were recruited in an open study which lasted up to three months. All patients started treatment with etodolac 600 mg/die per os. 74 patients were treated and followed for 15 days, 94 for one month, 54 for two months, and 132 for three months. Clinical evaluations, performed at baseline and after 15, 30, 60, and 90 days of treatment were made on the following parameters: intensity of pain, index of sleep disturbance caused by symptoms related to osteoarthritis, investigator's evaluation of the global patient's condition, patient's self-evaluation about his own condition, presence and duration of morning stiffness, presence and duration of stiffness at rest, and finally the investigator's integrated evaluation about the effectiveness tolerance of etodolac during the study. All the parameters showed a noticeable and significant improvement in all groups of patients, stratified by sex, age, and duration of the disease. The younger patients and those patients with osteoarthritis of a less prolonged duration achieved the best results. Only slight differences were registered by examining the baseline values of the various parameters or the extent of the different improvements achieved, on the basis of sex, and duration of osteoarthritis and the non-steroidal anti-inflammatory drugs previously used. Among the 27 patients who withdrew, eight dropped out for clinical inefficacy and 15 for intolerance. In all these latter cases a prompt and complete resolution of the adverse reaction was achieved and maintained after the interruption of therapy. In the 49 patients who presented side-effects, these were almost always related to the gastrointestinal tract and of slight intensity. A complete resolution was promptly achieved in 25 cases, while in 17 other patients the side-effect persisted during the course of the study, but it was considered not worthy of the patient dropping out. The profile of routine laboratory parameters, measured both at inception and at the end of the study, did not show relevant changes after treatment with etodolac. In conclusion this study demonstrated that etodolac is effective and well tolerated in the prolonged treatment of patients with active osteoarthritis.

A double-blind, parallel group study was carried out in 61 patients suffering from acute gouty arthritis to compare the effectiveness of etodolac and naproxen in the relief of symptoms. Patients were allocated at random to receive either 300 mg etodolac twice daily (31 patients) or 500 mg naproxen twice daily (30 patients) for 7 days. Both groups were comparable for sex, age and weight of patients, but there was a tendency for patients in the etodolac group to have more severe gout as shown by baseline clinical assessment scores. The variables assessed on entry and on Days 2, 4 and 7 of treatment were pain intensity, swelling, tenderness, erythema, joint heat, range of motion, and physician's and patients' overall evaluation of the condition. The results showed that there was a significant improvement from baseline in all of the variables at each time point in both treatment groups. However, more etodolac-treated patients (81%) than naproxen-treated patients (53%) showed overall improvement at Day 2, and etodolac was significantly better than naproxen on the Day 2 evaluation of joint swelling and at the Day 4 evaluations of joint tenderness, range of motion and the physician's global assessment. At the final evaluation on Day 7, 97% of the etodolac group reported that their condition had improved as compared to 93% of the naproxen group. Both drugs were well tolerated and only a few mild side-effects were reported.

The synthesis of gastric and duodenal mucosal prostaglandin E2, prostaglandin I2, and thromboxane B2 during a 60 minute incubation of biopsy specimens, the degree of endoscopic and histological damage, and the anti-inflammatory response were all studied after a four week, double blind study of therapeutic doses of two non-steroidal anti-inflammatory drugs, naproxen and etodolac, received by 27 patients with active rheumatoid arthritis (13 receiving naproxen, 14 etodolac). Prostaglandin values after treatment did not differ from the baseline levels when all the patients were analysed as one group. Subgroup analysis showed that naproxen suppressed gastric prostaglandin E2 from a median of 29 to 9 ng/mg protein, duodenal prostaglandin E2 from 34 to 11 ng/mg, and duodenal prostaglandin I2 from 62 to 15 ng/mg protein. No overall suppression occurred with etodolac. Also, on the second assessment patients receiving naproxen had lower gastric and duodenal prostaglandin E2 and prostaglandin I2, but higher values of duodenal thromboxane B2, than patients receiving etodolac. Both drugs had comparable anti-arthritic activity and caused microscopic gastritis in similar proportions of patients. No correlation was detected between prostaglandin values and the mucosal damage which developed in seven patients receiving naproxen (54%) and three receiving etodolac (21%). These findings indicate that, unlike naproxen, etodolac does not seem to affect gastric or duodenal prostaglandin synthesis; other mechanisms of injury need to be considered.

Nonsteroidal anti-inflammatory drugs have been implicated in renal impairment. The purpose of this report is to review the effect of etodolac, a new anti-inflammatory agent, on renal function and the effect of renal impairment on etodolac pharmacokinetics. Pharmacokinetic and renal function studies were conducted in normal and in renally impaired volunteers. Additionally, the renal safety of etodolac was assessed in 2,629 arthritic patients who were treated in clinical trials. The results suggest that etodolac does not affect renal function in normal individuals, nor does it exacerbate underlying renal insufficiency when administered to patients with mild to moderate renal impairment. The pharmacokinetics of etodolac are unchanged in patients on hemodialysis and in elderly patients. Furthermore, no patient was withdrawn from clinical trials for significantly abnormal renal function test values resulting from etodolac therapy alone.

Etodolac is a new nonsteroidal anti-inflammatory drug (NSAID) with potent analgesic and antiarthritic properties. The purpose of these randomized, double-blind, parallel-group studies was to compare etodolac with other standard NSAIDs or placebo for the treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Results of rheumatoid arthritis and osteoarthritis studies showed etodolac (200 to 300 mg b.i.d. or 200 mg t.i.d.) to be comparable to naproxen (500 mg b.i.d.), piroxicam (20 mg once daily), and diclofenac (50 mg t.i.d.). Key efficacy variables improved significantly (p less than or equal to 0.05) in all treatment groups, and there were no significant between-group differences. Studies comparing etodolac (200 mg b.i.d.) with indomethacin (50 mg t.i.d.) for treatment of ankylosing spondylitis showed significant improvement from baseline in both the patient's and physician's global assessments for both treatments. Titrated-dose studies compared etodolac (50 to 200 mg b.i.d.) with naproxen (250 to 375 mg b.i.d.) and placebo for the treatment of ankylosing spondylitis. Both active drugs resulted in greater improvement than did placebo in the patient's and investigator's global assessments. These results indicate that etodolac is as effective as naproxen, piroxicam, and diclofenac for the treatment of rheumatoid arthritis and osteoarthritis. Moreover, it is comparable to naproxen and indomethacin and superior to placebo for the treatment of ankylosing spondylitis.

One hundred and seventeen outpatients (87 females and 30 males; mean age 53.5 +/- 13.2 years) encompassing the 1987 American Rheumatism Association criteria for rheumatoid arthritis were admitted into a multicentre open study. All patients were evaluated at baseline and after two months of therapy with etodolac (400 or 600 mg/die per os). Clinical evaluation was performed by using the following indicators: viso-analogic scale of global pain; index of pain on active movements; index for sleep disturbances, and duration of morning stiffness. The erythrocyte sedimentation rate was chosen for the laboratory evaluation of the activity of the disease. One hundred patients received 400 mg/die, while only 17 patients received 600 mg/die; 115 patients undertook the evaluation after treatment, whereas two patients were considered "lost to follow-up". One hundred and five patients completed the study while ten patients withdrew (seven because of inefficacy and three because of intolerance of the gastrointestinal tract). Only nine patients presented side-effects, among these: five were judged etodolac-related, whereas four were not. A complete resolution of all these side-effects was achieved in all cases. Significant improvements were registered for all the four clinical variables. At the end of the study 56.5% of patients expressed a preference for etodolac, 16.5% for one of the non-steroidal anti-inflammatory drugs previously taken and 27% did not answer or were not able to express any definite preference. Strict concordance was found between the degree of clinical improvement achieved and the preferences expressed. The laboratory parameters did not reveal any variation at the end of the study in comparison with baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)

Etodolac has been shown to have a favorable safety profile in short-term and long-term studies in both osteoarthritis (OA) and rheumatoid arthritis (RA). Two studies were conducted to further assess the gastrointestinal (GI) safety profile of this drug. These studies were designed to compare the therapeutic efficacy and upper GI effects of etodolac (600 mg/day) and naproxen (1000 mg/day) administered over 4 weeks in patients with active rheumatoid arthritis. In addition, the relative effects of the drugs on prostaglandin levels in the stomach and duodenum were assayed in one study. Fifteen patients were included in each study and received either 300 mg b.i.d. of etodolac or 500 mg b.i.d. of naproxen. In both studies, endoscopic examinations were performed on day 1 of the study and again 4 weeks later. In the second study, at the time of each endoscopy, samples of gastric and duodenal mucosa were taken for histologic study and prostaglandin assay. Endoscopy results from the first study showed significant differences in favor of etodolac between the two treatment groups. In the second study more naproxen-treated patients had abnormal endoscopy results than did etodolac-treated patients. Results from prostaglandin assays in gastric and duodenal mucosa showed no overall suppression of gastric or duodenal prostaglandin levels for etodolac-treated patients in contrast to naproxen-treated patients, who showed suppression of PGE2 and PGI2. The results of these studies show that etodolac therapy caused less gastric and duodenal injury than naproxen and also support the theory that the GI safety of etodolac may be due to selective sparing of cytoprotective prostaglandins.

Numerous clinical trials have shown etodolac to be an effective analgesic. The purpose of the present report is to review results of 14 studies that demonstrate the effectiveness of etodolac in a variety of painful conditions. Presented are the results of four postsurgical pain studies, one study of acute gouty arthritis and nine studies of acute musculoskeletal disorders: acute low back pain, acute painful shoulder, tendinitis and bursitis, and acute sports injuries. A single oral dose of etodolac (25, 50, 100, 200, or 400 mg) was compared with aspirin (650 mg) or a combination of acetaminophen (600 mg) plus codeine (60 mg) for the relief of pain up to 12 h following oral, urogenital or orthopedic surgery. In multiple dose studies of acute gouty arthritis and musculoskeletal conditions, etodolac 200 or 300 mg twice a day (b.i.d.) or 200 mg three times a day (t.i.d.) was compared with naproxen 500 mg b.i.d. or t.i.d., diclofenac 50 mg b.i.d. or t.i.d., and piroxicam 20 or 40 mg once a day (o.d.) administered over 5 to 14 days. The efficacy of etodolac was at least equal and in some ways superior to aspirin and acetaminophen plus codeine in the relief of postsurgical pain. In studies of acute gouty arthritis, significant improvement from baseline were seen for all efficacy parameters evaluated for both the etodolac- and naproxen-treated patients. All the present studies of musculoskeletal conditions have shown etodolac to be effective and comparable in analgesic efficacy to naproxen, diclofenac or piroxicam. In summary, etodolac therapy for pain following surgery, in acute gouty arthritis and in acute musculoskeletal conditions resulted in analgesia comparable to that provided by several well-established analgesic or anti-inflammatory agents.

Two large-scale open-label studies were performed in France to confirm the efficacy and safety of etodolac (Lodine), a new non-steroidal anti-inflammatory drug (NSAID). Study I, a 6-week study performed by 974 rheumatologists, involved 4947 patients who had rheumatoid arthritis (RA), ankylosing spondylitis (AS), or osteoarthritis (OA). Both efficacy and safety were assessed. Study II, a postmarketing safety study performed by approximately 9000 general practitioners, involved 51,355 patients who had rheumatic conditions requiring therapy with NSAIDs. The daily dose of etodolac ranged from 200 to 600 mg/day in these studies, depending on the protocol and patient response. By the end of study I (visit 3), spontaneous pain improved by 33% for patients with RA, by 42% for patients with AS, and by 50% for OA patients. A total of 1276 adverse reactions (AR) were reported during the study, and fewer than half of these were related to study treatment. Only 6 severe reactions were reported; three of these were considered unrelated to study treatment, including 2 deaths. In study II, 10.1% of patients reported 6236 ARs and 9.0% of patients dropped out because of AR. Twenty-one of the ARs reported in study II were judged severe, and all of these patients recovered completely. The overall opinion of safety was assessed as very good or good by 89% of patients. In both studies (greater than 55,000 patients), 11% of patients reported an AR, and severe reactions were rare. These results confirmed the very acceptable risk/benefit ratio of etodolac and rank this drug high for efficacy and safety among the NSAIDs recently introduced in France.

A double-blind study was carried out to compare the effectiveness and tolerability of two non-steroidal anti-inflammatory drugs, etodolac and piroxicam, in patients with osteoarthritis of the knee. Sixty-five patients with active, radiologically verified osteoarthritis were randomly assigned to receive either 300 mg etodolac twice a day (33 patients) or 20 mg piroxicam once a day (32 patients) for 8 weeks. Effectiveness was measured by changes in the patients' and physician's overall evaluations, pain intensity, and night pain, recorded on 5-point scales. Other efficacy assessments included tenderness on pressure, the degree of swelling, knee flexion, the time needed to walk 50 feet, and duration of morning stiffness. After 4 weeks of therapy, mean values for patients' and physician's global evaluations, pain intensity, and night pain were significantly improved from baseline values in both treatment groups. Improvement continued throughout the study. Significant improvement in the other efficacy assessments was seen in both treatment groups after 4 weeks of therapy. There were no significant differences between the treatment groups in any efficacy assessment at any observation. Three etodolac-treated patients and 2 piroxicam-treated patients withdrew from the study because of adverse events. The results of this study indicate that 600 mg etodolac per day is as effective as 20 mg piroxicam per day in the treatment of osteoarthritis.

Etodolac is a new nonsteroidal anti-inflammatory drug (NSAID). Published and unpublished data on etodolac in pain management are reviewed to assess the analgesic effectiveness of this drug. Data are presented from four representative studies that showed the analgesic activity of etodolac in postsurgical pain models. These results suggest that the drug would have analgesic utility in other painful conditions such as gout and musculoskeletal disorders. The efficacy of etodolac in such conditions is confirmed by the results from eight controlled clinical studies in patients with gouty arthritis, tendinitis and bursitis, and acute sports injuries. Etodolac 200 or 300 mg twice a day (b.i.d.) or 200 mg three times a day (t.i.d.) was compared with naproxen 500 mg b.i.d. and diclofenac 50 mg b.i.d. or 50 mg t.i.d. All three NSAIDs provided analgesia, and etodolac was comparable in efficacy to the comparators. The data presented in this review suggest a future role for etodolac as an analgesic as well as an anti-inflammatory agent.

Etodolac is a new nonsteroidal anti-inflammatory drug (NSAID) that has shown a favorable safety profile in clinical trials in osteoarthritis (OA) and rheumatoid arthritis (RA). Four postmarketing surveillance studies were conducted with patients who had OA and RA to further assess the safety of etodolac. One study also had patients with ankylosing spondylitis (AKS). These studies were conducted in Italy, Switzerland, the United Kingdom, and France. A total of 8334 patients received oral doses of 200 to 600 mg/day for periods ranging from 4 weeks to 1 year. The incidence of study events was low, 77% of the patients treated in these postmarketing surveillance studies reported no study events. Only 9% of all the patients treated withdrew from these studies because of adverse effects. Gastrointestinal events were the most commonly reported among the study events that did occur, as expected for an NSAID. These results further support the safety of etodolac that was previously established in clinical trials.

Maintenance therapy with proglumetacin was studied in an open investigation in 25 patients with classical or definite rheumatoid arthritis and in 34 patients with osteoarthrosis. Proglumetacin (150 mg) was administered twice daily, at meals, and therapy was continued without interruption for 12 months. Patients with rheumatoid arthritis showed a progressive improvement in objective parameters (erythrocyte sedimentation rate, haemoglobin) and in semi-objective parameters (pain, articular tenderness, number of painful joints, morning stiffness, grip strength, Ritchie articular index). Patients with osteoarthrosis also showed a progressive improvement in objective parameters (movement angles of the affected joints) and in subjective parameters (pain, mobility, response to therapy). During the study, 4 patients reported occasional nausea (3 with vomiting), and 3 reported episodes of slight headache. These symptoms did not require interruption of treatment. Haematology, blood chemistry and urinalysis were not adversely affected by the treatment. Five drop-outs were recorded in the rheumatoid arthritis group: 2 because patients failed to report, 2 because of severe relapses which required a radical change in the therapeutic programme and 1 for incorrect enrollment. Fourteen drop-outs were recorded in the osteoarthrosis group: 6 because the patients failed to report, 4 because of orthopaedic surgery and 4 because it was necessary to change the therapeutic programme. No drop-out was due to an intolerance to proglumetacin. It is concluded that proglumetacin appears to have the effectiveness of tolerability features required for a first-choice medicament for long-term maintenance treatment of patients with rheumatoid arthritis or with osteoarthrosis.

In a controlled double blind study the therapeutic efficacy and tolerability of [1-(p-chlorobenzoyl)-5-methoxy-2-methylindol-3-acetoxy] acetic acid (acemetacin, TV 1322, Rantudil¿) and tolmetin were compared in 40 patients suffering from acute and subacute painful irritant conditions in the spinal area and joints. The maximal duration of the study was 20 days. In the case of acemetcin the daily dose was 90 mg and in the case of tolmetin it was 600 mg. The clinical symptoms kinesalgia, pain caused by pressure, and functional impairment were significantly improved by both acemetacin and tolmetin. A comparison of the two therapy groups did not reveal any difference. Also a statistical comparison of the evaluations of the therapeutic efficacy by the physician did not reveal any significant difference, although the assessment "very good" occurred twice as frequently in the acemetacin group (13 out of 20) as in the tolmetin group (6 out of 20). In only one patient treated with tolmetin undesired drug reactions occurred. These resulted in discontinuation of the therapy. No side effects occurred in the acemetacin group. Acemetacin, which in experimental animal investigations not only showed an antiinflammatory but also an analgesic effect, is according to the results of our study also suitable for the therapy of symptoms in which the analgesic efficacy of a drug decisively influences the therapeutic success.

Non-steroidal antiinflammatory drugs (NSAID) are indispensable for modern treatment of rheumatoid arthritis. Reports on drug concentration in rheumatoid human tissues are still lacking. We now report about steady-state concentrations of Indomethacin and Acemetacin in blood, synovial fluid, synovial membrane, muscle, bone and fat 6h after the last application of Acemetacin resp. Indomethacin. Levels in all tissues, except fat, were found to be significantly higher than in blood. Therefore, a noticeable accumulation of drug occurs in all rheumatoid tissues.

Proglumetacin was administered as a sole treatment during 15 days at 450 mg/day to 20 patients with osteoarthritis localized in several joints. Within the observation period, pain at rest and on loading, joint mobility and morning stiffness improved significantly. Tolerance also resulted very good, as only two patients reported mild and transient gastric upsets. The peculiar combination of good efficacy also in short-term treatment and very good tolerance, points to proglumetacin as a drug of choice for the ambulatory management also of degenerative-reactive joint disorders.

Thirty patients with articular pain had been treated with proglumetacin during average 12 days. Twenty-three (77%) responded well to very well to the treatment. Total symptom score decreased by 49%, and each tested symptom (painful, inflammatory and functional) significantly improved, in spite of the short observation period. Tolerance was defined good to excellent in 26 patients (87%). Overall, 10 patients complained of mild to moderate accessory symptoms, mainly heartburn and epigastric pain. No C.N.S. symptoms were observed, nor variations of the laboratory tests, carried out in 16 patients. Proglumetacin, therefore, showed to be a suitable drug for the fast and safe management of articular pain of orthopedic interest.

Forty out-patients with acute 'flare' of chronic rheumatoid arthritis were treated orally with either 150 mg proglumetacin or 250 mg naproxen twice daily over 3 weeks, according to a randomized, double-blind design. Before and after 1 and 3 weeks of treatment, the number of painful and of swollen joints, the intensity of pain and function tests (morning stiffness, time to walk over 15 metres and hand grip strength) were measured and recorded. Haematology was investigated before and after treatment. Two patients in the proglumetacin group did not report to control and were considered drop-outs; 2 more (1 in each group) interrupted treatment before completion because of the onset or aggravation of accessory symptoms. Efficacy, assessed in 17 patients on proglumetacin and in 19 on naproxen, was good with both drugs, even though only those patients given proglumetacin experienced a significant (p less than 0.01) decrease in the number of painful joints. None of the haematological tests showed clinically significant variations after either treatment. Tolerance could be assessed in 18 and 20 patients given proglumetacin or naproxen, respectively. Accessory symptoms appeared or were aggravated in 5 and 3 patients, respectively.

Etodolic acid (1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano(3, 4-b) indole-1-acetic acid) showed potent anti-inflammatory and analgesic properties in rats. In adjuvant arthritic rats etodolic acid was approximately six times more potent than phenylbutazone. In the carrageenin and the analgesic assays (inflamed paw pressure test) its potency was comparable to that of phenylbutazone. The potency of etodolic acid in the adjuvant arthritic rat suggests that this novel anti-inflammatory compound will be effective in the treatment of arthritic conditions of man.

In an open clinical study the anti-inflammatory effect and tolerability of the new non-steroidal drug, [1-(p-chlorobenzoyl)-5-methoxy-2-methylindol-3-acetoxy] acetic acid (acemetacin, TV 1322, Rantudil) were investigated on 12 female and 10 male patients aged between 20 and 67 years and suffering from the following syndromes: vasculitis, thrombophlebitis, erythematodes cutaneus, morbus Reiter, atopic dermatitis, non-specific prostatitis, periarteriitis nodosa, pemphigus vulgaris and dermatitis herpetiformis Duhring. Although the number of patients treated with the anti-inflammatory agent, acemetacin, was relatively small it was established that for in correct indications acemetacin had a good analgesic effect and reduced the consumption of cortison. Particularly interesting was the fact that no side effects occurred in any of the patients.

The efficacy of proglumetacin , a new non-steroidal antiinflammatory drug, was assessed in 32 patients with rheumatoid arthritis. During treatment with 400-650 mg daily of proglumetacin over a period of 7-14 days, morning stiffness and side-effects were checked weekly or in severely ill patients daily. All patients but one completed the period of treatment. In spite of the short period of observation, a significant improvement was seen in the majority of cases (55%), while in 39% proglumetacin was not more effective than treatments before the admission to the study. In the group of patients treated for 14 days, morning stiffness parameters showed a significant improvement after 7 days and at the end of the period of study. Overall , only 3 patients referred side-effects: 1 case of transient headache and 2 cases of severe gastric pain. In our preliminary study, proglumetacin results to be effective as an antiinflammatory drug also in severe rheumatoid arthritis and safe for its low incidence of side-effects.

The authors report the results of an open clinical study of 60 outpatients of whom 20 were suffering from rheumatoid arthritis and 40 from osteoarthritis. The study was aimed at evaluating the efficacy and tolerability of the new indole derivative acemetacin and at a comparison with etodolac. The drug studied was found to be effective and to be tolerated better than indomethacin, particularly the absence of the most unpleasant side-effect of indole compounds, i.e., headache, was noted.

Ninety-seven patients (44 males and 53 females of mean age 42.6 +/- 12,9 years) with orthopedic-traumatologic disorders (osteoarthritis, 38; painful joints, 26; fibrositis, painful shoulder, 20; peri- and extra-articular disorders, 13) had been treated during 7 to 30 days with two suppositories (400 mg) or three capsules (450 mg) proglumetacin (Proxil Rorer). Most patients responded well to very well to the treatment with significant improvement of pain and inflammatory symptoms as well as restoring of limited function. Such a response resulted proportional to the dose (53% of good responders among those given the lower dose and 82% among those at the higher dose) and to the kind of pathology. The patients with acute disorders (7) responded all very well in 7 days; those with subacute disorders (57) responded well to very well in a proportion of 57% within 15 days; those with chronic disorders responded to a proportion of 48% within 30 days. Tolerance resulted very good anyway: in no case had the treatment to be withdrawn, nor allergic or C.S.N. reactions were observed, so that the overall tolerance was defined excellent to good in 90% of patients. Thirty-three patients complained of accessory symptoms, mainly epigastric pain and nausea, almost always mild and anyway transient. Proglumetacin can therefore be properly defined as a firstchoice treatment for the management, also ambulatory, of orthopedic-traumatologic disorders.

Efficacy, safety and therapeutic benefit of etodolac (Lodine 200) in rheumatological practice. An open clinical trial performed by 974 rheumatologists enabled an evaluation of efficacy, safety and therapeutic benefit of etodolac (Lodine 200) on 4,947 patients with rheumatoid arthritis, ankylosing spondylitis and osteoarthritis of the lower limbs; the initial dosage was 600 mg/d (for 2 weeks), then 400 to 600 mg/d (for 2 to 4 weeks, according to the indication). Efficacy, assessed by classical items for NSAID's, was shown to be excellent to good by 61-77 p. 100 of patients, according to the indication. 7.7 p. 100 of patients only dropped out for lack of efficacy. 20.4 p. 100 of patients developed adverse effect(s) (AE), but the relationship between etodolac and AE was assessed "possible" or "probable" only for 9.6 p. 100 of patients; this figure should be compared to the 7.6 p. 100 of patients who dropped out for AE and to the 92 p. 100 of patients who assessed the global safety as "excellent or good". The therapeutic benefit was estimated very favorable: 75 p. 100 of patients felt better than at the beginning of the study, 64.5 p. 100 of patients wished to continue the treatment and the (mean) benefit-risk ratio assessed with a logarithm scale (-1 to +1), ranged from 0.45 to 0.6 according to the indication. Therefore, this trial confirmed the good efficacy and safety profile of etodolac on a large scale in normal clinical practice in France, following assessments during controlled trials. It also permitted to perfect new items of evaluation for NSAID's, in particular for therapeutic benefit.

Twenty patients with inflammatory (15) or degenerative (5) joint disorders had been treated with 450 mg/day of proglumetacin during 35 +/- 18 days. Articular symptoms showed a definite and continued improvement, particularly evident during the initial 15 days of treatment on both painful and inflammatory components. The final physician's evaluation rated 75% of results as excellent or good, versus 15% of poor (3 patients, one of whom already refractory to diclofenac). The tolerance was defined as excellent to good in 90% of patients: one (5%) was dropped out upon the onset of sweating and palpitation, already observed with other drugs. Overall, only one case each of heartburn, anorexia and diarrhoea were considered as possibly related to the treatment. Laboratory tests did not show any variation that could be attributed to the drug. Proglumetacin therefore, by force of its efficacy and safety, appears to be particularly suited as a first-choice drug for the management of both inflammatory and degenerative joint disorders.

The synthesis of 4,6-diethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-4-acetic acid, an isomer of the antiinflammatory agent etodolac, is described. The compound was found to have an ED50 of 3 mg/kg po in the rat curative adjuvant arthritis assay, and an IC50 of 50 nM for inhibiting prostaglandin production in cultured chondrocytes.