Pharmacological treatment for familial amyloid polyneuropathy.

BACKGROUND: Disease-modifying pharmacological agents for transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on their efficacy and safety is limited. This review focuses on disease-modifying pharmacological treatment for TTR-related and other FAPs, encompassing amyloid kinetic stabilisers, amyloid matrix solvents, and amyloid precursor inhibitors. OBJECTIVES: To assess and compare the efficacy, acceptability, and tolerability of disease-modifying pharmacological agents for familial amyloid polyneuropathies (FAPs). SEARCH METHODS: On 18 November 2019, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We reviewed reference lists of articles and textbooks on peripheral neuropathies. We also contacted experts in the field. We searched clinical trials registries and manufacturers' websites. SELECTION CRITERIA: We included randomised clinical trials (RCTs) or quasi-RCTs investigating any disease-modifying pharmacological agent in adults with FAPs. Disability due to FAP progression was the primary outcome. Secondary outcomes were severity of peripheral neuropathy, change in modified body mass index (mBMI), quality of life, severity of depression, mortality, and adverse events during the trial. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: The review included four RCTs involving 655 people with TTR-FAP. The manufacturers of the drugs under investigation funded three of the studies. The trials investigated different drugs versus placebo and we did not conduct a meta-analysis. One RCT compared tafamidis with placebo in early-stage TTR-FAP (128 randomised participants). The trial did not explore our predetermined disability outcome measures. After 18 months, tafamidis might reduce progression of peripheral neuropathy slightly more than placebo (Neuropathy Impairment Score (NIS) in the lower limbs; mean difference (MD) -3.21 points, 95% confidential interval (CI) -5.63 to -0.79; P = 0.009; low-certainty evidence). However, tafamidis might lead to little or no difference in the change of quality of life between groups (Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score; MD -4.50 points, 95% CI -11.27 to 2.27; P = 0.19; very low-certainty evidence). No clear between-group difference was found in the numbers of participants who died (risk ratio (RR) 0.65, 95% CI 0.11 to 3.74; P = 0.63; very low-certainty evidence), who dropped out due to adverse events (RR 1.29, 95% CI 0.30 to 5.54; P = 0.73; very low-certainty evidence), or who experienced at least one severe adverse event during the trial (RR 1.16, 95% CI 0.37 to 3.62; P = 0.79; very low-certainty evidence). One RCT compared diflunisal with placebo (130 randomised participants). At month 24, diflunisal might reduce progression of disability (Kumamoto Score; MD -4.90 points, 95% CI -7.89 to -1.91; P = 0.002; low-certainty evidence) and peripheral neuropathy (NIS plus 7 nerve tests; MD -18.10 points, 95% CI -26.03 to -10.17; P < 0.001; low-certainty evidence) more than placebo. After 24 months, changes from baseline in the quality of life measured by the 36-Item Short-Form Health Survey score showed no clear difference between groups for the physical component (MD 6.10 points, 95% CI 2.56 to 9.64; P = 0.001; very low-certainty evidence) and the mental component (MD 4.40 points, 95% CI -0.19 to 8.99; P = 0.063; very low-certainty evidence). There was no clear between-group difference in the number of people who died (RR 0.46, 95% CI 0.15 to 1.41; P = 0.17; very low-certainty evidence), in the number of dropouts due to adverse events (RR 2.06, 95% CI 0.39 to 10.87; P = 0.39; very low-certainty evidence), and in the number of people who experienced at least one severe adverse event (RR 0.77, 95% CI 0.18 to 3.32; P = 0.73; very low-certainty evidence) during the trial. One RCT compared patisiran with placebo (225 randomised participants). After 18 months, patisiran reduced both progression of disability (Rasch-built Overall Disability Scale; least-squares MD 8.90 points, 95% CI 7.00 to 10.80; P < 0.001; moderate-certainty evidence) and peripheral neuropathy (modified NIS plus 7 nerve tests - Alnylam version; least-squares MD -33.99 points, 95% CI -39.86 to -28.13; P < 0.001; moderate-certainty evidence) more than placebo. At month 18, the change in quality of life between groups favoured patisiran (Norfolk QOL-DN total score; least-squares MD -21.10 points, 95% CI -27.20 to -15.00; P < 0.001; low-certainty evidence). There was little or no between-group difference in the number of participants who died (RR 0.61, 95% CI 0.21 to 1.74; P = 0.35; low-certainty evidence), dropped out due to adverse events (RR 0.33, 95% CI 0.13 to 0.82; P = 0.017; low-certainty evidence), or experienced at least one severe adverse event (RR 0.91, 95% CI 0.64 to 1.28; P = 0.58; low-certainty evidence) during the trial. One RCT compared inotersen with placebo (172 randomised participants). The trial did not explore our predetermined disability outcome measures. From baseline to week 66, inotersen reduced progression of peripheral neuropathy more than placebo (modified NIS plus 7 nerve tests - Ionis version; MD -19.73 points, 95% CI -26.50 to -12.96; P < 0.001; moderate-certainty evidence). At week 65, the change in quality of life between groups favoured inotersen (Norfolk QOL-DN total score; MD -10.85 points, 95% CI -17.25 to -4.45; P < 0.001; low-certainty evidence). Inotersen may slightly increase mortality (RR 5.94, 95% CI 0.33 to 105.60; P = 0.22; low-certainty evidence) and occurrence of severe adverse events (RR 1.48, 95% CI 0.85 to 2.57; P = 0.16; low-certainty evidence) compared to placebo. More dropouts due to adverse events were observed in the inotersen than in the placebo group (RR 8.57, 95% CI 1.16 to 63.07; P = 0.035; low-certainty evidence). There were no studies addressing apolipoprotein AI-FAP, gelsolin-FAP, and beta-2-microglobulin-FAP. AUTHORS' CONCLUSIONS: Evidence on the pharmacological treatment of FAPs from RCTs is limited to TTR-FAP. No studies directly compare disease-modifying pharmacological treatments for TTR-FAP. Results from placebo-controlled trials indicate that tafamidis, diflunisal, patisiran, and inotersen may be beneficial in TTR-FAP, but further investigations are needed. Since direct comparative studies for TTR-FAP will be hampered by sample size and costs required to demonstrate superiority of one drug over another, long-term non-randomised open-label studies monitoring their efficacy and safety are needed.

Non-steroidal anti-inflammatory drug (NSAID)-derived poly(anhydride-esters) in bone and periodontal regeneration.

Bioresorbable polymers offer the potential to deliver biologically active agents that selectively modulate wound healing in bone and periodontal regeneration. This preliminary study characterizes early wound healing in calvarial defects grafted with demineralized bone matrix (DBM) overlaid with membranes made from a novel class of non-steroidal anti-inflammatory drug (NSAID)-derived poly(anhydride-esters). These polymers chemically incorporate either salicylic acid (SA) or 5-(2',4'-difluorophenyl)salicylic acid (diflunisal) into the polymeric backbone and release the NSAIDs upon hydrolysis. Inflammatory cell infiltrate in response to the novel NSAID-derived polymers was compared to defects grafted with DBM alone at 10 days and to defects grafted with DBM and overlaid with poly(lactic acid) (PLA; Atrisorb) at 21 days in 8 Wistar rats (350-450 g). Histological analysis of the calvarial sites at 10 days revealed that the NSAID-derived polymers were associated with moderate levels of inflammation similar to defects grafted without polymer (2.3 +/- 0.96 versus 2.0 +/- 0.82, respectively), consistent with the therapeutic activity of salicylic acid and diflunisal. Defects grafted with DBM and overlaid with NSAID-derived polymers at 21 days exhibited mild inflammation; whereas, defects treated with PLA were consistently associated with moderate to severe inflammatory cell infiltrate (1.8 +/- 0.50 versus 2.7 +/- 0.58, respectively). Histopathological findings, such as foreign body giant cells or fibrous encapsulation, were not observed in any defects with NSAID-derived polymers. Cellular features consistent with bone formation were found in all grafted defects. This novel class of non-steroidal anti-inflammatory drug-derived poly(anhydride-esters) were well tolerated and elicited no demonstrable increase in inflammation, as shown with PLA, during osseous wound healing in a regenerative application.

Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis.

BACKGROUND: A recent 2-year randomized controlled trial indicated that the transthyretin (TTR) tetramer stabilizer, diflunisal, inhibits polyneuropathy progression and preserves quality of life in hereditary ATTR amyloidosis. However, its long-term outcomes are unknown. Here, we report tolerance and efficacy of long-term diflunisal administration in hereditary ATTR amyloidosis. METHODS: Diflunisal was administered orally at 500 mg/day to 40 Japanese hereditary ATTR amyloidosis patents who were not candidates for liver transplantation. The observation period ranged from 2 to 116 months (mean ± SD: 38.0 ± 31.2 months). RESULTS: Diflunisal-related adverse events included deterioration of renal function and thrombocytopenia resulting in discontinuation of the drug in three patients. Orally administered diflunisal significantly increased serum TTR concentration (p = 0.001) and stabilized TTR tetramer structure in each patient. Longitudinal analyses of data collected at baseline, 24 months, and after 24 months confirmed sustaining effects of diflunisal on both neurological and cardiac functions. Notably, ulnar compound muscle action potential amplitude, cardiac wall thickness, and ejection fraction were not deteriorated after 24 months of treatment. CONCLUSIONS: Diflunisal was tolerated well by most hereditary ATTR amyloidosis patients, although renal function and blood cell counts must be carefully monitored. Clinical effects of diflunisal were sustained after 2 years of treatment.

A double-blind study of diflunisal and codeine compared with codeine or diflunisal alone in postoperative pain.

A double-blind, randomized, parallel-group study compared the analgesic efficacy of a single oral dose of 500 mg diflunisal, 60 mg codeine, 500 mg diflunisal plus 60 mg codeine given as separate agents, and placebo in 161 patients with moderate to severe postoperative pain. Standard subjective measures were used to evaluate analgesia. Eight-hour sum of pain intensity differences and total pain relief scores for all active treatments were significantly better than were those for placebo (p less than 0.05). Diflunisal plus codeine performed the best followed by diflunisal, codeine, and placebo. Diflunisal plus codeine was better than placebo from 1 1/2 to 8 hours (p less than 0.01), better than codeine from 1 1/2 to 6 hours (p less than 0.05), and better than diflunisal alone from 1/2 to 1 1/2 hours (p less than 0.05) for most measures of analgesia. Factorial analysis demonstrated a significant early codeine effect and a significant diflunisal effect throughout. No significant treatment group differences were observed regarding adverse effects. Our data demonstrate that diflunisal plus codeine is generally well tolerated and provides analgesia superior to that of diflunisal or codeine alone in the treatment of moderate to severe postoperative pain.

Diflunisal: a review of its pharmacological properties and therapeutic use in pain and musculoskeletal strains and sprains and pain in osteoarthritis.

Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It has been studied in osteoarthritis, pain resulting from musculoskeketal sprains and strains and from minor surgery and cancer. The duration of its analgesic effect is longer than that of aspirin and diflunisal is effective when given twice daily. Diflunisal is not metabolised to salicylic acid and has a lesser effect than aspirin on platelet function in vivo. In osteoarthritis, diflunisal appears comparable in efficacy to moderate doses of aspirin (2 to 3g daily), but is better tolerated. It has not been compared with the most active phenylalkanoic acid derivatives such as naproxen in adequate numbers of patients. Diflunisal is comparable with glafenine in pain and with propoxyphene/paracetamol combinations and oxyphenbutazone in pain and in musculoskeletal strains and sprains. As with other non-steroidal agents, gastrointestinal complaints are the most frequently reported side effects.

A case of eosinophilic pneumonia and vasculitis induced by diflunisal.

Drug-induced pneumonitis is an uncommon complication of nonsteroidal anti-inflammatory drug administration. Herein is the first reported case of pneumonitis resulting from diflunisal therapy. The patient demonstrated clinical and biopsy evidence of systemic vasculitis. She responded dramatically to administration of systemic glucocorticoids.

A 12-hour evaluation of the analgesic efficacy of diflunisal, aspirin, and placebo in postoperative dental pain.

Two-hundred and one outpatients with postoperative pain following oral surgery were randomly assigned, on a double-blind basis, a single oral dose of diflunisal (250, 500, or 1000 mg), aspirin (650 mg), or placebo. Using a self-rating record, the subjects rated their pain and its relief hourly for 12 hours after medication. Measures of peak and total analgesia were derived from the patients' subjective reports. Diflunisal 250 and 1000 mg were significantly superior to aspirin for every measure of total and peak analgesia; the 500-mg diflunisal dose was significantly superior to aspirin for measures of total analgesia only. All doses of diflunisal were significantly superior to aspirin and placebo at each hour from hour 3 through hour 12. Approximately 60 per cent of the patients treated with diflunisal completed the 12-hour observation period without the need for additional analgesic therapy. Adverse effects were mild and transitory and occurred in less than 10 per cent of the patients.

A multiple-dose comparison of ketorolac tromethamine with diflunisal and placebo in postmeniscectomy pain.

The efficacy of oral ketorolac 5 mg and 10 mg taken qid was compared in a randomized double-blind study with that of oral diflunisal 500 mg bid (interleaved with placebo twice daily) and of placebo, in 120 patients suffering at least moderate pain following meniscectomy. The trial comprised two phases: (1) an acute phase (the first postoperative day) and (2) a chronic phase (days 2-5 postoperatively). Acutely, pain was assessed before drug administration, and then 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, and 9.0 hours after the first dose. The second of the four daily doses was administered at four hours after the first dose. During the chronic phase, pain was assessed using visual analogue scales at 8 AM and 4 PM daily. The acute phase results show that all the active treatments were statistically significantly superior to placebo but were not distinguished from each other. Over the chronic phase, ketorolac 5 mg and placebo showed similar results, with diflunisal showing the least pain relief and ketorolac 10 mg the most. All the active treatments showed a low incidence of side effects and, in an overall evaluation, no one treatment was distinguishable. Ketorolac would seem to be an acceptable therapy for acute postoperative pain.

Diflunisal versus placebo for treatment of pain in general practice.

The efficacy and safety of diflunisal versus placebo in the treatment of pain were compared in a multicenter, double-blind study of 1,037 patients treated for seven days by general practitioners. A statistically significant (P less than 0.001) difference in favor of diflunisal was seen using four evaLuation criteria. The incidence of side effects was generally low with both treatments; nevertheless, the number of patients suffering at least one side effect was greater after diflunisal than after placebo (P less than 0.05). A comparison of the profile of responders to diflunisal and to placebo showed no particular pattern.

Diflunisal versus naproxen in the management of rheumatoid arthritis.

Diflunisal (500 mg orally, twice daily) and naproxen (375 mg orally, twice daily) were compared for efficacy and tolerability in a 12-week open-label study in 33 patients with active rheumatoid arthritis (RA). Both drugs resulted in marked reduction in the number of swollen, tender, and painful joints and comparable improvement in patients' assessment of disease activity and pain. There were no significant differences between the two medications in the measured indices of disease activity. No adverse experiences were reported by patients in either treatment group. The results indicate that both diflunisal and naproxen were equally effective and that both agents are generally well tolerated in this group of patients with RA.

Comparison of diflunisal and piroxicam in the management of patients with rheumatoid arthritis.

The efficacy and tolerability of diflunisal (500 mg orally, twice daily) and piroxicam (20 mg orally, once daily) were compared in a 12-week open-label study in 44 patients with active rheumatoid arthritis. Both medications were equally effective and generally well tolerated. No significant differences were found between drug groups. Both groups showed statistically significant improvement in the overall number of swollen and tender joints, painful joint count, and the patients' assessment of pain and disease severity. Two (9%) of 23 patients in the diflunisal group and one (5%) of 21 patients in the piroxicam group reported adverse effects. Only one patient withdrew from the study because of side effects (lightheadedness during use of diflunisal). It is concluded that both diflunisal and piroxicam are highly effective and generally well tolerated in the management of rheumatoid arthritis.

Comparison of diflunisal and an aspirin-codeine combination in the management of patients having one-visit endodontic therapy.

One hundred seventy-nine patients with asymptomatic or mildly symptomatic endodontic disease had single-visit therapy and were given either diflunisal (n = 94) or aspirin with codeine (n = 85) to control posttreatment pain. In this open-label, randomized study, diflunisal was judged superior to the aspirin-codeine combination in all major categories evaluated. Of patients receiving diflunisal, 93.6% needed the medication for only one day. In contrast, 77.7% of patients receiving aspirin with codeine needed the medication for only one day. Almost 64% of patients receiving diflunisal needed only one dose, while 32.9% of patients using aspirin with codeine needed only one dose. Four or more doses were required by 5.3% of patients receiving diflunisal and by 23.5% of patients receiving the aspirin-codeine combination. In patients receiving diflunisal, 20.2% experienced side effects. In contrast, 29.4% of patients receiving aspirin with codeine reported side effects. Thirty-five percent of patients receiving diflunisal rated the analgesic as excellent; 5.3% rated it as fair or poor. In contrast, 12.9% of patients receiving aspirin with codeine rated the analgesic combination as excellent; another 12.9% rated it as fair or poor. Diflunisal was found to be generally effective and well-tolerated, and superior to aspirin with codeine in the management of pain from endodontic treatment.

A comparison of the efficacy and tolerability of diflunisal and dextropropoxyphene napsylate with acetaminophen in the management of mild to moderate pain after arthroscopy of the knee.

We conducted an open-label randomized clinical trial comparing the efficacy and tolerability of diflunisal and dextropropoxyphene napsylate with acetaminophen (DPN-A) in the management of mild to moderate pain following arthroscopic surgery of the knee. Patients used a self-rating pain scale to evaluate the analgesia provided by each medication. Twenty-six patients completed the study; 12 received diflunisal and 14 received DPN-A. The physicians found no significant differences between the two groups in their preoperative or postoperative assessment of pain, tenderness, swelling, and active range of motion. There were no statistically significant differences between the two groups' mean pain scores or assessment of the overall efficacy of their respective drugs. No patient in either treatment group reported any adverse effects.

Diflunisal and ibuprofen: effects on gastric and duodenal mucosa in patients with osteoarthritis.

Patients with osteoarthritis make up the largest group of users of nonsteroidal anti-inflammatory drugs (NSAIDs), but the effects of these agents on the gastrointestinal mucosa of such patients have not been well studied. This article describes a short-term comparison of two widely used NSAIDs, diflunisal and ibuprofen, in patients requiring these medications for their osteoarthritis. Efficacy, tolerability, and endoscopically documented effects of these drugs on the gastric and duodenal mucosa were assessed. Consenting, eligible patients were randomly assigned to one of the two study drugs for a two-week course. Clinical assessments were made after each week of treatment. Fiberoptic endoscopy and laboratory tests were performed before and after the treatment period. Thirty patients completed the study: 16 received diflunisal and 14 received ibuprofen. Similar improvements in pain, joint mobility, functional capacity, and joint swelling and tenderness were observed in both treatment groups. Transient, mild abdominal cramping was reported by two patients in each group; one patient receiving ibuprofen complained of transient dizziness. No patient withdrew from the study because of side effects. Follow-up endoscopy revealed slight (grade 1) changes in the gastric mucosa of two patients in each treatment group. An additional patient in the ibuprofen group had gastric erosions (grade 2) at the end of the study. Endoscopic changes were not correlated with symptoms. Diflunisal and ibuprofen were found to be similarly effective and well tolerated in the treatment of osteoarthritis. Their use may be associated with some gastrointestinal side effects even during short-term use.

A double-blind comparison of flurbiprofen with diflunisal in the treatment of acute ankle sprains and strains.

Fifty patients with acute ankle sprains/strains were treated with either 100 mg flurbiprofen or 500 mg diflunisal twice daily in a double-blind fashion for 18 days or until symptoms of the injury resolved. Tolerability of the drugs was evaluated by recording the occurrence of adverse drug reactions and monitoring laboratory parameters. Efficacy measurements were performed at enrollment and at Visit 2-Day 7, Visit 3-Day 14 and Visit 4-Day 21 to determine relief of symptoms and return to normal activities. Patients in both treatment groups exhibited marked improvement by Visit 2-Day 7 with almost complete recovery by Visit 3-Day 14. Flurbiprofen patients had a significantly shorter duration of therapy. Results from three of the six physician assessments were marginally to significantly superior for patients in the flurbiprofen group. The only reported adverse event was mild gastro-intestinal intolerance in a patient receiving diflunisal. Flurbiprofen and diflunisal appear to be effective and well-tolerated medications for the treatment of acute ankle sprains and strains.

Double-blind parallel study of meptazinol versus diflunisal in the treatment of lumbago.

Seventy out-patients with acute back pain participated in a double-blind comparative trial of the clinical efficacy and tolerance of orally administered meptazinol and diflunisal. Half of the patients received 200 mg meptazinol or 250 mg diflunisal 4-times daily for up to 3 weeks, depending on the duration of pain. Patients were examined 4 times at 1-week intervals for their capability to do daily tasks, for their capacity for forward bending, thoraco-lumbar torsion, straight leg raising, static hip flexion and sit-ups, and for subjective assessment of pain. Side-effects were recorded on a questionnaire. Both treatments produced marked improvement in most of the parameters assessed, often within the first week and, overall, the results were similar with the two drugs. Few side-effects were reported and those that were recorded were slight and similar in incidence apart from nausea in 5 meptazinol-treated patients and smarting and burning on urination in 2 patients receiving diflunisal.

Comparison of slow-release indomethacin and diflunisal in patients with arthrosis.

A double-blind, crossover study was carried out in 44 patients with osteoarthrosis of the hip or knee to compare the efficacy and tolerability of treatment with a new slow-release formulation of indomethacin (50 mg) with that of diflunisal (250 mg). After a 1-week wash-out period, patients were allocated at random to receive 2 tablets daily of one or other preparation for 6 weeks before being crossed over to the alternative drug for a further 6 weeks. Aspirin was allowed as a rescue analgesic throughout the study. Subjective assessments of pain and objective assessments of joint mobility were made before the start of treatment and at the end of each period, and details were recorded of rescue analgesic usage and any side-effects. Analysis of the results from 42 patients showed that whilst both treatments helped to alleviate pain, patients' overall evaluation of efficacy at the end of the study indicated that indomethacin was slightly more effective than diflunisal and there was a significant preference for indomethacin. Both drugs were well tolerated and none of the side-effects, reported in about 15% of patients on each drug, resulted in any withdrawals.

Diflunisal ('Dolobid') once-a-day in the treatment of rheumatoid arthritis.

A 4-week, double-blind, controlled multi-centre study was carried out in 235 patients with active rheumatoid arthritis to compare the efficacy and tolerance of 500 mg or 1000 mg diflunisal per day administered once daily, in the evening, or in divided, twice daily dosage. The results showed that diflunisal given once daily was at least as effective as diflunisal given twice daily. Day pain, morning stiffness, average grip strength and erythrocyte sedimentation rate improved similarly in both groups. Significant differences favouring the once-daily regimen were observed for improvement in night pain, Ritchie index and overall assessments by patient and investigator. Adverse experiences were slightly more common in patients taking diflunisal once daily (24% vs 19%) but this difference was not significant. It is concluded, therefore, that diflunisal once-a-day is an alternative regimen for the treatment of rheumatoid arthritis. It is at least as effective as the twice-daily regimen and may provide additional convenience to the patient and potential enhancement of compliance.

Comparison of fecal blood loss after use of aspirin and diflunisal.

Diflunisal 1,000 mg/day, aspirin 4.0 g/day, or placebo were given to 36 healthy volunteers for 14 days to determine fecal blood loss. There was a significant increase in fecal blood loss from baseline in the aspirin group compared to both the diflunisal and placebo groups. A slight but significant increase in fecal blood loss in the diflunisal group at Week 1 was reported; however, there was no significant increase at Week 2. Use of diflunisal was not associated with any consistent blood loss or serious adverse reactions.

Chemical and pharmacological properties of diflunisal.

Diflunisal, 5-(2',4'-difluorophenyl) salicylic acid, was discovered as a potent antiinflammatory analgesic agent after an extensive investigation of more than 500 salicylic acid analogs. The addition of a difluorophenyl substituent at the C5 position of salicylic acid yielded a new molecule with much improved lipophilicity, a longer duration of action, and a molecular configuration that is optimal for greater antiinflammatory and analgesic activities. The difluorophenyl group is metabolically stable; the acyl and phenolic glucuronides of the intact diflunisal are major urinary metabolites. The absence of an O-acetyl group in this novel salicylate analog circumvents the well-known in vivo acylation potential of aspirin and renders diflunisal a reversible cyclooxygenase inhibitor with a secondary oxygen radical scavenging effect. In a variety of analgesic, acute, and chronic antiinflammatory models, diflunisal is active at 10 mg/kg, approximately 5 to 10 times more potent than aspirin. It has a relatively low potential to cause gastrointestinal irritation as indicated by the lack of acute effect on the integrity of gastric mucosa barrier, no change of intragastric potential, and no disturbance of prostaglandin production by the gastric tissue. Diflunisal holds promise as a new clinically useful analgesic and antiinflammatory drug with good tolerance and a long duration of action.