Search

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used therapeutic agents, however, they are associated with a high prevalence of intestinal side effects. In this investigation, rat precision cut intestinal slices (PCIS) were evaluated as an ex vivo model to study NSAID-induced intestinal toxicity. Firstly, PCIS were incubated with 0-200 μM diclofenac (DCF), one of the most intensively studied NSAIDs, to investigate whether they could correctly reflect the toxic mechanisms. DCF induced intestinal toxicity in PCIS was shown by morphological damage and ATP depletion. DCF induced endoplasmic-reticulum (ER) stress, mitochondrial injury and oxidative stress were reflected by up-regulated HSP-70 (heat shock protein 70) and BiP (binding immunoglobulin protein) gene expression, caspase 9 activation, GSH (glutathione) depletion and HO-1 (heme oxygenase 1) gene up-regulation respectively. Furthermore, DCF intestinal metabolites, which gave rise to protein adduct but not toxicity, were detected in PCIS. Secondly, PCIS were incubated with various concentrations of five NSAIDs. Typical NSAID-induced morphological changes were observed in PCIS. The ex vivo toxicity ranking (diflunisal> diclofenac = indomethacin > naproxen ≫ aspirin) showed good correlation with published in vitro and in vivo data, with diflunisal being the only exception. In conclusion, PCIS correctly reflect the various mechanisms of DCF-induced intestinal toxicity, and can serve as an ex vivo model for the prediction of NSAID-induced intestinal toxicity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Recent studies showed that the metal-coordinated non-steroidal anti-inflammatory drug (NSAID), copper indomethacin, reduced aberrant crypt formation in the rodent colon cancer model, while also exhibiting gastrointestinal sparing properties. In the present study, the stability and biological activity of three BiNSAIDs of the general formula [Bi(L)3]n, where L=diflunisal (difl), mefenamate (mef) or tolfenamate (tolf) were examined. NMR spectroscopy of high concentrations of BiNSAIDs (24h in cell medium, 37°C) indicated that their structural stability and interactions with cell medium components were NSAID specific. Assessment of cell viability using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium]bromide (MTT) assay showed that the toxicity ranking of the BiNSAIDs paralleled those of the respective free NSAIDs: diflH

Aspirin shows a high incidence of gastric side effects. These are thought to result from both systemic and local effects during drug absorption. In contrast, a lipophilic derivative of salicylic acid, diflunisal, causes significantly fewer adverse gastric effects. This is thought to be due to a lack of gastric absorption. To test this hypothesis, three types of experiments were performed with diflunisal: 1. Transgastric permeation was quantified under different pH conditions, using an isolated mouse stomach model. 2. Ulcerogenic potencies of buffered and unbuffered drug solutions were determined in rats. 3. The time course of its anti-inflammatory effect and the serum concentrations of diflunisal, given alone and with neutralizing buffer, were measured in rats with carrageenan-induced paw edema. Corresponding to the low gastric ulcerogenicity, absorption of diflunisal in the isolated stomach preparations was very small. However, absorption was pH-dependent and ranged between 0.69 and 8.73% with a maximum at pH 4.5. Gastric lesions were found to be more evident 24 hr after drug administration than after 5 hr. Comparing buffered vs. unbuffered diflunisal preparations, no difference in ulcerogenicity was detectable. However, using a buffered preparation, the anti-inflammatory effect of diflunisal was enhanced significantly (p less than 0.01), and elevated serum concentrations were found (p less than 0.05). The results show that raising the solubility of diflunisal does not influence gastric absorption or gastric toxicity considerably. However, its serum concentrations and systemic anti-inflammatory effects were significantly enhanced.

Two nonsteroidal anti-inflammatory drugs, diflunisal and naproxen, were compared for efficacy in relieving anterior knee pain of mild to moderate severity. Of 36 patients completing the study, 20 received diflunisal and 16 received naproxen. Eleven (55%) patients given diflunisal and ten (63%) given naproxen had significant relief of pain, but there were no statistically significant differences between the two treatments. Although adverse reactions were frequent in both groups, they were not severe and they abated upon discontinuation of medication.

Effective pain relief and patient tolerance and acceptance are essential in outpatient management of mild to moderate pain of acute low back strain. This study evaluated the efficacy, tolerability, and acceptability of diflunisal and acetaminophen with codeine in patients with mild to moderate pain after an initial or recurrent acute low back strain. Both drugs demonstrated equipotent analgesic efficacy; however, diflunisal was superior to acetaminophen with codeine for patient tolerability and acceptability. The results demonstrated that the study drugs were effective in treating mild to moderate pain caused by acute low back strain in an ambulatory care setting.

An open-label comparison of diflunisal, a nonacetylated salicylate nonsteroidal anti-inflammatory drug (NSAID), and piroxicam, an NSAID belonging to the oxicam family, was conducted in patients with osteoarthritis. Efficacy assessments were made biweekly by the physician and patients during a 12-week treatment and observation period. The physician's evaluations showed that both drugs resulted in significant reductions in knee pain, tenderness, swelling, stiffness, and difficulty walking. A greater number of statistically significant differences were noted with diflunisal than with piroxicam, but there were no statistically significant differences between the two treatment groups. Patients' efficacy ratings tended to favor diflunisal, and diflunisal was significantly more effective than piroxicam in relieving night pain. Seventy-five percent of patients receiving diflunisal and 40% of those receiving piroxicam considered their condition improved after treatment; however, the proportion of good to excellent drug ratings was similar for the two drugs. Both drugs were generally well tolerated. Adverse effects were encountered in five (28%) of 18 patients given diflunisal and in four (33%) of 12 patients given piroxicam. Six patients were withdrawn from the study because of side effects, four from the piroxicam group and two from the diflunisal group. In this study, diflunisal was found to be an effective and well tolerated drug for use in the management of osteoarthritis.

A combination of indomethacin and diflunisal, a new salicylic acid derivative, when given to rats, gave a greater reduction in the size of permanganate induced granulomas and less gastric irritation, than either drug given alone.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, suppress renal prostaglandins and markedly reduce renal perfusion and diuretic response in some renal disorders. Mild renal impairment may occur in healthy subjects. Pharmacodynamic characteristics of certain NSAIDs, such as the nonacetylated salicylates, suggest that they may have less deleterious renal effects. We compared the renal effects of standard therapeutic doses of indomethacin, ibuprofen, aspirin, and the nonacetylated salicylate, diflunisal, in 6 healthy supine volunteers. Only indomethacin significantly reduced creatinine clearance (by 13%) and renal plasma flow (by 23%; p less than 0.05). Indomethacin also tended to reduce furosemide-induced diuresis and natriuresis, and this effect was significantly greater than with diflunisal (p less than 0.05). Serum thromboxane, a reflection of platelet cyclo-oxygenase activity, was reduced by 99% with aspirin, ibuprofen and indomethacin, but by only 78% with diflunisal. Nonacetylated salicylates may be the preferred drugs, at least in short-term usage, when it is necessary to minimize the effects of NSAIDs on platelet or kidney function.

Diflunisal [5-(2,4-difluorophenyl)-salicylic acid] is a new analgesic antiinflammatory drug that, when administered orally to rabbits at 40 and 60 mg/kg/day, caused terata, most commonly axial skeletal defects. These same dosage levels also caused a severe maternal hemolytic anemia following a dramatic decrease in erythrocyte ATP levels. The teratogenicity, anemia, and depletion of ATP were unique to the rabbit among species examined. To test the possible causality between the teratogenic effects and anemia induced by diflunisal, a single dose of 180 mg/kg diflunisal was administered to rabbits on gestation day 5. This treatment produced an anemia that persisted through gestation day 15 in addition to causing the characteristic axial skeletal defects. Since diflunisal was cleared from maternal blood before gestation day 9, the critical day for induction of similar axial skeletal defects by hypoxia, the skeletal malformations probably resulted from maternal hypoxia secondary to anemia and not from a direct and specific effect of the drug on the embryo. In addition, we observed that the diflunisal level in the embryo was less than 5% of the peak maternal blood level probably as a result of high plasma protein binding of diflunisal in the maternal blood (greater than 98%). This relatively low placental transfer may explain the lack of diflunisal teratogenicity in rats and mice compared to aspirin which crosses the placenta more readily. These studies demonstrate that a species that exhibits unusually severe drug-specific maternotoxicity is probably an unsuitable model for the prediction of the teratogenic potential of that drug in humans.

Thirty-one patients with osteoarthritis of the knee were treated with either diflunisal (n = 17) or naproxen (n = 14) in a 12-week open-label study. Treatment was begun with 500 mg BID of diflunisal or 375 mg BID of naproxen. Patients not showing an adequate response to these dosages were given increases to 750 mg BID of diflunisal (n = 7) or 500 mg BID of naproxen (n = 8). Both drugs achieved statistically significant improvements in pain indices, tenderness, swelling, morning stiffness, functional capacity, knee flexion, and 50-foot walking time, and no significant difference was found between the two drugs. At the end of the study, all patients taking diflunisal and 11/14 patients taking naproxen felt that they had improved with treatment. Drug safety and tolerability were assessed in 21 patients given diflunisal and 16 given naproxen (including patients not part of the efficacy evaluation). Six (29%) patients in the diflunisal group and four (25%) in the naproxen group experienced side effects; three were withdrawn from the diflunisal group and one from the naproxen group because of adverse effects. In general, both drugs were well tolerated.

This study examined the pharmacokinetics and potential teratogenicity of the nonsteroidal antiinflammatory drug, diflunisal, in cynomolgus monkeys. Pregnant cynomolgus monkeys were administered 0.5% methyl cellulose, 20 mg/kg/day diflunisal, or 80 mg/kg/day diflunisal on Days 25 to 48 of gestation. There was no evidence of maternal toxicity, increased abortion rate, fetal growth retardation, or malformation. These data demonstrate that diflunisal is not teratogenic in cynomolgus monkeys over a dosage range of 20 to 80 mg/kg/day. Peak plasma levels of diflunisal were found 1 hr after oral administration of [14C]diflunisal at a dosage of 60 mg/kg and declined to low levels by 24 hr. The plasma elimination half-life was calculated to be 10.2 hr over the period of 1 to 8 hr postadministration. Intact diflunisal accounted for 96.4% of total plasma radioactivity at 0.5 hr and declined to a value of 74% at 8 hr. Plasma protein binding averaged greater than 99% over a concentration range of 62.5 to 250 micrograms/ml. Urinary excretion of diflunisal and metabolites averaged 66.5% of the dosage over the first 4 days postadministration, compared with 0.8% in the feces. The majority of activity represented conjugates of diflunisal. Embryo concentrations of diflunisal on Days 35 to 37 of gestation were 0.7 and 1.1% of maternal plasma level at 4 hr postadministration of 20 or 60 mg/kg, respectively.

The object of the studies reviewed here has been to correlate the time-course of ultrastructural changes induced by oral administration of a range of non-steroidal anti-inflammatory (NSAI) drugs with effects on eicosanoid metabolism and drug absorption, so as to discriminate what biochemical/cellular and pharmacological factors account for their varying ulcerogenicity. Oral administration of highly ulcerogenic drugs (e.g. aspirin, diclofenac, indomethacin, piroxicam) to rats causes rapid damage to surface and gastric mucous cells, selective parietal cell damage, and extensive disruption of endothelial cells of submucosal microcapillaries (especially with aspirin) with accompanying extravasation of blood cell components. These changes are coincident with depressed levels of PGE2/6-keto-PGF1 alpha (measured by GC/MS or RIA) and uptake of the drugs (measured by scintillation counting or HPLC). Low ulcerogenic NSAI drugs (e.g. azapropazone, benoxaprofen and fenclofenac) causes very little damage to the surface mucosal cells. Azapropazone has been found to be well absorbed, and benoxaprofen and fenclofenac somewhat more slowly, so for the latter two drugs their low rate of absorption might also be a factor in their reduced ulcerogenicity. Aspirin, azapropazone and benoxaprofen have been shown to reduce 5-HETE levels (RIA), although the latter two drugs were more effective than aspirin. Thus, they result in the inhibition of PG production, by cyclo-oxygenase inhibition (with potential adverse effects from excess oxyradical and/or production of HETE's) with inhibition of the lipoxygenase pathway. The time-sequence of changes induced by single oral doses of indomethacin or other NSAI drugs on the ultrastructure and the prostanoid metabolism of the pig gastric mucosa parallelled those seen in the rat. Attempts to determine whether co-administration of NSAI drugs might reduce the inhibition of PG cyclo-oxygenase by more potent inhibitors (e.g. indomethacin) have been explored as a means for reducing the gastric ulcerogenicity of the latter. The results suggest that pharmacokinetic factors may largely account for the reduced ulcerogenicity of these drug mixtures.

A multicenter, open-label clinical trial evaluated the efficacy and tolerability of diflunisal given twice daily and aspirin given four times daily in the long-term treatment of patients with rheumatoid arthritis. Patients who successfully completed a 12-week, double-blind, parallel study comparing diflunisal (500 to 750 mg daily) with aspirin (2.6 to 3.9 gm daily) continued on the same medication in a 40-week, open-label segment of the study. The dosage of diflunisal could be increased to a maximum of 1 gm daily during the open-label phase. Both regimens were effective during the 40-week study. Diflunisal was better tolerated than aspirin as judged by the overall incidence of clinical adverse experiences. Patients treated with diflunisal had significantly fewer adverse experiences involving the digestive system and organs of special sense than did those treated with aspirin.

Fifty-six patients entered into an open-label, randomized study to compare the efficacy and tolerability of diflunisal and naproxen in the treatment of mild to moderate pain associated with acute low back strain. Thirty-three patients completed the two-week study. No patients withdrew because of side effects, and both drugs were well tolerated. Results showed that diflunisal was more effective than naproxen (81% versus 41%) in relieving pain. Of the 16 patients taking diflunisal, 13 rated its efficacy as very good or excellent; six (35%) of 17 patients taking naproxen rated their drug similarly. Overall, diflunisal rated slightly better in efficacy and tolerability and in improving limitation of function and motion. In addition, diflunisal has a longer duration of action and thus requires less frequent dosing than naproxen.