Preclinical overview of nabumetone. Pharmacology, bioavailability, metabolism, and toxicology.

Nabumetone is a novel nonacidic nonsteroidal anti-inflammatory drug (NSAID) developed by Beecham Pharmaceuticals. After absorption, nabumetone undergoes extensive metabolism, the main circulating material being 6-methoxy-2-naphthylacetic acid, (BRL 10720). This, unlike nabumetone, is a potent inhibitor of prostaglandin synthesis and is considered to be the active anti-inflammatory metabolite. Nabumetone is active in all standard laboratory models of inflammation and has a greater ratio of active to gastric irritant doses (therapeutic ratio) in the rat than any other NSAID tested. The lack of effect on the gastric mucosa in all species has been a notable feature of the toxicology studies. In humans, relative bioavailability is similar after administration of different dose levels, the mean terminal plasma half-life of BRL 10720 being about 24 hours, allowing for once-daily dosing. The half-life of BRL 10720 does not change on repeated dosing, and no unexpected or irreversible accumulation occurs in elderly patients.

Inhibition of arachidonic acid-induced ear oedema as a model for assessing topical anti-inflammatory compounds.

We have found that mouse ear oedema induced by the topical application of arachidonic acid is not a specific screen for compounds inhibiting the lipoxygenase or cyclo-oxygenase pathways of arachidonic acid metabolism. Although such compounds are able to reduce the oedema substantially, pharmacological agents such as histamine antagonists, phosphodiesterase inhibitors, free radical scavengers, and also various compounds not normally considered to have anti-inflammatory properties, can equally effectively reduce the oedema. A mutual potentiation of the effects of prostaglandins, leukotrienes and mast cell-derived histamine would allow many, but not all, of the active agents to be rationalised. The ability of compounds not influencing these three types of inflammatory mediators to reduce the oedematous response means the model is of limited value for directed screening.

7-Aroyl-2,3-dihydrobenzo[b]furan-3-carboxylic acids and 7-benzoyl-2,3-dihydrobenzo[b]thiophene-3-carboxylic acids as analgesic agents.

The synthesis of a series of 7-aroyl-2,3-dihydrobenzo[b]furan-3-carboxylic acids and 7-benzoyl-2,3-dihydrobenzo[b]thiophene-3-carboxylic acids is described. The isomeric 4-benzoyl-1,3-dihydrobenzo[c]furan-1-carboxylic acid was also prepared. Compounds were evaluated for analgesic activity in the mouse phenyl-p-quinone-induced writhing test. Selected compounds were tested for their ability to produce gastric damage in fasted mice and for inhibition of prostaglandin synthetase activity in vitro. Zomepirac was used as a reference. Structure-activity relationships are discussed. One of the compounds, 7-benzoyl-5-chloro-2,3-dihydrobenzo[b]furan-3-carboxylic acid (2c), combined potent analgesic activity with low gastric irritancy.

The effect of adjuvant arthritis on the subsequent local inflammatory response in rats.

An assessment was made of the cellular inflammatory response to the subcutaneous implantation of sterile nitrocellulose discs and polyvinyl sponges in both normal rats and rats with adjuvant-induced arthritis. It was found that from 3 days after adjuvant injection the treated animals exhibited a reduced accumulation of inflammatory cells onto the nitrocellulose discs and that this impairment in response was not apparent until the discs had been retained for longer than 24 h. When discs were implanted after non-arthritogenic doses of adjuvant constituents or injection of brewer's yeast no effect was seen on the subsequent response. When polyvinyl sponges were used in adjuvant-treated animals a similar initial reduction in cellular accumulation was observed, which was later followed by increased cell numbers associated with enhanced granuloma formation. Differential cell counts revealed that both neutrophil and mononuclear cell types were affected. Some of the possible mechanisms involved in these observations are discussed.

BRL 20459, a novel topically active non-steroidal anti-inflammatory drug.

BRL 20459 is a novel compound which displays anti-inflammatory activity when applied topically in the croton oil and cantharadin rat ear inflammation models. The compound does not inhibit uv-induced erythema in the guinea-pig or granuloma formation in the cotton pellet test in the rat. BRL 20459 does not inhibit prostaglandin synthesis nor does it interact with corticosteroid receptors in the thymus. In contrast to hydrocortisone, BRL 20459 did not cause thymus involution or reduce body weight gain in rats. BRL 20459 would seem to have a different mechanism of action to hydrocortisone, but this mechanism is as yet unknown.

Penetration of nabumetone into inflammatory exudates in the rat.

The penetration of radioactivity into inflamed sites induced by subcutaneously implanted cotton pellets was studied in the rat after oral administration of [14C]nabumetone. Equilibration between inflamed site and plasma concentrations was slow, maximum concentrations in the pellet granuloma being later than those in the plasma. Nabumetone itself was found only in very low concentrations at the inflamed site and was not found in plasma. The major component (70%) of the radioactivity at both sites was the metabolite 6-methoxy-2-naphthylacetic acid, a compound which has anti-inflammatory properties. Elimination of radioactivity from the plasma and inflamed site was virtually complete within 24 h of dosing. Daily dosing with [14C]nabumetone confirmed that there was no progressive accumulation of radioactivity at the inflamed site.

The effect of anti-inflammatory and anti-rheumatic drugs on cell accumulation onto nitrocellulose discs implanted subcutaneously into mice.

Nitrocellulose discs were implanted subcutaneously into mice and cell accumulation measured 96 hours later. Cell accumulation was inhibited by the anti-inflammatory steroids hydrocortisone, dexamethasone and triamcinolone acetonide, but higher doses of the latter two compounds were required than are normally used in rat models of inflammation. Cell accumulation was not inhibited by the cyclo-oxygenase inhibitors naproxen, indomethacin, tolmetin or aspirin, nor by the dual cyclo-oxygenase and lipoxygenase inhibitors BW 755C and benoxaprofen. Anti-rheumatic drugs such as D-penicillamine, dapsone and colchicine and the metal chelator 1,10 phenanthroline were all inactive on cell accumulation in this model.

Nabumetone (BRL 14777, 4-[6-methoxy-2-naphthyl]-butan-2-one): a new anti-inflammatory agent.

Nabumetone is a compound of novel structure which displays acute anti-inflammatory activity in the carrageenan-induced oedema model in rats and the ultraviolet-induced erythema model in guinea-pigs. Its activity in these tests is greater than that of aspirin but less than that of naproxen and indomethacin. In the cotton pellet-induced granuloma model in the rat, the compound is active and produces no signs of toxicity at doses much greater than the lowest effective dose, unlike aspirin, naproxen or indomethacin. Nabumetone is also active in the adjuvant-induced arthritis test in rats. In contrast to aspirin, indomethacin and naproxen, the compound is well tolerated by the stomach of fasted rats at doses in excess of those with anti-inflammatory activity. These findings could be linked to the relatively poor ability of nabumetone to inhibit the synthesis of prostaglandins in vitro and to its non-acidic structure. The compound has greater mild analgesic activity than paracetamol, is equi-active with phenylbutazone, but less active than aspirin, naproxen and indomethacin. Nabumetone also has antipyretic activity in the rabbit. No interactions with the hypothalamic-pituitary-adrenal axis have been found.

The effect of a novel, non-steroidal anti-inflammatory compound, nabumetone (BRL 14777), on cellular infiltration into 24-hour polyvinyl sponge implants in the rat, compared with some steroidal and non-steroidal anti-inflammatory drugs.

The time-course of cell migration into saline-soaked sponge implants over 5 days showed peak polymorphonuclear leucocyte (PMNL) infiltration at 24 h. In common with the corticosteroids dexamethasone and hydrocortisone, and the non-steroidal anti-inflammatory drugs indomethacin, (+)-naproxen, BW 755C and benoxaprofen, nabumetone decreased cell migration into the sponges. PMNLs and mononuclear cells were reduced at 24 h, and there was a parallel decrease in exudate levels of the lysosomal acid hydrolase beta-N-acetyl glucosaminidase [NAG ECB, 3, 2, 1, 30]. Impregnation of sponges with lambda-carrageenan (1%) caused a 2-3 fold increase in cell numbers, with a relatively greater proportion of PMNLs; drug effects were more marked in these implants.

A study of the effects of nabumetone (BRL 14777), a novel anti-inflammatory drug, on cell infiltration into sterile cotton pellets implanted in rats.

Nabumetone a new non-steroidal anti-inflammatory drug is active in reducing the DNA content of implanted cotton pellets in rats on various dosing regimens. The effect of nabumetone can be seen during the early and late phases of the cellular reaction to the implant implicating effects upon polymorphonuclear leucocytes and monocytes. The levels of two lysosomal enzymes are reduced in the exudate by the drug treatment.

The histology and collagen content of cotton pellet and polyvinyl sponge-induced granulomas in normal and drug-treated rats.

Comparison of cotton wool and sponge-induced granulomas in the rat showed that collagen contents were very similar despite the different pattern of granuloma formation. There was significantly less variation of individual results in the sponge. Although collagen accounted for less than 10% of the dry weight, there was a positive correlation between the 2 parameters in both models of 9 days but only in the pellet at 15 days. Hydrocortisone treatment significantly decreased dry weight and collagen content. There was rapid cell proliferation and collagen synthesis in the sponge granuloma from Day 5, reaching a peak between the ninth and twelfth day, when DNA levels dropped and collagen increased more slowly to plateau by Day 15. Day 9 was chosen as the most suitable stage to study drug effects. Dexamethasone significantly decreased collagen synthesis whereas indomethacin and phenylbutazone did not. Soluble collagen levels were increased with beta-amino-propionitrile and d-penicillamine; a dose-related effect was obtained with d-penicillamine.

The effect of steroidal and non-steroidal antiinflammatory drugs on chronic muscle inflammation.

Zymosan (400 microgram) and thioglycollate medium (0.1 ml of 2.4% w/v) have each been shown to induce a chronic inflammation when injected into the hamstring muscle of the mouse. The inflammation is characterized by an increase in muscle weight and N-acetylglycosaminidase concentrations. The response is not inhibited by oral treatment with hydrocortisone, dexamethasone or naproxen, but is inhibited by the local injection of methylprednisolone. The relevance of this model to polymyositis and fibrositis is discussed.

The role of copper in preventing gastrointestinal damage by acidic anti-inflammatory drugs.

The ability of several non-steroidal acidic anti-inflammatory drugs to cause ulceration when given as copper complexes has been examined. The damage caused by clopirac, niflumic acid and aspirin was virtually abolished when they were given as copper complexes whereas the damage caused by indomethacin, ketoprofen and (+)-naproxen was unaltered. The lack of ulceration with three of these preparations appeared to be correlated with a much reduced ability to inhibit prostaglandin synthesis as determined using an in vitro enzyme system.

Specific changes in the messenger ribonucleic acid content of the rat ventral prostate gland after androgenic stimulation. Evidence from the synthesis of aldolase messenger ribonucleic acid.

1. Aldolase was selected as a suitable marker for following the androgenic regulation of mRNA synthesis in the prostate gland. 2. Antibodies raised in rabbits against crystalline prostate aldolase were used to monitor the synthesis of this androgen-induced enzyme after hormonal stimulation of castrated animals, by using procedures in vivo and in vitro for the translation of prostate poly(A)-rich mRNA. 3. After androgenic stimulation in vivo the poly(A)-rich mRNA was isolated from the prostate gland and other tissues of castrated rats, and added to a protein-synthesizing system in vitro derived from Krebs II ascites-tumour cells. By using this approach it was found that androgens regulate the synthesis of aldolase mRNA in a highly tissue-specific manner. Stimulation of aldolase mRNA synthesis reached a maximum after 8h of androgenic treatment and then declined. 4. The androgenic control of aldolase mRNA synthesis was also investigated in vivo. After treatment of castrated animals with various steroids in vivo [(35)S]methionine was injected directly into the prostate gland, and labelled aldolase was selectively precipitated from isolated polyribosomes with anti-aldolase serum. The regulation of aldolase mRNA synthesis in the prostate gland was stringently steroid-specific and could only be evoked by androgens. After a single injection of testosterone, aldolase synthesis reached a maximum after 16h of hormonal stimulation and then declined. 5. Although androgens exert significant control over transcriptional processes in the prostate gland, and appear to regulate the synthesis of aldolase mRNA de novo, the possibility exists for additional means of control at the translational level of aldolase synthesis. The results are discussed in the context of the overall mechanism of action of androgens.