Potential antiarthritic agents. 2. Benzoylacetonitriles and beta-aminocinnamonitriles.

Benzoylacetonitrile and beta-aminocinnamonitrile are shown to possess potent antiinflammatory activity in the rat adjuvant arthritis model. In a series of phenyl-substituted analogues, only o-, m-, and p-fluorobenzoylacetonitrile and m- and p-fluoro-beta-aminocinnamonitrile retained activity. Additionally, beta-amino-2- and beta-amino-3-thiopheneacrylonitrile and beta-oxo-2- and beta-oxo-3-thiophenepropionitrile exhibited similar activity. These agents are not believed to be acting via prostaglandin synthetase inhibition. The metabolic profile of benzoylacetonitrile is also described.

Fenbufen, a new anti-inflammatory analgesic: synthesis and structure-activity relationships of analogs.

One hundred analogs of fenbufen were prepared and tested using the carrageenan, polyarthritis, and UV erythema anti-inflammatory tests and the 2-phenyl-1,4-benzoquinone writhing and inflamed paw pressure analgesic tests. Only three retained the same full spectrum of activity as fenbufen: dl-4-(4-biphenylyl)-4-hydroxybutyric acid, dl-4-(4-biphenylyl)-1,4-butanediol, and 4-biphenylacetic acid. Fenbufen had the same spectrum of activity as aspirin, phenylbutazone, and indomethacin in the five tests. In addition, dose-response derived potencies show fenbufen more potent than aspirin and at least as potent as phenylbutazone in all five tests. Two related compounds were generally similar.

Anti-inflammatory and analgesic profile of amidines of 3-amino-1,2,4-benzotriazine and 3-amino-1,2,4-benzotriazine-1-oxide.

Several formamidine and acetamidine derivatives prepared from 3-amino-1,2,4-benzotriazine and 3-amino-1,2,4-benzotriazine-1-oxide displayed an aspirin-like anti-inflammatory and analgesic profile. The test systems include adjuvant-induced arthritis in rats, carrageenan-induced edema in rats, UV-induced erythema in guinea pigs, the analgesic gait test, the antipyretic test, and GI ulcer studies.

The pharmacology of fenbufen, 3-(4-biphenylylcarbonyl)propionic acid, and 4-biphenylacetic acid, interesting antiinflammatory-analgesic agents.

Fenbufen [3-(4-biphenylylcarbonyl)propionic acid] was shown to be an orally and parenterally effective nonsteroidal antiinflammatory analgetic and antipyretic agent in animals. Like clinically useful drugs (aspirin, phenylbutazine and indomethacin) it has potent antiinflammatory activity in a wide spectrum of laboratory tests in mice, rats, guinea pigs, and dogs and was of particular interest since it appears to have high analgetic efficacy and a long duration of antiinflammatory and analgetic action. While shown to have ulcerogenic potential in rats at toxic doses, it appeared to have a superior margin of gastrointestinal safety in treatment of dogs with urate synovitis. Evidence was also presented to show that BPAA (4-biphenylacetic acid), a metabolite of fenbufen, has a similar profile of antiinflammatory activity, although appearing to produce slightly more gastrointestinal injury. It appears that BPAA may be the agent responsible for at least part of fenbufen's pharmacologic effects. The data presented suggest that fenbufen has the potential to be used safely and effectively to provide relief for patients with inflammatory disease.

Studies on the effect of D-penicillamine on type II collagen-induced polyarthritis.

The effect of D-penicillamine on a preestablished lesion of type II collagen-induced polyarthritis is reviewed. D-penicillamine treatment (100 and 200 mg/kg/d)for 21 d had no significant effect on rat hind paw inflammation associated with this polyarthritis. At the lower dose, the drug caused an increase in circulating antibody titers to type II collagen. X-ray examination of the hind paws of D-penicillamine-treated animals showed a significant improvement in the joint lesions induced by type II collagen.

Studies on the effect of fenbufen and sulindac on type II collagen-induced arthritis in rats.

The effect of fenbufen and sulindac, two novel antiinflammatory agents, on the developing and established lesion of type II collagen arthritis was investigated. Using paw diameter and radiology as parameters, these studies suggest that fenbufen is more efficacious than sulindac in this model.

Studies of the effect of mitoxantrone on adjuvant induced arthritis in rats.

When rats with developing or established adjuvant arthritis are treated with mitoxantrone, the hind paw inflammation associated with the disease is inhibited. Radiographic analysis of the hind paws indicates that the agent suppresses joint destruction associated with the lesion. Comparative studies with cyclophosphamide indicate that mitoxantrone is more efficacious and at least 20 times more potent than cyclophosphamide. Mitoxantrone also appeared more effective when given by the subcutaneous route than the peritoneal route of administration.

Destruction of articular cartilage by arthritic synovium in vitro: mechanism of breakdown and effect of indomethacin and prednisolone.

Arthritic synovial tissue when cultured with normal articular cartilage induces a breakdown of articular cartilage proteoglycans. No collagen breakdown occurs unless the macroglobulins are inactivated by pretreatment with acid. Proteoglycan breakdown is most likely due to the continuous secretion of hydrolases by the synovium. A proteolytic enzyme has been found in the culture medium which has a pH optimum around 7.6, and is Ca++ dependent. Both indomethacin and hydrocortisone are inhibitors of proteoglycan breakdown.

A new non-steroidal anti-inflammatory analgesic: gamma-oxo (1,1'-biphenyl)-4-butanoic acid (fenbufen). Chemistry and activity of analogs.

100 analogs of gamma-oxo(1,1'-biphenyl)-4-butanoic acid (fenbufen) were prepared and tested using the carrageenin, polyarthritis, and UV erythema anti-inflammatory tests and the 2-phenyl-1,4-benzoquinone writhing and inflamed paw pressure analgesic tests. Only three retained the same full spectrum of activity as fenbufen: dl-4-(4-biphenyly)-4-hydroxybutyric acid, dl-4-(4-biphenylyl)-1,4-butanediol, and 4-biphenylacetic acid. Fenbufen had the same spectrum of activity as acetylsalicylic acid (ASA), phenylbutazone, and indometacin in the five tests. In addition, dose-response derived potencies show fenbufen more potent than ASA and at least as potent as phenylbutazone in all five tests.

Studies on type II collagen-induced polyarthritis in rats. Effect of antiinflammatory and antirheumatic agents.

The effect of a variety of antiinflammatory and antirheumatic agents on both developing and established lesions of type II collagen induced polyarthritis in rats was examined. Administration of the nonsteroidal antiinflammatory agents indomethacin or phenylbutazone suppressed the paw inflammation associated with the disease without affecting type II collagen antibody titers. Radiographic analysis of the joints showed suppression of several parameters related to joint destruction. This was most probably related to the antiinflammatory properties of the two drugs. Administration of prednisolone, a steroidal antiinflammatory agent, suppressed paw inflammation; type II collagen antibody titers were significantly decreased in the developing lesion, but the drug had no effect on antibody titers in the established lesion. Radiographic analysis of the joints showed decreases in several parameters of joint destruction. Cyclophosphamide, an immunosuppressive agent, completely suppressed the inflammation associated with the developing lesion but had only minimal effect against the established disease. Collagen antibody titers were decreased and an improvement in only one radiologic parameter (periostitis) was detected. Treatment with antirheumatic agents such as gold thioglucose or levamisole enhanced severity of inflammation in the established lesion and caused increases in collagen antibody titers. Radiographic analysis of the joints indicated that while gold had no effect, levamisole enhanced joint destruction. Treatment with D-penicillamine had no effect on paw inflammation, despite increases in collagen antibody titers. Radiographic analysis of the joints indicated an improvement in all parameters related to joint destruction in animals treated with penicillamine.

Studies on type II collagen induced polyarthritis in rats. Effect of complement depletion.

The effect of cobra venom factor on the developing and the established lesion of collagen-induced rat polyarthritis has been examined. In the developing lesion, decomplementation by cobra venom factor results in a delay in the onset of inflammation and a decrease in the radiological parameters of joint destruction. Under the conditions of the decomplementation, antibody titers to collagen are not decreased. In the established lesion, treatment with cobra venom factor has no effect, on either the inflammatory lesion or the various radiological parameters of joint destruction.

The pharmacological properties of fenbufen. A review.

gamma-Oxo(1,1'-biphenyl)-4-butanoic acid (fenbufen) was shown to be an orally and parenterally effective nonsteroidal antiinflammatory, analgesic and antipyretic agent in a variety of animal species. Like other clinically active antiinflammatory drugs such as acetylsalicylic acid (ASA), indometacin and phenylbutazone, fenbufen has demonstrated potent activity in a variety of laboratory test systems including carageenin edema (rats), UV erythema (guinea pigs), adjuvant arthritis (rats), urate synovitis (dogs), phenylquinone writhing (mice), and yeast-induced pyresis (rats). In general, fenbufen was less potent than indomethacin and more potent than ASA, and appeared of special interest because of its high analgetic efficacy and long duration of antiinflammatory and analgetic action. While shown to have ulcerogenic potential in rats at toxic doses, fenbufen was less potent than indometacin in this respect and had a superior margin of gastrointestinal safety in treatment of dogs with urate synovitis. One of fenbufen's major metabolites, 4-biphenylacetic acid (BPAA), was found to be potent inhibitor of prostaglandin (PG) synthesis both in vitro and in vivo with a variety of tissues tested. Fenbufen itself was devoid of this anti-PG-synthetase activity although it interacted with prostaglandins in other ways. These results, coupled with the fact that only BPAA showed pharmacological activities when applied locally, led to the conclusion that BPAA was the principle responsible for fenbufen's antiinflammatory action. Fenbufen thus appears to be a pro-drug capable of circumventing at least some of the gastric toxicity usually incurred when compounds, which are themselves capable of inhibiting PG synthesis, are introduced directly into the stomach. Fenbufen's relatively low gastric toxicity in dogs and humans seems to substantiate this hypothesis. The pharmacological evidence indicates that fenbufen should be a highly effective and clinically useful antiinflammatory, analgetic and antipyretic drug.

A new prostaglandin E1 analogue (CL115,574). I. antisecretory and cytoprotective effects in the rat.

The effects of a new analogue of PGE1 (CL115,574) on gastric acid secretion, mucus secretion and protection against stress and indomethacin-induced ulcers were studied in the rat. CL115,574 was more potent than PGE1 and cimetidine in inhibiting acid secretion. CL115,574 protected against the development of stress and indomethacin-induced ulcers and prevented the indomethacin-induced decrease in hematocrit at an ED50 (3 micrograms/kg) far below the antisecretory ED50 (1 microgram/kg). While inhibiting acid secretion, CL115,574 increased the volume of gastric secretion indicating a stimulation of nonparietal cell secretion by the rat stomach. In addition the compound stimulated the secretion of mucus into the gastric juice. On the basis of its potency as an inhibitor of acid secretion and these additional effects which are indicative of cytoprotective activity, CL115,574 should be further studied as a possible anti-ulcer agent in man.

Suppression of experimental allergic encephalomyelitis by mitoxantrone.

Treatment of rats with a developing or an established lesion of experimental allergic encephalomyelitis (EAE) with mitoxantrone (Novantrone) suppressed the hind limb paralysis associated with the disease. Histopathological examination of the spinal cords of these rats showed that mitoxantrone-treated rats had reduced vascular lesions that are associated with EAE. Spleen cells derived from immunized rats that had been treated in vivo with mitoxantrone did not transfer disease when these cells were administered to naive syngenic recipients. In addition, spleen cells from diseased rats did not transfer EAE lesions when these cells were administered to recipients that had been treated with mitoxantrone. Recipients treated with mitoxantrone were resistant to EAE lesions induced by sensitized cells in a rapid passive transfer system. Finally, when spleen cells from rats with EAE were incubated, in vitro, with mitoxantrone, these cells did not transfer disease to recipients. Thus the present studies indicate that treatment with mitoxantrone can suppress the lesions associated with both the active and passive forms of EAE.

Antiinflammatory and antiarthritic properties of a substituted quinoline carboxylic acid: CL 306,293.

CL 306,293, a substituted quinoline carboxylic acid at a daily oral dose between 1.5 and 3.0 mg/kg suppressed the inflammation and joint destruction (radiological criteria) associated with both developing and established adjuvant arthritis. When a weekly oral dosing regimen was used, joint destruction was attenuated when this agent was administered at a dose of 50 to 200 mg/kg. Inflammation associated with a delayed type hypersensitivity reaction in dogs was suppressed at a daily dose of 0.25 mg/kg or a weekly dose of 1 mg/kg. At efficacious doses, CL 306,293 had no effects on cyclooxygenase or lipoxygenase activities nor did it have an effect on carrageenin induced paw edema. In acute tests, the compound was not ulcerogenic. The above observations indicate that the antiinflammatory effects of CL 306,293 are distinct from those observed with nonsteroidal antiinflammatory agents. Mechanistic studies conducted and to be published indicate that CL 306,293 down regulates T cell function and this mechanism may account, at least in part, for the antiinflammatory and antiarthritic properties observed in animal models of inflammation and joint destruction.