Adolph E. Sloboda

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.

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.

Destruction of articular cartilage by arthritic synovium in vitro: Mechaniss 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.

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 fenbufens 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 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.

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

The effects 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.