Combination of theophylline and prostaglandin E1 as inhibitors of the adjuvant-induced arthritis syndrome of rats.

Abstract

SUMMARY The effects of daily subcutaneous administration of prostaglandin E1 (PGE,), theophylline, and of both drugs together were studied on the Freund's adjuvant-induced inflammatory and arthritic syndrome in rats. In the doses used, neither drug affected the acute inflammatory response in the adjuvant-treated paw, but together they caused marked inhibition. Chronic inflammation in the contralateral (nontreated) hind paws was slightly inhibited by each drug and combined treatment resulted in marked inhibition. The drugs also counteracted splenomegaly in adjuvantdiseased rats and their effects on spleen weight paralleled the inhibition of chronic inflammation. Arthritic lesions, as judged by x-rays of tibiotarsal joint destruction in the nontreated paws, were partially prevented by PGE1 alone, but not by theophylline. The combined treatment entirely prevented these joint lesions. PGE1 did not cause an increase in adrenal weight, but enhanced the effect of theophylline on adrenal weight. Only PGE1 improved gait in arthritic rats, simultaneous theophylline treatment having little additional effect.Other workers have found that PGE1 increases intracellular cAMP and that this effect is enhanced by the phosphodiesterase inhibitor, theophylline. We propose that the anti-inflammatory and antiarthritic effects of combined drug treatment involve cAMP changes in phagocytic cells at the site of tissue injury and in systemic lymphocytes.

Cyclic AMP and prostaglandin E in perfusates of rat hind paws during the development of adjuvant arthritis

“…This is in contrast to previous results (Aspinall and Cammarata, 1969;Zurier and Quagliata, 1971;Bonta et al, 1977bBonta et al, , 1978. However, there is some indication that low doses of PGE1 increase lysosomal enzyme release from granulocytes in vitro (Weissmann, 1972) and this may have accounted for the increase in paw volume in our study.…”

“…The inhibitory effects of PGE on leucocyte function in vitro are related to increases in intracellular cyclic AMP Accepted for publication September 5, 1977 Correspondence to Dr M. J. Parnham (cAMP) (Boume et al, 1974), and theophylline, an inhibitor of cAMP phosphodiesterase, was found in vivo to potentiate the PGE l-induced suppression of the arthritic syndrome (Bonta et al, 1977b(Bonta et al, , 1978.…”

The influence of topical prostaglandins on HSA-induced uveitis in the rabbit

“…Inhibition of leukocyte infiltration in acute immune complex vasculitis after systemic administration of PGE1 and PGE: has been reported [3,11,17]. These prostaglandins participate in the activation of T-suppressor cells, thereby directly inhibiting the humoral response to a delayed hypersensitivity reaction [7].…”

TIME‐DEPENDENT STIMULATORY AND INHIBITORY EFFECTS OF PROSTAGLANDIN Ex ON EXUDATIVE AND TISSUE COMPONENTS OF GRANULOMATOUS INFLAMMATION IN RATS

“…PGE1 was used because it has been shown, by several authors, to be slightly more potent than PGE2 both in stimulating intracellular cyclic adenosine 3',5'-monophosphate (cyclic AMP) and in producing anti-inflammatory effects in vitro (Parker, 1972;Lichtenstein, 1974;Smith, 1977). Furthermore, while PGE2 is the more important endogenous prostaglandin of the E series released during inflammation in the rat (Youlten & McCall, 1976), the pharmacology of PGE, as an anti-inflammatory agent in vivo has been more extensively studied (Zurier & Quagliata, 1971;Zurier & Ballas, 1973;Zurier, Hoffstein & Weissmann, 1973;Nusbickel, 1976;Bonta, Parnham & van Vliet, 1978). Since experimental granulomata become more sensitive to the vascular permeability increasing effects of exogenous PGE1 and PGE2 as the inflammatory process becomes increasingly chronic , we treated the granulomata with PGE1 at different times to investigate possible changes in the effects of PGE, on developing granulomata.…”