Mode of action of antirheumatic drugs on the cyclic 3′,5′-AMP regulated glycosaminoglycan secretion in fibroblasts

The effect non-steroidal anti-inflammatory drugs on formation and release of glycosaminoglycans (GAG) and cyclic 3',5'-AMP levels was studied in embryonic mouse fibroblasts. The results were compared and correlated with the action of these drugs on cyclic 3',5'-AMP-dependent as well as independent protein kinase obtained from bovine diaphragm. 1. Phenylbutazone dose-dependently decreased cyclic 3',5'-AMP levels and GAG secretion both in unstimulated and PGE1 stimulated cells. 2. Indometacin decreased cyclic 3',5'-AMP levels and GAG secretion only in cells with elevated cyclic 3',5'-AMP levels after stimulation by PGE1. 3. Sodium salicylate decreased cyclic 3',5'-AMP levels in the presence and absence of PGE1. However, GAG secretion was reduced only in cells with elevated cyclic 3',5'-AMP levels, since the drug activated cyclic 3',5'-AMP-independent protein kinase activity, thus presumably precluding changes in GAG formation at low levels of cyclic 3',5'-AMP. 4. Mefenamic acid decreased cyclic 3',5'-AMP levels in cells stimulated by PGE1, whereas GAG secretion was increased both in the absence and presence of PGE1. This increase in GAG secretion was closely correlated to an enhanced cyclic 3',5'-AMP-dependent and independent protein kinase activity. The results indicate that non-steroidal anti-inflammatory drugs may exert their effects on GAG formation by interfering with cyclic 3',-5'-AMP formation or function.     

Danazol therapy in hormone-sensitive mammary carcinoma.

The effect of Danazol, a synthetic gonadotropin inhibitor, on two groups of Sprague-Dawley rats with dimethylbenze (a) anthracine (DMBA) induced mammary carcinoma was studied. Twenty-four (83%) of 29 control animals developed mammary tumors. Forty-four rats in one treatment group received Danazol after tumor reached 0.5 cm in diameter. Twenty-nine (66%) demonstrated tumor regression (p less than 0.005) and in 16 (36%) tumor disappeared (p less than 0.005). In a second treatment group (given Danazol daily after administration of DMBA), only seven of 50 rats (14%) developed palpable mammary carcinoma (p less than 0.0005). Danazol therapy resulted in regression of established mammary carcinoma in rats, and produced a striking inhibition of carcinogenesis in those animals treated from the time DMBA was administered. Danazol is clinically safe; studies using it in the treatment of breast cancer in women who are candidates for hormonal ablative therapy seem warranted.     

Memory enhancement after physostigmine treatment in the amnesic syndrome

Central anticholinergic agents (eg, scopolamine) are known to produce transient memory deficits in human and animal subjects. Damage to the limbic system frequently results from herpes simplex encephalitis (HSE) and produces a memory deficit. If this deficit is due to limbic cholinergic pathway destruction, it might improve with central cholinergic agonists (eg, physostigmine). In a doubleblind study over a three-week period, we compared memory performance on three days after 0.8-mg subcutaneous physostigmine therapy (three sessions) to baseline performance and that obtained in three randomly interspersed control sessions. Serial assessment of memory by the Selective Reminding Test showed reproducible enhancement of long-term storage and retrieval with physostigmine treatment. Performance after control injections did not exceed baseline levels. Our findings encourage the hypothesis that cholinergic mechanisms subserve memory and that their pharmacological potentiation might favorable influence some amnesic conditions.