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Compared the effects of play on the psychosocial adjustment of 46 children hospitalized for acute illness, who were placed in one of four groups: therapeutic play, diversionary play, verbal support, and no treatment. Ratings of psychological adjustment included self-report, as well as nurse and parent ratings. Children in the therapeutic play condition evidenced a significant reduction in self-reported hospital fears. Parent ratings were not affected by therapeutic treatments; rather, parents in all four groups rated their children less anxious from pre- to posttesting. Results are discussed in terms of methodological considerations that have affected outcomes in this type of research.

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Leukotriene D4 (LTD4) causes contractions of guinea pig isolated ilea, evokes pulmonary bronchoconstriction and induces lesions of the dermal vasculature. In the present study, we assessed the antagonism of these actions by SC-39070 compared to FPL-55712, a known LTD4 receptor antagonist. In guinea pig isolated ileum preparations, SC-39070 displayed selective antagonism of LTD4 with a pA2 = 8.20 +/- 0.06 (S.E.) and a Schild plot slope of -1.20. Administered intravenously to artificially-respired guinea pigs one minute prior to the agonist, SC-39070 antagonized (p less than 0.05) the bronchoconstrictive effect of LTD4 in a dose-dependent manner (0.5-10 mg/kg). At a dose of 2.0 mg/kg, i.v. this activity was retained through a 60 minute pretreatment interval. Similarly, after oral administration of SC-39070, there was a dose-dependent antagonism of the bronchoconstrictive activity of LTD4 (MED50 = 3.8 mg/kg). Antagonism of LTD4-induced bronchoconstriction was evidenced after oral administration of SC-39070 within one hour of treatment and efficacy was retained as long as 20 hours after treatment at a dose of 10 mg/kg. Finally, intravenously administered SC-39070 blocked LTD4-induced dermal permeability in guinea pigs with a minimum effective dose of 1.0 mg/kg. In each assay, the LTD4 antagonism evidenced after treatment with SC-39070 appeared to be equal to or greater than that observed after treatment with FPL-55712.

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Analogues of bradykinin were synthesized containing single substitutions by N alpha-methyl amino acids in the 1, 4, 5, 5, and 9 positions. [MeArg]Bradykinin possessed 60% of the muscle-contracting activity of the parent compound in a guinea pig ileum assay. The other analogues were very weak agonists (less than 2%) and, disappointingly, failed to show blocking activity except at very high doses.

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The synthesis and biological activities of some compounds with novel modifications of the omega side chain of prostaglandin E1 (PGE1) are described. The preparation of (+/-)-omega-Me-PGE1 (3) (+/-)-omega-Pr-PGE1 (5), and (+/-)-omega-Bu-PGE1 (6) is outlined. The compounds were evaluated for in vitro smooth muscle stimulating activity on isolated gerbil colon preparations, for hypotensive action in anesthetized rats, and for gastric antisecretory effects in histamine-stimulated Heidenhain pouch dogs. Structural changes in the omega position of the noncarboxyl side chain of PGE1 influenced the biological potency of the resulting compound when compared to the reference standard PGE1 (2). The homologues demonstrated interesting separation of biological activities; for example, 4 showed potent hypotensive activity (84% of PGE1, it showed very low smooth muscle stimulating activity. Compound 3 possessed the same order of potency as 2 in the gastric antisecretory assay.

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Certain structural similarities between prostaglandins with close-packed side chains and the perhydrocyclopentanophenanthrene nucleus of steroids prompted the synthesis and biological evaluation of 6beta, 17 beta-dihydroxy-5alpha-androstane-2alpha-carboxylic acid (30), its 6-deoxy derivative 28, and the corresponding 6-deoxy-2beta derivative 29 in an attempt to evaluate carbocyclic acids as potential prostaglandin analogs. Preliminary in vitro studies on isolated guinea pig ileum have shown weakly specific, prostaglandin-stimulated smooth muscle antagonism for 28 when compared with antagonism of bradykinin- and acetylcholine-induced contractions. Complete dose-response curves for 28 on prostaglandin-stimulated guinea pig ileum have shown a reduction in the maxium response and a decrease in the slope of the curve, indicating a noncompetitive type of inhibition for this type of derivative.

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The macrophage is the main cell participating in chronic inflammation. It contains an acid-acting, cathepsin D-type proteinase with the specificity of pepsin, which may release mediators of the inflammatory process. To find new pharmaceutical inhibitors of this proteinase, we tested a variety of chemical compounds in vitro. For this survey, the possible inhibitor (at a concentration of 0.4 mg/ml) was assayed with partially purified cathepsin D-type proteinase from beef lung (a macrophage-rich tissue) and hemoglobin as the substrate. Diazophenylbutanone, three acetophenones, two barbiturates, a gold salt, a copper chelate of a substituted nicotinic acid, a hexapeptide containing a d-amino acid, and Pepstatin inhibited this enzyme; over 200 other potential inhibitors did not. By far the most active and specific inhibitor found to date is Pepstatin, a pentapeptide with two gamma-NH linkages, two beta-OH groups, and five branched aliphatic side chains. Banyu Pharmaceutical Co., Tokyo, Japan, produces this nontoxic compound for the treatment of peptic ulcers. In vitro, as little as 4 ng of Pepstatin inhibits the acid-acting cathepsin D-type proteinase purified from beef and rabbit lung as well as the similar proteinase of rabbit peritoneal and pulmonary macrophages.

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